tbuckley/cabot-search huggingface dataset:
Incorporating biomarkers into adaptive clinical trials.
Authors: Lorenzo Trippa, Patrick Y. Wen, Brian Michael Alexander
Journal: Journal of Clinical Oncology (2015)

e13009 Background: Multi-arm randomized controlled trials with Bayesian interim analyses improve efficiencies over conventional two arm trials. We expand on this to include biomarkers and a set of heterogeneous drugs that are linked to distinct treatment-biomarker interaction hypotheses. While biomarker hypotheses can be incorporated into clinical trials in a myriad of ways, we developed a novel methodology to incorporate prior information to gain the efficiency associated with biomarker-only trials while preserving the valuable biomarker information generated by all patient trials. Experimental arms are linked to biomarker-defined subgroups within the enrolled population, with treatment/biomarker links estimated with various degrees of uncertainty by previous studies including preclinical experiments. Methods: We propose statistical designs and analyses of multi arm trials using a priori information on treatment-biomarker interactions formalized through Bayesian modeling. A priori information is represented as confidence levels that positive effects may extend beyond the targeted subgroup, which vary across experimental arms. We compared the proposed algorithm to alternative trial schemes using realistic scenarios defined through biomarker frequency estimates. We contrast power and other pivotal operating characteristics using computer simulations. Results: In our simulation study with up to three biomarkers and three experimental treatments, under realistic biomarker frequencies (20%-45%), we observed a sample size reduction of 25% to 40% necessary to report positive results compared to two arm randomized studies and a 10%-20% reduction compared to two arm enriched studies. Additionally, we observed efficiency gains of the treatment effect estimates on the non linked subpopulations. Conclusions: Our multi-arm, Bayesian adaptively randomized design that includes a priori estimates of biomarker/therapeutic effect linkages provides efficiency gains over separate two arm studies, even ones that are enriched for biomarker-only populations, and provides valuable data to confirm or refute biomarker hypotheses.
Beyond the performance rate: Understanding differences in treatment status using the Rapid Quality Reporting System (RQRS).
Authors: Erica J. McNamara, Andrew Stewart, E. Greer Gay, James Banasiak, Dmitry Eremin, Dennis Harman, Rafael Flores, Stephen B. Edge
Journal: Journal of Clinical Oncology (2012)

6088 Background: RQRS is a cancer registry based tool for rapid case ascertainment and real-time care tracking using 5 National Quality Forum approved quality measures for breast (BC) and colon cancer (CC) and 1 American Society of Clinical Oncology, National Comprehensive Cancer Network and Commission on Cancer (CoC) endorsed rectal cancer (RC) measure. RQRS was introduced in 2009 for testing at selected CoC accredited programs. The purpose of this study was to evaluate the proportion of cases with treatment administered for 4 measures where care is concordant with treatment either “administered” or “considered but not administered” (CNA). Methods: Case information on 19,631 breast, colon and rectal cancer patients diagnosed from 2009 – 2010 submitted by 64 RQRS participating sites were reviewed for 4 measures: (1) hormone therapy within 1 year of diagnosis (dx) for AJCC T1c, N0M0, or stage II or II; hormone receptor positive BC (HT), (2) multi-agent chemotherapy within 4 months of dx; age &lt; 70; hormone receptor negative BC (MAC), (3) adjuvant chemotherapy within 4 months of dx; age &lt;80; AJCC Stage III CC (ACT), and (4) radiation therapy within 6 months of dx; age &lt;80; AJCC T4N0M0 or stage III patients receiving surgical resection for RC (AdjRT). Treatment status was defined as concordant (administered or CNA) or non-concordant (NC – not part of planned first course therapy or received after required time frame). Patient demographics and Charlson-Deyo (CD) co-morbidity scores were compared by concordance status using Chi-square tests. Results: The aggregate concordance rate was 83.3%. Among these 889 (5.4%) were CNA. Co-morbidity score was &gt; 0 for 15% of cases. Patients age &gt; 70, with Medicare insurance, CD score &gt; 0 were significantly more likely to be CNA compared to completed or NC. Patient choice was the most common reason for CNA (64%). Conclusions: Among patients treated at RQRS test sites for which RQRS measures applied and care was concordant, only 5% were CNA. Patients over age 70 or with CD &gt; 0 were more likely to have treatment CNA. Inclusion of CNA as concordant care has a minor impact on concordance rates and provides cancer programs with important information for targeting care review and quality improvement programs.
Serum Haptoglobin and Hemopexin Levels in Pediatric SS and SC Disease Patients: Biomarker of Hemolysis and Inflammation
Authors: Rayra Pereira Santiago, Caroline Conceição Guarda, Camylla Vilas Boas Figueiredo, Luciana Magalhaes Fiuza, Corynne Stephanie Ahouefa Adanho, Milena Magalhães Aleluia, Dalila Luciola Zanette, Magda Oliveira Seixas Carvalho, Isa Menezes Lyra, Valma Maria Lopes, Julia Nguyen, Trevor Killeen, Hao Nguyen, Gregory M. Vercellotti, John D. Belcher, Marilda Souza Goncalves
Journal: Blood (2016)
TCR use and cytokine response in PD-1 blockade.
Authors: Jesse M Zaretsky, Steven M Blum, Lidia Robert Faja, Ryan O Emerson, Antoni Ribas
Journal: Journal of Clinical Oncology (2015)

3027 Background: PD-1 blockade releases effector T-cells in the tumor microenvironment, but little is known on the effects in peripheral blood. We used T cell receptor (TCR) sequencing and multiplex serum cytokine analysis to assess treatment-induced changes and correlation with clinical response. Methods: Patients with metastatic melanoma were administered PD-1 inhibitor pembrolizumab (MK-3475) across three clinical trials at UCLA (NCT01295827, NCT01704287, NCT01866319). Among those consenting to blood collection (UCLA IRB#10-000870), we selected cases with paired samples (baseline and at second dose), yielding 19 responders and 22 non-responders per irRECIST. Peripheral TCRs were sequenced by immunoSEQ assay (Adaptive Biotechnology). Serum cytokines were analyzed by Milliplex 38 Cytokine kit (HCYTMAG-60K-PX38). Mann-Whitney and Wilcox signed-rank tests evaluated group differences and treatment effects. Results: Unlike previous reports with CLTA4 blockade, anti-PD-1 treatment itself did not cause a net expansion in unique TCR repertoire size (p = 0.42). However, post treatment samples in responders had significantly more unique TCRs compared to non-responders (p = 0.022). Fold change in the number of clones comprising the top 25% of total TCR reads, a metric which minimizes noise from rare clonotypes, differed significantly between groups (p = 0.015, MW), showing a net decrease in non-responders but no net change in responders (p = 0.013 vs p = 0.77, WSR). Among serum cytokines, higher FGF-2 (p < 0.01) and eotaxin (p = 0.04) levels at baseline correlated with response, as did a post treatment decrease in relative levels of IL-8 (p < 0.01), MCP-1 (p < 0.01) and FGF-2 (p = 0.01). Changes in FGF-2 correlated with IL-8 and MCP1 (Spearman rho σ = 0.35, p = 0.03 and σ = 0.70, p < 0.0001). Among all study patients there was a mean increase in IP-10 (p < 0.001), IL-12.p40, IL-10, and TNF-a (all p < 0.05), and decrease in MDC (p = 0.037). Conclusions: Greater diversity of post-treatment peripheral T-cell repertoire favorably correlates with response to PD-1 inhibition, and differs from the non-specific increase observed with CTLA4 blockade. Of 38 circulating cytokines analyzed, 8 showed treatment induced changes, of which a decrease in FGF-2, MCP1, and IL-8 correlated with response.
Increase of CXCL14 and CXCR7 expression in human squamous lung cancers compared to its adjacent normal lung tissues.
Authors: Yoon Hee Choi, Soo Young Chung, Jae Hyun Kim, Bong-Gun Seo, Ha-young Lee, Kyung A. Kwon, Yoo Sang Yoon, Hee Sam Na
Journal: Journal of Clinical Oncology (2015)

e22099 Background: Lung squamous cell carcinoma (SQCC) is the second-largest histological subtype of non-small-cell lung cancer, but relatively less biomarkers are available compared to adenocarcinoma. Recently, chemokines and their receptors have been suggested to play important roles in the initiation or progression of cancers. In this study we examined the expression of chemokine and their receptor in human lung squamous cancer compared with adjacent normal tissue. Methods: Tumor and its adjacent normal lung specimens were collected from fresh frozen samples of 10 patients with primary lung SQCC subjected to curative surgical resection from November 2011 to October 2012 at our institute. To detect chemokines and their receptors mRNA, human chemokines and receptors PCR array (Qiagen) was used. We employed a tissue microarray to examine CXCL14 and CXCR7 expression by immunohistochemical staining in 35 consecutive lung SQCC specimens and their adjacent normal lung tissues collected from November 2011 to March 2013. Results: Compared with matched normal tissues, mRNA levels of CXCL14 (p = 0.000) and CXCR7 (p = 0.025) in SQCC were significantly increased compared to its adjacent normal lung tissues. CXCL14 and CXCR7 protein expression were detected in 25 (71%, p = 0.000) and 21 (60%, p = 0.000) of 35 cases for tumor, respectively. In normal lung tissues, CXCL14 and CXCR7 were stained negative. Tumoral CXCR7 protein expression was also significantly correlated with advanced stage (I, II (11/24, 46%) vs III (10/10, 100%) (p = 0.005) and lymphatic invasion (No: 8/18, 44% vs Yes: 13/16, 81%) (p = 0.039). Although not significant, CXCL14 protein expression also showed positive correlation with the stage and lymphatic invasion. Conclusions: Our results indicated that CXCL14 and CXCR7 might play important roles in lung squamous carcinogenesis and might be a potential novel target for the patients with lung SQCC.
Central nervous system conditions in abiraterone or enzalutamide-treated prostate cancer patients.
Authors: Dominic Pilon, Lorie Ellis, R. Scott McKenzie, Laurence Gozalo, Marie-Helene Lafeuille, Patrick Lefebvre
Journal: Journal of Clinical Oncology (2015)

e16067 Background: Abiraterone acetate (AA) and enzalutamide (ENZ) are novel oral therapies offering survival benefit to metastatic castration-resistant prostate cancer (mCRPC) patients. Development of central nervous system (CNS) conditions is an important consideration among this population. This study assessed development of CNS conditions in AA or ENZ-treated patients. Methods: Retrospective claims from Truven Health MarketScan database were used to identify AA or ENZ-treated patients with ≥ 1 PC diagnosis; > 1 year of observation and no AA or ENZ use prior to index. The index date was the 1stAA or ENZ claim on/after 9/1/2012. Patients were followed until 7/2014 or loss to follow-up. A CNS condition was defined as a diagnosis code for cognitive disorder, fall, seizure, headache, convulsion dizziness, confusion, ataxia, weakness, insomnia, paresthesia, anxiety, amnesia, memory impairment, disturbance in attention, hallucination, fatigue, or pain. Patients were excluded if they had a pre-existing CNS condition 3-months before or on index date or < 3 months of AA or ENZ exposure post-index. Kaplan-Meier (KM) rates and time to CNS conditions were compared between cohorts. Results: A total of 859 AA and 195 ENZ patients were identified. Mean age was 73 years. A higher proportion of ENZ-treated patients developed a CNS condition post-treatment initiation than did AA-treated patients. Median time to a CNS condition was 15.6 months (AA) and 12.2 months (ENZ); log-rank P = 0.038. The Table displays the KM rates of CNS conditions up to 18 months from index date. Respectively 4.7% and 8.2% of AA and ENZ patients had some fatigue diagnoses within 3 months of index date (log-rank P = 0.049) and 4.3% and 7.2% of AA and ENZ had pain diagnoses within the same time period (log-rank P = 0.086). Conclusions: In this real-world study of PC patients treated for at least 3 months with AA or ENZ, significantly more ENZ-treated patients developed a CNS condition(s) than did AA-treated patients. Time to CNS condition, % AA cohort N=859 ENZ cohort N=195 Log-Rank P-value 3 months 12.8% 20.5% 0.005 6 months 25.2% 32.3% 0.021 9 months 33.9% 41.6% 0.022 12 months 42.0% 49.5% 0.027 15 months 48.0% 56.6% 0.021 18 months 56.3% 61.6% 0.038
Safety and preliminary activity of hydroxychloroquine and aldesleukin in metastatic renal cell carcinoma (mRCC): A cytokine working group study.
Authors: Leonard Joseph Appleman, Theodore F. Logan, Daniel Paul Normolle, Marc S. Ernstoff, Rahul Atul Parikh, David F. McDermott, Paul Monk, Thomas Olencki, David Friedland, Jodi Kathleen Maranchie, Michael T. Lotze
Journal: Journal of Clinical Oncology (2017)

440 Background: Aldesleukin (recombinant human interleukin-2) has been an FDA-approved treatment for mRCC since 1992, based on a 5-10% rate of durable complete remissions. Autophagy is a protective mechanism that enables cells to survive the metabolic stress of cancer therapy. Hydroxychloroquine (HCQ) inhibits cellular autophagy and has shown synergy with interleukin-2 in animal tumor models. We hypothesized that this combination would be tolerable and active in patients with mRCC. Methods: The Cytokine Working Group initiated a study of high-dose aldesleukin in combination with oral HCQ for patients with mRCC. Subjects receive up to 6 cycles of aldeskleukin, 600,000 International Units per kg, on a standard schedule. HCQ is administered orally starting 2 weeks prior to the first dose of aldesleukin and continuing up to one year. The initial HCQ dose was 600 mg daily, with a planned dose escalation to 1200 mg daily after safety was demonstrated in five subjects. Subjects were monitored for safety and tolerability as well as response per RECIST 1.1. Results: Five subjects were treated at the first dose level of 600 mg daily HCQ plus aldesleukin with no unexpected toxicity. Thirteen subjects were then treated at HCQ 1200 mg daily with aldesleukin. Of these, two experienced hypotension and tachycardia and 1 patient died from pulmonary emboli. The cardiac events were consistent with aldesleukin toxicity, but were observed earlier in the course of treatment than anticipated for aldesleukin alone. HCQ dose was therefore de-escalated to 600 mg daily, and 8 additional subjects have been enrolled with no unexpected toxicity. In 26 of 39 planned subjects, there has been 1 complete response (CR) and 1 partial response (near CR), both in the 600 mg cohort. As of Oct 24, 2016, after a median of 36.6 months of follow-up, seven out of 26 subject have died, with median overall survival not yet obtained (95% C.I. = (29.6 months,unknown)). Conclusions: HCQ in combination with aldesleukin was found to be tolerable at a dose of 600 mg daily, with expected toxicities. Clinical responses have been observed. Clinical trial information: NCT01550367.
S0713: A phase II study of cetuximab (CET) added to induction chemotherapy (ICT) of oxaliplatin (OX) and capecitabine (CAP), followed by neoadjuvant chemoradiation (NACR) for locally advanced rectal cancer (LARC).
Authors: Cynthia G. Leichman, Shannon L McDonough, Stephen R Smalley, Kevin G. Billingsley, Heinz-Josef Lenz, Matthew A. Beldner, Aram F. Hezel, Mario R. Velasco, Katherine A Guthrie, Charles David Blanke, Howard S. Hochster
Journal: Journal of Clinical Oncology (2015)

3516 Background: NACR for LARC has been standard for 2 decades. Pathologic complete response (pCR) associates with improved survival and is an outcome surrogate in NACR clinical trials. In modern phase III trials of NACR in LARC, pCR ranges 15-20%. CET improves response rates in KRAS wild-type (KRAS-WT) metastatic colorectal cancer. S0713 was designed to select patients (PTS) by KRAS-WT status to assess improvement in pCR with CET added to ICT and NACR for LARC. Methods: Eligibility: Stage II-III biopsy proven LARC, KRAS-WT, without bowel obstruction or prior therapy, adequate hematologic, hepatic and renal function, and performance status of 0-2. Peripheral neuropathy > grade 2 was exclusionary. Enrollment target was 80 eligible PTS with planned interim analysis after 40 PTS received all therapy; if < 7 pCR were observed at interim, the study was to close. Treatment consisted of ICT then NACR and surgery. Treatment regimen: Cycle 1: OX 50 mg/m2 day (d) 1,8,15,22,29, CET 400mg/m2 d1 then 250 mg/m2 d 8, 15, 22, 29 and CAP 825 mg/m2 p.o. BID Monday through Friday (M-F) d1-35; Rest d 36-49; Cycle 2: OX 50 mg/m2 d 50, 57, 71, 78, CET 250 mg/m2 d 50, 57, 64, 71, 78 and CAP 825 mg/m2 p.o. BID M- F d 50-85 with radiation 180 cGy/d M-F x 5 weeks (4500 cGy) followed by 540 cGy boost x 3 (stage II; 5040cGy) or 5 (stage 3; 5400cGy). Surgery occurred 3-8 weeks after NACR. 80 eligible PTS would give a power of 90% if true pCR > 35% at a significance of 0.04. The regimen would lack future interest if pCR < 20%. Results: From February 2009 to April 2013, 83 PTS registered; 5 were ineligible; 4 not treated. 74 were available for toxicity evaluation (TOX); 72 had available data; 62 PTS (86%) had surgery. 1 grade 5 TOX and 2 grade 4 TOX occurred. 7 PTS withdrew for TOX, 2 for other reasons. 18 of 62 PTS had pCR (25%, 95% CI 16-37%). 19 PTS (26%) had microscopic cancer; 35 PTS (49%) had minor/no response (10 no surgery). Conclusions: ICT and NACR with CET improved pCR over historical and recent rates of ~20%. Toxicity was generally acceptable. This approach can serve as a base for adding additional agents in KRAS-WT LARC. Additional analysis for resistance genes is ongoing. Clinical trial information: NCT00686166.
FACTORES ASOCIADOS CON UN RESULTADO FALSO POSITIVO EN EL CRIBADO DE CÁNCER COLORRECTAL
Authors: G Ibáñez-Sanz, M Garcia, J Gómez-Matas, X Domènech, G Binefa, F Rodríguez-Moranta, C Vidal, N Milà, A Soriano, V Moreno
Journal: Endoscopy (2015)

Introducción: El efecto adverso más frecuente en programas poblacionales de cribado es obtener un resultado falso positivo que conlleva riesgos innecesarios de procedimientos diagnósticos
Phase II, prospective, single-arm, single-institutional, open-label clinical trial on laparoscopic sentinel node navigation surgery in early gastric cancer.
Authors: Do Joong Park, Young Suk Park, Hye Seung Lee, Young Soo Park, Kyoung Ho Lee, Young Hoon Kim, Kyoung Un Park, Sang-Hoon Ahn, Hyung-Ho Kim
Journal: Journal of Clinical Oncology (2017)

90 Background: The aim of this study was to evaluate the feasibility and safety of laparoscopic limited gastrectomy with sentinel basin (SB) dissection for gastric cancer using simultaneous indocyanine green and 99mTc-antimony sulfur colloid injections. Methods: The primary end point was the 3-year relapse-free survival rate of the patients who underwent laparoscopic sentinel node navigation surgery (SNNS). Secondary end points included sentinel node (SN) detection rate, false negative rate of intraoperative pathologic examinations for metastatic SN detection, postoperative morbidity and mortality, quality of life (QOL), and overall survival. Results: From July 2010 to April 2013, 100 patients were enrolled to this study. The SBs were identified in all patients (100%) by dual method. The mean number of SN and non-SN was 6.07 ± 3.84 [range 0-17] and 4.60 ± 4.76 [range 0-25]. Eleven patients had SN metastasis and they were converted to conventional laparoscopic gastrectomy with radical lymphadenectomy. Among 89 patients with negative SNs, 3 patients were considered as false negative of intraoperative pathological examination (3.37%). There was no significant difference between SN negative (n = 89) and positive (n = 11) groups in estimated blood loss, postoperative hospital stays and complication rate. Overall, QOL scores are more likely to be better in SNNS group than in conventional laparoscopic distal gastrectomy group. After median follow-up periods of 47.5 months in all patients, 4 patients who underwent SNNS died, and 2 patients who underwent SNNS had recurrences of cancer. The 3-year relapse-free survival rate for all patients (n = 100) was 97.0 %. In the subgroup analysis, the 3-year relapse-free for the SN negative group was 96.6%, and 100% for the SN positive group (P = 0.374). The 3-year overall survival rate was 98.0% for all patients; 97.7% for the SN negative group and 100% for the SN positive group (P = 0.418). Conclusions: Laparoscopic SNNS was feasible and safe in early gastric cancer. Phase III randomized controlled trial on comparing laparoscopic SNNS and conventional laparoscopic gastrectomy will be needed based on the present study. Clinical trial information: NCT01441310.
Quantitative assessment of CD3, CD8, and CD20 in tumor-infiltrating lymphocytes and predictive value for response to neoadjuvant chemotherapy in breast cancer.
Authors: Jason R. Brown, Yalai Bai, Veerle Bossuyt, Christian Nixon, Donald R. Lannin, David L. Rimm
Journal: Journal of Clinical Oncology (2014)

1027 Background: Tumor infiltrating lymphocytes (TILs) have been associated with response to neoadjuvant therapy. However, typical analysis of TILs is subjective, semi-quantitative and does not differentiate between subpopulations. Here we describe a quantitative objective method for measurement of TIL subsets, including CD3, 8, and 20 and assess their predictive value for therapeutic response. Methods: We used a quantitative immunofluorescence (QIF) assay to measure stromal expression of CD3 (T cell), CD8 (cytotoxic T cell), and CD20 (B cell) on a single slide using AQUA technology. This method was validated by comparison to flow cytometry on fresh tonsil tissue. To assess the predictive value of TIL markers, we used a cohort of 105 consecutive (2002 - 2010) invasive breast cancer patients that received neoadjuvant therapy and had obtainable pre-surgical biopsy tissue. Percentage TIL infiltrate in the tumor stroma was estimated by two pathologists on H and E stained slides of these biopsies. Images from each specimen were collected in 4 to 118 fields of view, and we obtained summary scores for CD3, 8 and 20. Results: In tonsil specimens, lymphocyte percentage and proportions of CD3, CD8, and CD20 positive lymphocytes were similar between flow cytometry and QIF. Pathologist TIL count (H&E TIL) was predictive of pCR (p = 0.0171, OR: 6.458) despite fair interobserver reproducibility (k = 0.390). AQUA scores for CD3 (p = 0.0193, OR: 1.960), CD8 (p = 0.0225, OR: 2.021), and CD20 (p = 0.0033, OR: 1.868) within the stroma predicted pathologic complete response (pCR) in univariate analysis. CD3 (p = 0.0369, OR: 2.504) and CD20 (p = 0.0062, OR: 3.371) also predicted pCR in multivariate analysis with age, size, nuclear grade, nodal status, and ER, PR, and HER2 status, but only CD20 was significant with Ki-67 AQUA score added (p = 0.0341, OR: 5.532). CD20 was more sensitive and specific than CD3 and CD8 and equivalent to H&E TILs (AUC: 0.690 vs. 0.655 vs. 0.629 vs. 0.692). Conclusions: We have developed and validated an objective quantitative assay for measuring TILs. H&E TIL, CD3, CD8, and CD20 all predict therapeutic response, and CD20 is independently predictive including all variables.