tbuckley/cabot-search huggingface dataset:
Premature clinical trial discontinuation in all and genitourinary (GU) cancers in the era of immune checkpoint inhibitors (ICI).
Authors: Monica Khunger, Sagar Rakshit, Katherine Tullio, Matt D. Galsky, Petros Grivas
Journal: Journal of Clinical Oncology (2017)

394 Background: Clinical trial completion is critical for evaluating new therapies. Premature termination or withdrawal of clinical trials is common, impairs progress and results in waste of resources. We assessed features and reasons of early terminated and withdrawn cancer trials focusing on trials with ICI (anti-CTLA-4, anti-PD-1, anti-PD-L1). Methods: We reviewed all adult, intervention, cancer clinical trials registered in ClinicalTrials.gov from November 16, 2011 to April 16, 2015 to identify all early terminated and withdrawn trials. Reasons for termination were captured. Logistics regression model was used to identify factors associated with early termination or withdrawal. Discontinuation rate was compared between ICI and all trials (χ 2 ); p &lt; 0.05 was set as significant. Results: We identified 12875 clinical trials (35% industry-funded, 12% federal-funded; 772 in prostate and 386 in non-prostate GU cancers); 8.5% of all trials were prematurely terminated (5%) or withdrawn (3.5%); main reason for discontinuation was poor accrual (33%) followed by logistical reasons (26%). When comparing trials with ICI (n = 350) to all cancer trials, lower rate of termination or withdrawal was noted with ICI [5.4% vs 8.5%, p = 0.05]. Trials with ICI were less likely to discontinue due to poor accrual compared to all trials, but the difference was not significant (21% vs 33%, p = 0.4). Of the 1158 GU cancers trials, 75 (6.5%) were prematurely terminated and 56 (4.8%) withdrawn; reasons for discontinuation are shown in the table. Conclusions: Poor accrual represents the main cause of early termination of all cancer clinical trials. Premature termination/withdrawal rate appears lower in ICI trials which may be attributed to accrual differences. Clinical trial completion remains a high priority. [Table: see text]
Treatment patterns and outcomes in metastatic bladder cancer in community oncology settings.
Authors: Maxine Fisher, Rahul Shenolikar, Paul J. E. Miller, Mark Stephen Walker, Moon Jung Fenton
Journal: Journal of Clinical Oncology (2017)

396 Background: Current real-world data on treatment patterns in metastatic bladder cancer in the community setting are limited. This study describes patient characteristics, treatment patterns, and efficacy outcomes for these patients in the community setting. Methods: Medical records data from adults diagnosed with stage IV or metastatic bladder cancer between 1/1/2008 and 6/1/2015 were retrospectively collected from a network of 10 US community oncology practices. Patient characteristics, treatment patterns, and efficacy outcomes were assessed. Comparisons across groups were conducted using standard analyses. Progression-free survival and overall survival (OS) were assessed using Kaplan-Meier analysis. Results: Of 508 patients, 75% were male, 79% white, 15% African American, and 71.5% were age ≥65 years (median age, 71 years; range 35-92 years). Overall, 76.4% were current or past tobacco users. The most prevalent comorbidities were diabetes (23.4%), renal disease (16.5%), and chronic obstructive pulmonary disease (COPD; 12.4%). Patients age ≥65 years vs &lt;65 years had higher rates of renal disease (19.6% vs 9.0%; P=0.004), COPD (14.6% vs 6.9%; P=0.017) and congestive heart failure (CHF; 6.3% vs 2.1%; P=0.049), respectively. First-line platinum-based therapy was given to 56.3% of the patients, with the most common regimen being gem + carbo (23.6%) followed by gem + cis (17.0%). Overall, median OS was 9.4 months from diagnosis, 11.0 months from start of line-1, and 5.3 months from start of line-2. Cox regression analysis of OS from diagnosis showed that males (hazard ratio [HR]=1.26; P=0.046) and patients with impaired performance (HR=2.137; P&lt;0.001) were at greater risk of death. Conclusions: Although platinum-based chemotherapy is currently the preferred treatment for metastatic bladder cancer in the community setting, there is a large unmet need in this population, particularly among the elderly. Gender and performance status were associated with efficacy outcomes.
Prognostic value of <i>ALK</i> gene copy number (GCN) status for resected and metastatic non-small-cell lung cancer (NSCLC): A retrospective analysis of 205 patients (pts).
Authors: Sara Pilotto, Anna Calio', Isabella Sperduti, Umberto Peretti, Stefania Kinspergher, Antonio Santo, Roberto Ferrara, Marco Chilosi, Aldo Scarpa, Giampaolo Tortora, Matteo Brunelli, Emilio Bria
Journal: Journal of Clinical Oncology (2014)

e19059 Background: ALK rearrangement represents a powerful predictor of efficacy for Crizotinib in advanced NSCLC. Nevertheless, the prognostic implication of ALK GCN is currently under debate. Methods: Formalin-fixed and paraffin-embedded tissues of NSCLC pts referring to the University of Verona were retrospectively tested for ALK translocations and GCN status by fluorescence in situ hybridization (FISH) using a commercially available break-apart ALK kit (Abbott-Vysis) adopting 2 DNA probes upon ALK (3’ and 5’ regions). Pts were grouped as disomic (D), having 2 copies of the gene; polysomic having 3-7 copies (P3-7); and amplified, when polysomy was >7 (P>7). Disease-Free and Progression-Free Survival (DFS/PFS) were considered for resected and metastatic disease, respectively. Results: Data from 205 NSCLC pts (118 deaths) were retrieved, as follows: median age: 66 yrs (26-85); M/F 122/83: (59.9%/40.5%); median follow-up: 7 months (1-172); smoker/former/never/UKN: 63/78/52/12 (30.7%/38%/25.4%/5.9%); comorbidities yes/no/UKN: 136/57/12 (66.3%/27.8%/5.9%); PS [ECOG] 0/1/2/3/UKN: 121/46/10/3/25 (59%/22.4%/4.9%/1.5%/12.2%); adenocarcinoma/squamous/NOS: 183/7/15 (89.3%/3.9%/7.3%); EGFR wild-type/mutant/UKN: 146/23/36 (71.2%/11.2%/17.6%); resected/metastatic: 83/122 (40.5%/59.5%). Median DFS and PFS for resected and metastatic pts was 13 (95% CI 8-19) and 4 months (95% CI 3-6), respectively, with a 1-yr outcome rate of 51.6% and 19.3%. ALK re-arrangements was found in 13 pts (6.3%), while 83 were D (40.5%), 45 (22%) were P3-7 and 17 (8.3%) were P>7. With regard to resected pts, median DFS was 12 months (95% CI 5-18) for D, not reached for P3-7, and 6 months (95% CI 1-10) for P>7, with a 1-yr DFS of 42%, 80% and 26%, respectively (p=0.07). With regard to metastatic pts, median PFS was 4 months (95% CI 3-4) for D, 4 (95% CI 2-7) for P3-7, and 9 months (95% CI 1-18) for P>7, with a 1-yr DFS of 17.8%, 15.9% and 48.2%, respectively (p=0.14). Conclusions: Although considering the retrospective nature of the current analysis and the low numbers, these data do not show any significant prognostic role of ALK GCN status in both resected and metastatic NSCLC.
원저 : 말디토프 질량 분석을 이용한 한국인의 B형간염 바이러스 유전자형 및 임상적 의의에 대한 재평가
Authors: 이중민 ( Jung Min Lee ), 안상훈 ( Sang Hoon Ahn ), 장혜영 ( Hye Young Chang ), 신지은 ( Ji Eun Shin ), 김도영 ( Do Young Kim ), 심명기 ( Myoung Ki Sim ), 홍선표 ( Sun Pyo Hong ), 정현재 ( Hyun Jae Chung ), 김수옥 ( Soo Ok Kim ), 한광협 ( Kwang Hyub Han ), 전재윤 ( Chae Yoon Cho)
Journal: Clinical and Molecular Hepatology (2004)

목적: HBV에 의한 감염은 임상 경과 및 결과가 매우 다양한데, 이의 원인은 숙주 요소, 환경 요소 및 바이러스 요소가 서로 복합적으로 작용하기 때문이며 이 중에서 HBV 유전자형에 대한 연구가 최근에 많이 이루어지고 있다. 유전자 B형이 C형보다, A형이 D형보다 양호한 경과를 보인다고 알려져 있으나, 국내에서는 유전자 C형이 주된 유전자라고만 알려졌을 뿐 임상 경과와의 관련성에 관한 연구는 없다. 이에 본 연구는 이전의 연구보다 많은 수의 환자를
A Phase 1/11 trial of IV CG7870, a replication-selective, PSA-targeted oncolytic adenovirus (OAV), for the treatment of hormone-refractory, metastatic prostate cancer
Authors: G. Wilding, M. Carducci, D. C. Yu, J. Burke, F. Borellini, J. Aimi, P. Working, D. Ando, D. Kirn, E. Small
Journal: Journal of Clinical Oncology (2004)

3036 Background: CG7870 is a replication-selective OAV genetically engineered to preferentially replicate in prostate tissue.A Phase 1/2 trial of intraprostatic delivery of CG7870 for locally-recurrent prostate cancer (PCA) demonstrated that this virus was well-tolerated, with decreases in PSA noted. Methods: A Phase 1/2 study of systemically administered CG7870 was undertaken.CG7870 was administered as a single IV infusion in a dose-escalation design (1010 - 6 x 1012vp) to 23 patients with metastatic HRPC. Results: CG7870 was well-tolerated.Flu-like symptoms (fever, fatigue, rigors, nausea, and/or vomiting) were the most common AE. At doses > 1012vp all 5 patients experienced asymptomatic grade 1–2 transaminitis and/or isolated D-dimer elevations starting on d 2–8; dose-escalation was therefore halted. All tested patients had CG7870 genomes present in the serum for at least 7d after infusion; patients in the highest dose group had persistence of genomes through 28d. The concentration of CG7870 in the peripheral blood demonstrated a biphasic pattern in most patients, with rapid initial clearance followed by a delayed secondary peak (72hr post-treatment) consistent with viral replication. CG7870 was detected in the saliva of 3 patients, whereas all urine samples tested negative. All patients developed antibodies to CG7870. Dose-related increases in IL-6 and IL-10 blood levels were demonstrated. No partial or complete PSA responses were observed; however, 5 patients had a decrease in serum PSA of 25–49% following a single treatment.The median time to PSA progression was 57d and 3 patients were free-from-progression at 6 mos.Median OS has not been reached. Conclusions: The maximum dose of CG7870 given in this study was 6 x 1012vp. CG7870 was well tolerated at doses up to this level with reversible transaminitis as the only significant toxicity.There was a suggestion of anti-PCA activity following a single IV injection of CG7870 as demonstrated by PSA reduction.Future trials will explore the activity of IV CG7870 in combination with taxane chemotherapy for the treatment of advanced PCA. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cell Genesys, Inc. Cell Genesys, Inc. Cell Genesys, Inc.
Adding paclitaxel to trastuzumab enhances antibody-dependent cell-mediated cytotoxicity via increment of natural killer cells in patients with Her-2 overexpressing breast cancer
Authors: D. Miura, D. Kitagawa, K. Tsutsumi
Journal: Journal of Clinical Oncology (2006)

10548 Background: One of the mechanisms by which trastuzumab (TZ) inhibits the growth of Her-2 overexpressing breast cancer cells is the activation of a host tumor response via antibody-dependent cell-mediated cytotoxicity (ADCC). We questioned whether adding PTX to TZ enhances ADCC and also investigated kinetics of effector cells in ADCC. Methods: In ADCC, 5 cases with metastatic breast cancer receiving TZ (4mg/kg as a loading and 2 mg/kg weekly) with PTX (2qw, 100 mg/m 2 ) were investigated. ADCC was analyzed by 51 Cr releasing assay using SK-BR-3 cell line and white blood cells taken at the time of pretreatment, after 4 mg/kg of TZ, before/after 2 mg/kg of TZ, and before/after 2 mg/kg of TZ plus PTX. In of effector cell studies, we investigated fractions of natural killer (NK) cell, monocyte, and neutrophil taken at pre-administration and 10 minutes post-administration in 16 patients with Her-2 overexpressing breast cancer receiving weekly TZ and PTX (80 mg/m 2 ). We defined NK cells as being both CD16+ (FcγRIII) and CD56+ and neutrophils as CD64+ (FcγRI) by flow cytometry. Results: Compared with pretreatment ADCC level, cytotoxicity were enhanced to 220% (median, ranging 30–259) after 4 mg/kg of TZ, 129% (78–210) after 2 mg/kg of TZ, and 148% (42–557) after the combination of TZ and PTX, whereas suppressed to 94% (48–163) after PTX alone. 2 weeks after the combination therapy, ADCC was significantly enhanced to 169% (113–257, p&lt;0.05), compared with pre-treatment. In effector cells, NK cells increased in 131% (74–175, p&lt;0.05) by TZ and in 224% (169–286, p&lt;0.05) by the combination therapy. No significant changes were found in monocytes (98%, 50–160) and in neutrophils (100%, 50–160) by TZ alone, however monocytes decreased to 44% (34–50, p&lt;0.05) and also neutrophils did to 49% (9–133) by the combination. Conclusions: Higher doses of TZ induced NK cell recruitment and the combination of TZ and PTX has a significant increase in recruitment and activation of NK cells. Adding PTX to TZ significantly enhanced ADCC via the rapid kinetics of NK cells. This may reflect that the combination of TZ and PTX has a strong synergistic effect than we expected in patients with Her-2 overexpressing breast cancer. [Table: see text]
A phase I dose-escalation and cohort expansion study of lirilumab (anti-KIR; BMS-986015) administered in combination with nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients (Pts) with advanced refractory solid tumors.
Authors: Rachel E. Sanborn, William Howard Sharfman, Neil Howard Segal, F. Stephen Hodi, Jedd D. Wolchok, Walter John Urba, Bernard A. Fox, Suzanne Louise Topalian, Drew M. Pardoll, Kelly L. Covello, Dan McDonald, Su Young Kim, Ashok Kumar Gupta, Jon M. Wigginton, Thomas Gajewski
Journal: Journal of Clinical Oncology (2013)

TPS3110 Background: Immune checkpoint blockade represents a novel form of cancer immunotherapy. Killer cell immunoglobulin-like receptor (KIR) and programmed death-1 (PD-1) are immune receptors that down-regulate NK and T cell activity, respectively. Lirilumab, an anti-KIR antibody that potentiates innate immunity, has demonstrated modest side effects in a phase I monotherapy trial. Nivolumab, a PD-1 receptor blocking antibody that potentiates adaptive immunity, has shown clinical activity with various solid tumors in phase I and II trials. We hypothesized that coordinate modulation of innate and adaptive immunity with anti-KIR and anti-PD-1 antibodies could achieve more favorable biologic and clinical activity than either agent alone. Here, we describe a phase I study of lirilumab plus nivolumab in pts with advanced solid tumors, the first collaborative clinical trial being conducted by the International Immuno-Oncology Network (II-ON). Methods: This study will be performed in two parts and enroll approximately 150 pts. During dose escalation, pts with any solid tumor, except primary central nervous system tumors, will be enrolled. During cohort expansion, pts (N=16/cohort) with non-small cell lung carcinoma – squamous and non-squamous histology, renal cell carcinoma, melanoma, colorectal carcinoma, or ovarian carcinoma will be enrolled at the maximum tolerated dose (MTD), or the maximum administered dose, if no MTD is defined. The primary study objectives are to delineate the safety and tolerability, dose limiting toxicities, and MTD of this combination. Secondary objectives are to assess preliminary anti-tumor activity, pharmacokinetics, and immunogenicity in all pts, and pharmacodynamic effect on tumor infiltrating lymphocyte subsets from melanoma pts. Exploratory objectives include a thorough assessment of innate and adaptive immunity modulation by this combination in peripheral blood and/or tumor specimens, as well as preliminary associations with clinical outcome. As of Feb 1, 2013, three pts have started therapy. Clinical trial registration number: NCT01714739. Clinical trial information: NCT01714739.
Longitudinal comparisons of results in surgical resection and percutaneous ethanol injection therapy (PEI): Change in treatment strategy for small hepatocellular carcinoma (HCC)
Authors: T. Okusaka, K. Takasaki, H. Kasugai, J. Furuse, T. Sato, J. Yamamoto
Journal: Journal of Clinical Oncology (2004)

4135 Background: Both surgical resection and local ablation therapy such as PEI have been widely used for patients (pts) with small HCC. Each treatment is selected mainly according to the technical feasibility of treatment because retrospective data suggest that the two treatments are comparable in terms of survival. To assess longitudinal changes in treatment strategy for small HCC, two retrospective comparative studies were conducted in the 4 major center hospitals where pretreatment conferences are well organized by surgeons and nonsurgical specialists for PEI. Methods: Clinical information on the patient characteristics was compared between patients with newly diagnosed small HCC (smaller than 3 cm and 3 or less in number) in 1990–1994 and 1998–1999 who underwent surgery or PEI before introduction of radiofrequency ablation therapy in each hospital. Long-term results with reference to their survival significance were also analyzed. Results: Of the 97 pts in 1990–1994, 58 (60%) underwent surgery and 39 (40%) were treated with PEI. In the 151 pts in 1998–1999, 95 (63%) were surgically treated and 56 (37%) received PEI. No significant differences in patient characteristics between the 1990–1994 pts and the 1998–1999 pts were observed except for a better bilirubin level in the 1998–1999 pts. In the surgical pts, the 1998–1999 pts included more pts with solitary tumors and showed better hepatic reserve according to the ICG test, and better albumin and bilirubin levels compared to the 1990–1994 pts. In the PEI pts, the 1998–1999 pts were older and included more pts with cirrhosis than the 1990–1994 pts. Although the overall survival rates were identical between the 1990–1994 pts and the 1998–1999 pts, the 1998–1999 surgical pts survived significantly longer (p=0.03), and the PEI pts tended to survive shorter (p=0.09) compared to the 1990–1994 pts. Conclusions: This study suggests that either surgery or PEI is being selected according to risk of surgical morbidity is being promoted, resulting in longitudinal changes in outcome of pts treated with each approach. No significant financial relationships to disclose.
Effect of age and tumor size on prognostic outcome of women with breast cancer.
Authors: Shaheenah S. Dawood, Xiudong Lei, Rebecca Dent, Paul N. Mainwaring, Bhawna Sirohi, Rajendra A. Badwe, Sudeep Gupta, Javier Cortes, Ana M. Gonzalez-Angulo
Journal: Journal of Clinical Oncology (2014)

592 Background: Increasing tumor size is known to be associated with worse prognostic outcome. The objective of this study was to determine the prognostic impact of change in tumor size by age at diagnosis. Methods: Using the SEER registry we identified female patients with stage I to III breast cancer diagnosed between 1990 and 2006. Patients (pts) were divided into 4 groups according to age at diagnosis: a) 18 to 35 years, b) 36 to 50 years, c) 51 to 65 years, and d) > 65 years. Breast cancer specific survival (BCSS) was computed using the Kaplan-Meier method. 5-year BCSS were estimated for each tumor size within each age group. Next, the 5-year BCSS was modeled in a linear regression against tumor size as a continuous variable. Results: We identified 385,285 patients with following age distribution: 18-35 years =11,737 (3.05%) pts, 36-50 years = 99,442(25.81%) pts, 51-65 years = 130,011(33.74%)pts and >65 years = 144,095(37.40%) pts. The corresponding 5-year BCSS was 83%, 90%, 91% and 87% respectively (p<0.0001). 5-year BCSS among pts with T1, T2 and T3 disease was 96%, 84% and 67% respectively (p<0.0001). For pts aged 18-35 years, 36-50 years, 51-65 years and >65 years, a 1 cm increase in tumor size was associated with 4%, 4.1%, 4.4% and 5.3% decrease in 5-year BCSS respectively (p<0.0001 for difference between youngest and oldest age groups). Among pts with hormone receptor positive disease, a 1 cm increase in tumor size was associated in a significantly lower decrease in 5-year BCSS in the youngest (3.3%) compared to oldest (4.2%, p <0.0001) age groups; the corresponding decrease in 5-year BCSS among pts with hormone receptor negative disease was also significantly different ( 4.1% vs. 6.5%, p<0.0001). Similar results were obtained when the prognostic impact of tumor size in different age groups was analyzed by nodal status. Conclusions: Increasing tumor size has a significantly greater adverse prognostic impact in older compared to younger women and this result is consistent in subgroups defined by hormone receptor and nodal status. This observation could partly account for the greater impact of breast cancer screening in older compared to younger women.
Prognostic value of miRNAs in resected lung adenocarcinomas.
Authors: Sandra Gallach, Eloisa Jantus-Lewintre, Silvia Calabuig-Fariñas, Ana Blasco, Ricardo Guijarro, Miguel Martorell, Carlos Camps
Journal: Journal of Clinical Oncology (2015)

7532 Background: Adenocarcinoma (ADC) is one of the most common types of non-small cell lung cancer (NSCLC). Deregulated microRNAs (miRNA) in tumor were associated with poor prognosis. In this study, we analyzed the prognostic value of 22 deregulated miRNAs (identified by NGS in a previous study) in a group of early-stage ADCs. Methods: RNA was isolated from fresh-frozen lung ADC specimens (tumor and normal lung) (N = 78). Deregulated miRNA (miR-182, -29a, -19b-1, 34a, 339-5p, -590, -31, -188, -21, -135b, -199b, -224, -196b, -451a, -144, -195, -125a, -218, -145, -30a, -126, -139) were analyzed in paired tumor/normal samples by RTqPCR using TaqMan microRNA assays. Statistical analyses were considered significant at p<0.05. Results: For survival analysis, continuous variables were dichotomized using the median expression of each miRNA as a cutoff. Of the 22 miRNAs analyzed, high expression levels of miR-34a, miR-145, miR-19b-1, miR-29a, miR-339-5p, miR-21, miR-218 and miR-188 were associated with worse OS and/or PFS (Table 1). Furthermore, patients with combined high levels of miR-188 and miR-339-5p had significantly reduced OS and PFS (p < 0.0001 and p = 0.001, respectively). The multivariate analysis revealed that this combined variable (miR-188 & miR-339-5p) is an independent prognostic marker for PFS (HR 3.119 [1.500-6.487]; p = 0.002) and OS (HR 2.499 [1.003-6.224]; p = 0.003). Conclusions: Expression of miR-188 and miR-339-5p seems to have a prognostic role in resectable ADC, and the combination of both could be an independent prognostic biomarker in this type of patients. Supported by grants RTICC (RD12/0036/0025), TRACE (TRA09-0132) and Beca Roche Oncohematología. miRNAs univariate analysis for OS and PFS. OS PFS miR (high vs low) Median (months) p Median (months) p miR-34a 46.43 vs NR 0.036 19.1 vs NR 0.009 miR-145 46.67 vs NR 0.039 19.23 vs 49.30 0.039 miR-19b-1 42.90 vs NR 0.007 23.00 vs 49.30 0.114 miR-29a 49.63 vs NR 0.056 21.13 vs 66.97 0.047 miR-339-5p 37.00 vs NR 0.013 19.13 vs 66.97 0.037 miR-218 42.90 vs NR 0.014 26.70 vs 37.80 0.099 miR-21 37.50 vs NR 0.052 19.10 vs 66.97 0.019 miR-188 34.43 vs NR 0.002 18.20 vs 66.97 0.009 Combined miRNAs (miR-188high-miR-339high vs other combinations ) 23.93 vs NR <0.001 15.43 vs 66.97 0.001