tbuckley/cabot-search huggingface dataset:
Expression of angiopoietin (Ang) pathway markers and their relationship to progression-free survival (PFS) in TRINOVA-1.
Authors: Andres Poveda, Amit M. Oza, Michel Fabbro, Andrés Redondo, Aristotelis Bamias, Al Covens, Ignacio Romero, Duk-Soo Bae, Andrea De Censi, Rajnish Vasant Nagarkar, Gary Edward Richardson, Dolores Gallardo Rincon, Erik Rasmussen, John Rossi, Michael B. Bass, Douglas Warner, Bradley J. Monk
Journal: Journal of Clinical Oncology (2014)

5542 Background: Trebananib, an investigational recombinant peptide Fc-fusion protein, targets Ang1 and 2. In TRINOVA-1, a randomized phase 3 study, trebananib plus paclitaxel (P) compared with placebo plus P significantly improved PFS (primary endpoint) in recurrent ovarian cancer. Biomarker evaluation was an exploratory endpoint. Methods: Women (≥ 18 years, GOG ≤ 1) with recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer received trebananib 15 mg/kg IV QW or placebo IV QW plus P 80 mg/m2 IV QW (3 wks on/1 wk off). Serum samples were collected pre-infusion at wk 1 to evaluate baseline levels of Ang1, Ang2, and soluble Tie2 (sTie2). Analytes were quantified using enzyme-linked immunosorbent assays (ELISA; R&D Systems). Analyses of PFS as a function of biomarker expression addressing prognostic and predictive testing included: 1) subpopulation treatment effect pattern plots (STEPP) for Ang1, Ang2, sTie2, Ang1/Ang2, and Ang2/Ang1 (prognostic test); 2) evaluation of Ang1, Ang2, sTie2, Ang1/Ang2, and Ang2/Ang1 as continuous variables (prognostic test); and 3) median thresholds to dichotomize Ang1, Ang2, and sTie2 levels (prognostic and predictive tests). Results: Serum samples were available for 834 of 919 enrolled women. Per STEPP, no threshold in biomarker expression was associated with PFS. Using continuous models, there was no linear association with PFS (Ang1, p = 0.55; Ang2, p = 0.47; sTie2, p = 0.63; Ang1/Ang2, p = 0.17; Ang2/Ang1, p = 0.66). Using median thresholds, low Ang1 (median, 23.30 ng/mL) or Ang2 (median, 2.86 ng/mL) levels were associated with improved PFS (p = 0.044 and 0.009, respectively) when not corrected for multiple testing. Those relationships were not consistent at the extreme Ang1 or Ang2 values. There was no evidence of an interaction of either Ang1 or Ang2 by treatment arm (p = 0.10 and 0.68, respectively). sTie2 (median, 27.8 ng/mL) was not predictive or prognostic of PFS. Conclusions: In TRINOVA-1, no consistent predictive or prognostic relationships between baseline levels of Ang1, Ang2, or sTie2 were observed. Clinical trial information: NCT01204749.
Dendritic cells pulsed with leukemia blasts elicit jw vitro potent anti-leukemia cytotoxic t-cell response in patients given allogeneic bone marrow transplantation and in their donors
Authors: Daniela Montagna, Franco Locatelli, Antonia Moretta, Patrizia Comoli, Enrica Montini, Marco Zecca, Giovanna Giorgiani, [No Value] RitaMaccario
Journal: Blood (2000)
Outcome of elderly patients following platinum-based chemotherapy for advanced urothelial cancer
Authors: A. Bamias, E. Efstathiou, G. Hamilos, P. Zorzou, G. Bozas, D. Gika, C. Papadimitriou, M. A. Dimopoulos
Journal: Journal of Clinical Oncology (2004)

4542 Background: Elderly patients represent a significant proportion of patients with advanced urothelial tract cancer in Europe and USA. Nevertheless, there is limited information regarding the tolerability of and benefit from systemic chemotherapy in this population. We, therefore, analysed the tolerability and efficacy of platinum-based chemotherapy in patients of 70 years of age or older who had been entered into our database. Methods: 381 consecutive patients with advanced urothelial cancer were included in this analysis. All patients had been treated with cisplatin or carboplatin-based chemotherapy within the context of 4 studies. 116 patients were > 70 years and were analysed separately. Results: Elderly patients had lower baseline median creatinine clearance (52.4 vs. 68.7 ml/min, p<0.001), lower baseline hemoglobin (11.96 vs. 12.46 g/dl, p=0.017) and received carboplatin-based chemotherapy more frequently (32.8% vs. 11.7%, p<0.001) than younger patients. Median number of chemotherapy cycles, relative dose intensity and overall response rates were similar between the two groups. Grade 3 or 4 toxicity was also similar except from anemia, which was more frequent among elderly patients (13.7% vs. 4.7%, p=0.037). Median follow up of living was 34.8 months. Median survival for elderly patients was 9.3 months and for younger patients 10.8 months (p=0.16).Univariate analysis of baseline characteristics of elderly patients showed that ECOG PS 2 or 3, hemoglobin 10000, weight loss and liver metastases were associated with worse prognosis. Multivariate analysis showed that PS and baseline Hb were independently associated with prognosis (p=0.001 and p=0.017, respectively). Patients with PS 0 or 1 and hemoglobin >= 10 g/dl (n=71) had a median survival of 13.9 months, while patients with one or two adverse prognostic features (n=42) had a median survival of 5 months (p<0.0001). Conclusions: Elderly patients tolerate platinum-based chemotherapy as well as younger patients and benefit to the same extent. The combination of PS and baseline hemoglobin can be useful in accurately defining two groups of patients with distinctly different outcome. No significant financial relationships to disclose.
Revised graded prognostic assessment (GPA) index for small cell lung cancer (SCLC) patients (pts) with brain metastases (BM).
Authors: Lingling Du, Samuel T. Chao, Vyshak Alva Venur, Eberechi Sandra Agwa, Paul Elson, John H. Suh, Manmeet Singh Ahluwalia
Journal: Journal of Clinical Oncology (2014)

2090 Background: Pts with SCLC commonly develop BM and the GPA is frequently used as a prognostic index for overall survival (OS). GPA includes 4 groups (GPA scores 0-1.0 (worst), 1.5-2.0, 2.5-3.0, and 3.5-4.0 (best)). The purpose of this study is to develop a revised GPA in this population using a contemporary pt cohort. Methods: With IRB approval, the Cleveland Clinic Brain Tumor and Neuro-Oncology Center’s database was used to identify SCLC BM pts treated between 2000 and 2013. OS from the diagnosis (dx) of SCLC BM was the primary endpoint. Cox proportional hazards models with stepwise variable selection were used to identify independent prognostic factors. Results: 197 pts (52% male) with BM from SCLC were included for analysis. Median age at dx of BM was 64 yrs (range 36-85). 41% had BM at the initial dx of SCLC. Median number (No.) of BM was 2 (Range 1-25). 6% had leptomeningeal disease. Median OS after the dx of BM was 9.5 months (m) (95%C.I. 7.8-10.1 m). Conventional GPA for lung cancer is derived from KPS, No. of BM, presence of extracranial mets, and age. Overall GPA was prognostic of OS (p<.0001) but the categorizations of the factors comprising it were not optimal. A revised set of factors was identified (Table): the 4 original factors, but with different characterizations and weights, and control of the primary tumor. The revised GPA index categorizes pts into 3 groups - unfavorable (total score <8; 27% of pts), intermediate (8-13; 43% of pts), and favorable (>13; 30% of pts); with OS of 3.0m (vs 6.4m for pts with GPA <1.0; 36% of pts), 9.6m, and 15.8m (vs 13.3 for pts with GPA>2.5; 29% of pts) respectively (p<.0001). Conclusions: A revised prognostic index consisting of modified versions of the factors comprising the GPA and primary controlled/uncontrolled in pts with BM from SCLC is proposed. Factor No. of points Hazard ratio p No. of extracranial mets (based on liver, bone, and soft tissue mets). 0 6 1.62 (1.26-2.06) .0001 1 2 ≥2 0 No. of BM 0, 1, or 2 4 1.88 (1.30-2.70) .0007 ≥3 0 KPS ≥80 4 1.71 (1.20-2.43) .003 <80 0 Age <65 3 1.65 (1.16-2.35) .005 ≥65 0 Primary controlled Yes 4 1.85 (1.20-2.85) .006 No 0
Clinical pharmacokinetics of erlotinib (E) in glioblastoma multiforme (GBM) patients and its implication for dosing
Authors: J. Lu, S. Eppler, J. Ling, M. Prados, B. Klencke, B. Lum
Journal: Journal of Clinical Oncology (2006)

2010 Background: E is an orally active, highly potent and selective inhibitor of the epidermal growth factor receptor (EGFR). Preliminary results from both Phase I and Phase II trials of E in GBM patients have been reported (ASCO 2003, Abs#394 and ASCO 2004, Abs#1555). The purpose of this analysis is to characterize E PK in this patient population when administered with or without CYP3A4 enzyme inducing anti-epileptic drugs (EIAEDs) and to identify a dose to provide equivalent exposure during concomitant therapy in GBM patients. Methods: Intensive PK data were collected in the Phase I study and plasma trough concentration data were collected in the Phase II study at steady-state. A total of 775 E concentrations from 107 patients were available for the analysis. A population PK approach (NONMEM) was used to characterize the clinical PK in this patient population and the effect of EIAEDs on the PK of E. Results: Co-administration of EIAEDs was shown to increase the E clearance (CL/F) by 230% in GBM patients. This effect is similar to that seen in a previous drug-drug interaction study with a CYP3A4 enzyme inducer (rifampicin) in healthy volunteers. For patients with no EIAEDs, population estimates and the %CV of inter-individual variance for CL/F and Vc/F of erlotinib were 5.63 L/hr (44%) and 388 L (40%), respectively. Conclusions: Based on the modeling results, for GBM patients with EIAEDs, an estimate of erlotinib dose of 500 mg/d is needed to achieve an equivalent exposure as patients who receive the dose of 150 mg/d with no EIAEDs. The new population PK model provides an operational tool to predict E exposure during treatment, and simulate alternative dosing regimens for GBM patients. [Table: see text]
A prognostic factor (PF) index for overall survival in a HER2-negative endocrine-resistant metastatic breast cancer (MBC) population: Analysis from the ATHENA trial.
Authors: Antonio Llombart-Cussac, Xavier B. Pivot, Laura Biganzoli, Hernan Cortes-Funes, Kathleen I. Pritchard, Jean-Yves Pierga, Ian E. Smith, Christoph Thomssen, Gemma Palacios, Stefanie Srock, Miguel Sampayo, Javier Cortes
Journal: Journal of Clinical Oncology (2013)

555 Background: Chemotherapy is the standard of care for patients (pts) with HER2-negative endocrine-resistant MBC. The considerable variability in overall survival (OS) within this population relates essentially to prognostic factors (PF). Increasingly, large studies based on progression-free survival (PFS) as a primary endpoint are now being questioned. An accurate PF index may help in designing innovative trials with appropriate pts selection according to overall survival (OS) prognosis. Methods: The ATHENA trial assessed the safety of first-line bevacizumab combined with non-anthracycline-containing therapy in 2264 pts treated in 37 countries from 2006 to 2009. Pt characteristics, safety, and efficacy have been reported [Breast Cancer Res Treat 2011;130:133-43]. Sixty-one HER2-positive pts were excluded. A multivariate Cox regression model selected PF generating a simple PF index. Of note, skin, lymph node, ipsi-/contra- breast, or other soft tissue involvement was scored as a single organ. Results: After a median follow-up of 20.1 months and 1171 OS events (53% of pts), median OS for the entire sample and triple-negative (TNBC) and non-TNBC subgroups was 25.2 (95% CI 23.9–26.3), 18.3 (16.3–19.7) and 27.3 (26.3–29.3) months, respectively. PF most closely associated with poorer OS were: liver mets or &gt;2 involved organs (HR 1.6; 95% CI 1.5–1.8); DFI ≤24 months (HR 1.7; 1.5–2.0); adjuvant anthracyline and/or taxane (HR 1.1; 1.2–1.4); and TNBC (HR 1.6; 1.4–1.8). A predictive model was designed stratifying by number of PF present (0/1 vs 2 vs 3/4). The model was consistent in both TNBC and non-TNBC populations (Table). Conclusions: A PF index may estimate figures and balance arms in future trials considering OS as primary objective. A well-defined group of non-TNBC accounting for 37% of patients has an OS estimate similar to the most aggressive TNBC. [Table: see text]
Epigenetic Regulation of KPC1 Ubiquitin Ligase Affects the NF-κB Pathway in Melanoma
Authors: Yuuki Iida, Aaron Ciechanover, Diego M. Marzese, Keisuke Hata, Matias Bustos, Shigeshi Ono, Jinhua Wang, Matthew P. Salomon, Kevin Tran, Stella Lam, Sandy Hsu, Nellie Nelson, Yelena Kravtsova-Ivantsiv, Gordon B. Mills, Michael A. Davies, Dave S.B. Hoon
Journal: Clinical Cancer Research (2017)

Purpose: Abnormal activation of the NF-κB pathway induces a more aggressive phenotype of cutaneous melanoma. Understanding the mechanisms involved in melanoma NF-κB activation may identify novel targets for this pathway. KPC1, an E3 ubiquitin ligase, is a regulator of the NF-κB pathway. The objective of this study was to investigate the mechanisms regulating KPC1 expression and its clinical impact in melanoma.Experimental Design: The clinical impact of KPC1 expression and its epigenetic regulation were assessed in large cohorts of clinically well-annotated melanoma tissues (tissue microarrays; n = 137, JWCI cohort; n = 40) and The Cancer Genome Atlas database (TCGA cohort, n = 370). Using melanoma cell lines, we investigated the functional interactions between KPC1 and NF-κB, and the epigenetic regulations of KPC1, including DNA methylation and miRNA expression.Results: We verified that KPC1 suppresses melanoma proliferation by processing NF-κB1 p105 into p50, thereby modulating NF-κB target gene expression. Concordantly, KPC1 expression was downregulated in American Joint Committee on Cancer stage IV melanoma compared with early stages (stage I/II P = 0.013, stage III P = 0.004), and low KPC1 expression was significantly associated with poor overall survival in stage IV melanoma (n = 137; HR 1.810; P = 0.006). Furthermore, our data showed that high miR-155-5p expression, which is controlled by DNA methylation at its promoter region (TCGA; Pearson's r -0.455; P < 0.001), is significantly associated with KPC1 downregulation (JWCI; P = 0.028, TCGA; P = 0.003).Conclusions: This study revealed novel epigenetic regulation of KPC1 associated with NF-κB pathway activation, promoting metastatic melanoma progression. These findings suggest the potential utility of KPC1 and its epigenetic regulation as theranostic targets. Clin Cancer Res; 23(16); 4831-42. ©2017 AACR.
Characteristics and motivations of participants in a lung cancer screening study
Authors: Y. Zafar, B. Kleykamp, M. Foraida, J. Neu, R. Buncher, R. Shipley, A. R. Jazieh, J. Howington
Journal: Journal of Clinical Oncology (2004)

1032 Background: We examined the habits and motivations of participants in a lung cancer (LC) screening study. Methods: This is a prospective study to evaluate the efficacy of low-dose screening computed tomography (CT) in detecting early-stage LC. Eligibility criteria include age of 50 years or older, a minimum 20-pack-year smoking history, and no prior LC history. Initial and follow-up surveys were completed with questions pertaining to lifestyle, smoking habits, and medical history. Study participants underwent initial screening CTs with follow-up based on findings. Results: 104 of 106 participants were included in our survey (2 participants were ineligible). 53 men and 51 women completed the initial survey. Median age was 64 years (51–80). All participants but one were Caucasian. 22% of participants had a history of cancer. 83% had a family history of cancer with 52% of them reporting a family history of LC. 47% quit smoking prior to enrollment. The majority of participants maintained a healthy lifestyle, as measured by regular exercise (71%), healthy diets (85%), and dietary supplement use (58%). 89% considered themselves at a moderate or high risk for LC, and a majority (64%) believed early detection of LC could improve survival. Follow-up surveys after one year were obtained on 44 of the 55 participants (80%) smoking at enrollment. At follow-up, 11% of participants had quit smoking, and 45% reported decreased smoking. Participants younger than 65 were more likely to decrease their smoking than those 65 or older (85% vs. 15%, p<0.01). 32% of participants were exercising more, with a greater increase among men than women (50% vs. 21%, p=0.05). 39% were more concerned about their diet, and a 16% increase in dietary supplement usage was noted. Conclusions: Participants in LC screening have a strong family history of cancer and maintain a healthy lifestyle. They are sensitive to their cancer risk and believe early detection is vital. Participation in such studies may positively influence smoking habits and promote healthy lifestyles. No significant financial relationships to disclose.
The impact of interruptions on physician workflow, productivity, and delivery of care.
Authors: Matthew C. Cheung, Maureen E. Trudeau, Helen Mackay, Harsh Naik, Ben De Mendonca, Andrea Eisen, Simron Singh
Journal: Journal of Clinical Oncology (2017)

201 Background: Physician interruptions during clinic and non-clinic hours can lead to medical errors, provider fatigue, prolonged clinic times, reduced academic output and poor job satisfaction. Repetitive interruptions can hamper the ability of physicians to deliver high quality patient-centered care. This study aims to evaluate the type, frequency, duration and self-reported physician response interruptions physicians experience in clinic. Methods: A work observation study was conducted at the Odette Cancer Centre, Sunnybrook Health Sciences Centre in Toronto, Canada. In-clinic data were collected from September 22 to October 6, 2016 using time-motion analyses by shadowing multiple oncologists in clinic. Interruption data were collected and categorized as follows: type of interruption, length of interruption, reason for interruption and role of interrupter. Physicians were asked to record and track themselves regarding interruptions they experienced during non-clinic hours using the same criteria. Results: Over a 2-week period, 5 medical oncology clinics (median 4 hours (hrs) per clinic), were observed and tracked. The clinic physicians averaged 22 interruptions per block, equating to 6 interruptions/hr (one interruption every 10 minutes (mins)). Over the 5 sessions, 112 data points were collected totaling over 1 hr 48 mins of interrupted time. Interruptions averaged 80 seconds (range of 4 to 517) in length with a positive skewed distribution. This calculates to approximately 30 mins of cumulative interrupted time per clinic session. Most interruptions were under 4 mins in length (4.1 at 95 th percentile). The type of interruption varied but was most commonly in-person (67), email (24) and text message (10). Conclusions: Interruptions account for approximately 30 mins of physician time during a 4-hour clinic. An assessment of the type and frequency of requests proved highly variable, creating inconsistent ways messages are delivered to physicians. Interruptions potentially impact on patient care and disrupt the workflow of the clinic. These data provide future directions for exploring efficient clinic workflows and establishing standardized means of communicating with physicians during clinic hours.
Clinical utility of adenosine triphosphate-based chemosensitivity response assay (ATP-CRA) in non-small cell lung cancer: Preliminary study
Authors: B.-S. Kim, Y. M. Ahn, J. Kim, E. J. Yoon, S. H. Choi
Journal: Journal of Clinical Oncology (2004)

7259 Background: Selection of optimal agents by laboratory test would in theory allow individualization of cancer treatment. Objectives of this study were to verify th feasibility of ATP-CRA using bronchoscopic biopsy specimens and the accurate prediction of clinical response to chemotherapeutic agents in NSCLC. Methods: Biopsies (5.8 to 22.2 mg, mean 11.4 mg) were obtained during bronchscopy from 31 suspeted lung cancer patients. Tumor cells were isolated by mechanical and enzymatic disaggregation followed by picol density gradient centrifugation. After 48 hours treatment with anti-cancer drugs, we evaluated the cell viability by measuring the intracellular ATP levels of drug-treated cells and untreated controls at peak plasma concentration of each drug. The sensitivity defined as a 30% or more reduction of ATP compared to untreated controls (p<0.05, Fisher's exact test). Results: The assay results were available within four days. Interpretable results were obtained in 80.6% (25/31) of specimens. Six cases were failed to evaluate due to microbial contamination (5 cases) and less viable cells (1 case). Cinical outcomes were evaluable in 9 patients who were successfully tested, including one double comprison against the first and second line therapy in same patient.The regimen consisted fo taxol and carboplatin as first line therapy and gemcitabine alone as the second line therapy. The clinical responses were blindly compared with ATP-CRA results. The mean coefficient of variation for triplicate ATP measurement was 13.0%. The sensitivity and specificity was 83.3% and 100%, respectively. The positive predictive value and negative predictive value was 100% and 80%, respectively. The overall diagnostic accuracy was 90%. Conclusions: The ATP-CRA using the bronchoscopic biopsy specimens has potential usefulness as an in vitro chemosensitivity screening test in NSCLC. The high evaluability rate and observed correlation with tumor response supported the use of ATP-CRA in prospective assay-directed trials. This preliminary study, within the limitation of small size of enrolled patients, is ongoing. No significant financial relationships to disclose.
Kidney Injury Molecule-1 and its association with delayed clearance and drug exposure in pediatric oncology patients treated with high dose methotrexate.
Authors: Andrew J. Bukowinski, Tomoyuki Mizuno, Tsuyoshi Fukuda, A.a. Vinks, Stuart Goldstein, Adam Lane, John Peter Perentesis, Maureen Megan O'Brien
Journal: Journal of Clinical Oncology (2015)

10034 Background: High-dose methotrexate (HD-MTX) is a critical component of therapy for pediatric malignancies. The ability to identify patients at risk for delayed MTX clearance and acute kidney injury (AKI) is limited. Kidney Injury molecule-1 (KIM-1) is a urinary biomarker which is an early indicator of tubular injury. The current study evaluates associations between urinary KIM-1, delayed MTX clearance, and MTX exposure. Methods: 47 patients (31 M, 16 F; median age 9.5 yrs, range 3-31) received 1-12 g/m2HD-MTX over 4 or 24 hours for a total of 96 courses of MTX. Diagnoses included: leukemia/lymphoma (42 pts), osteosarcoma (5 pts). Data was collected on up to 4 courses of HD-MTX. Serum creatinine (SCr) and MTX were measured per standard clinical practice. Urine samples were obtained prior to the infusion and at 12, 24, and 36-48 hours after start. KIM-1 was measured by enzyme linked immunosorbent assay and normalized to urine creatinine. Delayed methotrexate clearance (DC) was defined by plasma MTX levels exceeding “high risk” concentrations per Crom & Evans (1992) as incorporated into standard oncology treatment regimens, failure to clear MTX within 72 hours, or a 50% rise in SCr. Toxicity data was collected by chart review. Univariate analyses were conducted using Wilcoxon Rank sum testing. MTX area under the curve (AUC) was calculated with MW/Pharm software using Bayesian estimation. Linear regression was used to analyze KIM-1 and AUC for correlations. Results: Patients with DC had higher AUC levels (p < 0.05). Kim-1 at 12 hours correlated with AUC (p < 0.04) in leukemia patients receiving 1st course of HD-MTX. KIM-1 is associated with DC at 12 and 24 hours for 1st and 2nd courses of HD-MTX (p < 0.05). Prior to infusion KIM-1 is associated with previous DC (p < 0.05). Conclusions: Increased KIM-1 is associated with both MTX AUC and DC and is indicative of renal tubular injury. This association is most pronounced in course 1 and may be due to attrition of patients with severe toxicity, dose reduction, and enhanced supportive care. KIM-1 provides an early indication of kidney injury from HD-MTX and with additional evaluation may be a target for enhanced supportive care strategies.