tbuckley/cabot-search huggingface dataset:
P05.12 Comparison of next-generation sequencing results between brain metastasis and blood in NSCLC patients with acquired EGFR-TKI resistance other than T790M mutation
Authors: H Lee, J Kim, J Kang
Journal: Neuro-Oncology (2018)

Mechanisms of acquired resistance for EGFR tyrosine kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC) has been studied broadly, and T790M mutation, bypass singaling, and phenotype change have been suggested. Questions remain in terms of the selection of sub-clones according to the sites during EGFR TKI therapy, especially in brain due to blood-brain barrier. Three metastatic NSCLC patients harboring sensitive EGFR mutation were treated with EGFT TKI with good response but became refractory and symptomatic brain oligo-metastasis occurred. Metastectomy was done and next-generation sequencing (NGS) was done with the brain tissue and blood. Fresh brain metastasis tissue was obtained during surgery and frozen in liquid nitrogen. Blood sampling was done within a week of the surgery and plasma was used for NGS. Amplicon sequencing (Thunderbolt) was performed. Library preparation and quality control sequencing amplicon libraries were prepared using ThunderBolts Cancer Panel, according to the manufacturer’s instructions. The ThunderBolts Cancer Panel uses 230 amplicons to interrogate mutations/hotspots in 50 oncogenes, tumor suppressors and drug resistance markers. All the 3 brain tissue had the same sensitive EGFR mutation (exon 19 deletion) as initial presentation, with PDGFRA, APC and TP53 mutations, while in the plasma, PDGFRA and APC mutations were identified in the 3 patients. From the case 1, PDGFRA, APC, MLH1 and EGFR mutations were identified in the plasma, and additional PIK3CA, KDR, TP53, ERBB2, and GNA11 mutations were found in the brain. From case 2, PDGFRA, APC, EGFR, MET, PTEN, HRAS, TP53 mutations were found in the plasma, and in the brain, PIK3CA, KDR, and ERBB2 mutations were identified in addition. From the case 3, PDGFRA, APC, HRAS, and TP53 mutations in the plasma, and additional EGFR mutation in the brain. Our data identified several additional mutations in brain metastasis compared to the plasma from patients with acquired EGFR TKI resistance, other than T790M mutation. Every mutation in the blood sample was identified in the brain tissue, while additional mutations were found in the brain tissue.
Biliary-Enteric Drainage vs Primary Liver Transplant as Initial Treatment for Children With Biliary Atresia
Authors: Elyse LeeVan, Lea Matsuoka, Shu Cao, Susan Groshen, Sophoclis Alexopoulos
Journal: JAMA Surgery (2018)

Some infants with biliary atresia are treated with primary liver transplant (pLT), but most are initially treated with biliary-enteric drainage (BED) with a subsequent salvage liver transplant. Given the improvements in liver transplant outcomes, it is important to determine whether BED treatment remains the optimal surgical algorithm for patients with biliary atresia.To compare the survival of patients with biliary atresia initially treated with BED with patients who underwent pLT.This cohort study used deidentified records from the California Office of Statewide Health Planning and Development database to identify patients with biliary atresia (n = 1252) between January 1, 1990, through December 31, 2015. Patients were categorized into 1 of 2 cohorts: those who received BED treatment and those who underwent pLT. Excluded from the study were those born before January 1, 1995, and those without any documented operative intervention by age 5 years. Data analysis was performed from January 1, 1990, to December 31, 2015.Overall survival was compared between the BED and pLT cohorts using the Kaplan-Meier method. The treatment's association with treatment era was examined by comparing survival before 2002 and on or after January 1, 2002.In total, 1252 patients with biliary atresia were identified. After exclusions, 626 remained; of these patients, 351 (56.1%) were female and 275 (43.9%) were male with a median (interquartile range) age at intervention for initial BED treatment of 65 (48-81) days. Among the 626 patients studied, initial BED treatment was performed in 313 patients (50.0%), and pLT was performed in 313 patients (50.0%). Although patients who underwent pLT had a higher mortality rate within the first 3 months after the procedure, they had a reduced risk of long-term mortality compared with patients initially managed with BED treatment (hazard ratio [HR] ≥6 months after the initial procedure, 0.19; 95% CI, 0.08-0.42; P = .01). Patients requiring salvage liver transplant had a substantially higher risk of mortality than patients who received pLT (HR, 0.43; 95% CI 0.25-0.76; P = .003). Those who underwent pLT had superior survival compared with BED treatment recipients on or after 2002 (HR, 0.16; 95% CI, 0.05-0.54; P < .001), and that persisted when censoring patients who underwent salvage liver transplant (HR, 0.23; 95% CI, 0.07-0.82; P = .01).Patients who underwent pLT experienced superior long-term survival compared with patients who underwent BED treatment. Multi-institutional trials are needed to determine which initial treatment is most advantageous to patients with biliary atresia.
Investigation of cutaneous radical formation in patients receiving 5-fluorouracil, paclitaxel, docetaxel and capecitabine.
Authors: Juergen Lademann, Bich-Na Lee, Sylvia Engel, Sora Jung, Jalid Sehouli, Maxim E. Darvin, Harald Fuss
Journal: Journal of Clinical Oncology (2016)

e21611 Background: Radical formation in the skin can cause hand-foot syndrome (HFS) as a frequent dermal toxicity in patients receiving doxorubicin. An antioxidant containing ointment can provide protection against the destructive action of free radicals. Here, changes in the antioxidant status due to radical formation in the skin were investigated after administration of further HFS-associated chemotherapeutics: 5-fluorouracil, paclitaxel, docetaxel and capecitabine. Methods: 54 patients aged from 27 to 89 years were enrolled, of whom 31 patients received 60-175 mg/m² paclitaxel, 8 patients 2000-2400 mg/m² 5-fluorouracil (5-FU), 6 patients 30-100mg/m² docetaxel and 7 patients 2000-4000 mg/d capecitabine in monotherapy. Cutaneous carotenoids were measured as marker substance for the antioxidant status using a measuring system based on reflectance spectroscopy on an arbitrary scale from 1 to 10. Measuring time points were immediately before and directly after intravenous infusion of 5-FU, paclitaxel or docetaxel. In patients receiving capecitabine, measurements were performed directly before and between the 8th and 10thday of continuous oral administration within the first cycle of chemotherapy. Results: A significant decay of the mean cutaneous carotenoid concentration after chemotherapy administration was found in patients receiving 5-FU (mean decay: 0.29±0.1; p < 0.042), docetaxel (mean decay: 0.7± 0.2; p < 0.027) and paclitaxel (mean decay = 0.19 ± 0.05; p < 0.001). Unlike these findings, capecitabine patients showed neither a decreasing tendency nor a significant change of the mean carotenoid concentration (p = 0.87). Conclusions: These findings indicate different pathomechanisms of HFS depending on the administered chemotherapeutic. Therefore, the topical application of an antioxidant containing ointment with a high radical protection factor has to be considered as an effective prevention strategy for 5-FU, docetaxel and paclitaxel induced HFS, but might not have preventive effects in capecitabine-induced HFS. This might explain the negative outcome of a study (PROCAPP) regarding the prevention of capecitabine-induced HFS by an antioxidant-containing cream.
Safety and efficacy of alternating treatment with EP2006, a filgrastim biosimilar, and reference filgrastim for the prevention of severe neutropenia, in patients with breast cancer receiving myelosuppressive chemotherapy.
Authors: Andriy Krendyukov, Nadia Harbeck, Pedro Gascon, Sreekanth Gattu, Yuhan Li, Kimberly L. Blackwell
Journal: Journal of Clinical Oncology (2017)

10116 Background: In 2015, filgrastim EP2006 (Zarxio) became the first biosimilar approved by the FDA for commercial use in the US. This phase III randomized, double-blind registration study in patients with breast cancer receiving (neo)adjuvant myelosuppressive chemotherapy (TAC) compares US-licensed filgrastim, Neupogen (reference), with two groups who received alternating treatment with reference and biosimilar every other treatment cycle. Methods: A total of 218 patients receiving 5µg/kg/day filgrastim over 6 chemotherapy cycles were randomized 1:1:1:1 into 4 arms. Two arms received only 1 product, biosimilar or reference (unswitched), and 2 arms (switched) received alternating treatments every other cycle (biosimilar then reference or vice versa over cycles 1─6). Since the switch occurred from Cycle 2 onwards, this analysis compared pooled switched groups to the unswitched reference group for efficacy during Cycles 2─6. Safety was also assessed. Non-inferiority in febrile neutropenia (FN) rates between groups for Cycles 2─6 was shown if 95% confidence intervals (CIs) were within a pre-defined margin of -15%. Results: A total of107 patients switched treatment, and 51 patients received reference in all cycles. Baseline characteristics were similar between groups. Incidence of FN was 3.4% (switched) vs. 0% (reference) (95% CI: -9.65; 4.96), which is within the predefined non-inferiority margins. Infections occurred in 9.3% (switched) vs. 9.9% (reference). Hospitalization due to FN was low with 1 patient in Cycle 6 (switched). TEAEs related to filgrastim were reported in 42.1% (switched) vs. 39.2% (reference) (all cycles). Musculoskeletal/connective tissue disorders related to filgrastim occurred in 35.5% (switched) vs. 39.2% (reference) (all cycles), including bone pain (30.8% vs. 33.3%). No anti-drug antibodies were identified. Conclusions: There was no evidence of clinically meaningful differences when patients with breast cancer were switched from reference to biosimilar filgrastim, or from biosimilar to reference filgrastim. Clinical trial information: NCT01519700.
A phase I trial of certolizumab plus chemotherapy in patients with stage IV lung adenocarcinomas.
Authors: Paul K. Paik, Juliana Eng, Leslie Perez, Erika Ritter, Ai Ni, Kenneth K. Ng, John Joseph Fiore, Phillip Wong, Charles M. Rudin, Joan Massague, Mark G. Kris
Journal: Journal of Clinical Oncology (2016)

9080 Background: We previously identified a paracrine inflammatory loop (TNF-α, CXCL1/2, S100A8/9) involving both tumor and stroma that develops in response to chemotherapy, engendering chemoresistance and metastatic propagation in breast and lung adenoca models (Acharyya, Cell 2012). Interruption of this loop at any point, including inhibition by TNF-α monoclonal antibodies (mabs), leads to chemo-resensitization and abrogation of metastases, supporting a new approach to improve the efficacy of chemotherapy. Methods: This was a phase 1 study of certolizumab pegol (Cimzia), a TNF-α mab, added to cisplatin + pemetrexed (C+P) in patients (pts) with untreated stage IV lung adenocas. The primary endpoint was identification of the RP2D by safety and pharmacodynamic criteria (suppression of TNF-α). Pts were treated with C 75mg/m2 and P 500mg/m2 q3wks for 6 cycles. Pts also received Cimzia in 2 dose cohorts (200mg, 400mg) every 2 wks x 1 month then monthly thereafter. Serial blood was collected for cytokine analysis by ELISA. Response was assessed using RECIST v1.1. Results: 18 pts were treated (N = 3,200mg, N = 15,400mg). Median age = 63; female = 61%; smoker = 94%; median KPS = 80%. The most common any-grade related AEs were nausea (67%), anemia (61%), constipation (61%), and leukopenia (50%). Grade ≥ 3 related AEs occurred in 61% of pts, mostly hematologic: decreased neutrophils (22%), anemia (6%), thrombocytopenia (6%). No febrile neutropenia was seen. No DLTs were present. There were 3 unrelated SAEs (gr3 lung infection, gr2 skin infection, gr5 cardiac arrest). No pt had CTCAE wt loss; 16% had grade 1 wt gain. Safety was similar across Cimzia doses. 16 pts were evaluable for response: 9 PR (56%), 6 SD (38%), and 1 PD (6%). With a median f/u of 8.2mo, 66% of pts remain on maintenance peme. All pts had a significant decrease in [TNF-α] from baseline (8.5 fold mean decrease, p < 0.001), which is different from a control group treated with chemo alone (16 fold mean increase, p = 0.001). Conclusions: Cimzia 400mg is tolerable when given with C+P with promising anti-tumor efficacy and TNF-α suppression. A phase 2 study of this combination in pts with early stage disease is planned to assess the effect of TNF-α blockade on cure rate and metastatic propagation. Clinical trial information: NCT02120807.
TCT-155 The FFR/iFR discrepancies and their possible reasons - findings from the Czech-Japan FFR/iFR registry.
Authors: Tomas Kovarnik, Hitoshi Matsuo, None Yoshiaki Kawase, Hiroyuki Omori, Toru Tanigaki, David Zemanek, Ales Kral, Jan Pudil, Alexandra Vodzinska, Roman Stipal, Petr Kala, Jan Mrozek
Journal: Journal of the American College of Cardiology (2018)
Association of metastasis-free survival (MFS) and overall survival (OS) in nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Matthew Raymond Smith, Maneesha Mehra, Sandhya Nair, Joe Lawson, Eric Jay Small
Journal: Journal of Clinical Oncology (2018)

5032 Background: Intermediate clinical end points are needed for prostate cancer to inform clinical decisions and facilitate drug development. The international Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) working group reported that MFS is a strong surrogate of OS in hormone-sensitive localized prostate cancer. We sought to determine the relationship between MFS and OS in patients with nmCRPC. Methods: Data from the phase 3 SPARTAN trial in men with high-risk nmCRPC were used to undertake a landmark analysis for MFS. A Cox proportional hazard regression model, adjusted for covariates, evaluated the relationship of OS and development of metastases. The correlation of MFS and OS was assessed by Spearman's and Fleischer's correlation statistics. Results: As of May 2017, 1207 patients with nmCRPC had a median time to metastasis of 40.5 months. A landmark analysis showed that patients who developed metastases at 6, 9, and 12 months had significantly shorter median OS compared with those patients without metastasis (Table); after adjusting for baseline covariates, the development of metastases remained associated with OS. A significant positive correlation was observed between MFS and OS (Spearman's correlation coefficient: 0.62; p < 0.0001). The more robust, parametric Fleischer's statistical model confirmed the positive correlation (correlation coefficient: 0.69), with ≈50% of variability in OS explained by MFS. Conclusions: MFS has a significant association with OS and is predictive of OS in high-risk nmCRPC. This analysis demonstrates that MFS is a meaningful and valid intermediate clinical end point for OS. Clinical trial information: NCT01946204.Landmark time 6 mo 9 mo 12 mo Patients with metastases, n 105 175 230 Median OS, mo Metastases NR 33.3 33.3 No metastasis NR NR NR HR (95% CI) 4.55 (2.94-7.04) 5.39 (3.61-8.06) 6.95 (4.59-10.53) p Value < 0.0001 < 0.0001 < 0.0001 NR, not reached.
CheckMate 012: Safety and efficacy of first-line (1L) nivolumab (nivo; N) and ipilimumab (ipi; I) in advanced (adv) NSCLC.
Authors: Matthew David Hellmann, Scott N. Gettinger, Jonathan Wade Goldman, Julie R. Brahmer, Hossein Borghaei, Laura Q. Chow, Neal Ready, David E. Gerber, Rosalyn A. Juergens, Frances A. Shepherd, Scott Andrew Laurie, Ye Zhou, William J. Geese, Shruti Agrawal, Xuemei Li, Scott Joseph Antonia
Journal: Journal of Clinical Oncology (2016)

3001 Background: Nivo + ipi is approved in adv melanoma and has demonstrated clinical activity and manageable safety in various solid tumors. CheckMate 012 is a phase I study of nivo monotherapy or combined with other therapies in 1L adv NSCLC; we report updated results, including tumor growth dynamic (TGD) modeling, from N+I dosing schedules explored to optimize safety and permit synergistic activity. Methods: Patients ([pts] N=148, any NSCLC histology) received N+I (mg/kg) across 4 dose cohorts (Table). Primary objective was safety; secondary objectives were ORR (RECIST v1.1) and 24-wk PFS rate; exploratory endpoints were OS and efficacy by tumor programmed death ligand 1 (PD-L1) expression. The effect of N+I dosing was assessed by TGD modeling generated using individual tumor assessments; model-predicted tumor shrinkage at wk 12 was compared across cohorts. Results: Treatment-related (TR) adverse events (AEs) and select TRAEs were manageable (Table). TRAEs leading to discontinuation (DC) were comparable to nivo alone (10%), with no TR deaths. Across cohorts, ORRs ranged from 13%–39% (Table), and median duration of response was not reached. Responses were noted regardless of PD-L1 expression, with a higher magnitude of benefit in tumors that expressed PD-L1. TGD modeling predicted enhanced tumor shrinkage for N3 + I1 schedules compared with nivo alone or any N1-containing schedule. Based on integrated efficacy/safety/TGD data, N3 Q2W + I1 Q6W was proposed for further evaluation. Conclusions: 1L therapy with N+I demonstrates clinical activity and a manageable safety profile. Updated safety and efficacy across cohorts (by histology, EGFR, smoking status, PD-L1 expression) and TGD modeling data will be presented. Clinical trial information: NCT01454102. N1 + I1 Q3W x 4 cycles, then N3 Q2W (n=31) N1 Q2W + I1 Q6W (n=40) N3 Q2W + I1 Q12W (n=38) N3 Q2W + I1 Q6W (n=39) TRAEs, % Any gr 77 73 74 69 Gr 3–4 29 35 29 28 Select TRAEs, gr 3–4, % Skin 13 5 3 5 Gastrointestinal 0 8 5 5 Endocrine 6 8 3 5 Hepatic 6 10 0 5 Pulmonary 3 0 3 3 Renal 0 0 5 0 Hypersensitivity/Infusion 0 0 0 0 TRAEs leading to DC, % 13 8 5 10 ORR, % 13 25 39 31 mPFS, mo 10.6 4.9 8.0 8.3 24-wk PFS rate, % 55 NC 63 NC Median follow-up, mo 16.6 6.2 8.4 7.7 NC = not calculated; Gr = grade.
Abstract 16708: Increasing Age and the Benefit From Higher-intensity Lipid Lowering With Ezetimibe/Simvastatin vs. Simvastatin Alone: Results From the IMPROVE-IT Trial
Authors: Richard G Bach, Christopher Cannon, Robert Giugliano, Jennifer White, Yuliya Lokhnygina, Andrew Tershakovec, Thomas Musliner, Eugene Braunwald, Michael Blazing
Journal: Circulation (2015)

Introduction: While lipid lowering reduces cardiovascular (CV) events, evidence supporting high-intensity lipid lowering among elderly pts is more limited, and recent guidelines recommend moderate rather than high-intensity therapy for pts &gt;75 yrs. We explored age subgroups within the IMPROVE-IT trial to evaluate whether age modified the benefit of adding ezetimibe (EZ) to statin therapy. Methods and Results: The IMPROVE-IT trial demonstrated the combination of EZ and simvastatin (EZ/S) significantly reduced major CV events vs. simvastatin (S) alone in pts with acute coronary syndrome (ACS) and LDL-C between 50 and 125 mg/dL. The primary composite endpoint was CV death, myocardial infarction, stroke, unstable angina requiring hospitalization, and coronary revascularization &gt;30 days. Outcomes according to age were compared in pre-specified subgroups using Kaplan-Meier (KM) analysis and Cox proportional hazards models using age as a continuous variable. Of the 18,144 pts enrolled, 7971 (44%) were 65 yrs or older and 2798 (15%) were 75 yrs or older at randomization. As age increased, event rate increased with KM rates at 7 yrs in the S arm of 30.8% for pts &lt;65 yrs, 39.9% for pts ≥65 yrs, and 47.6% for pts ≥75 yrs. Treatment with EZ/S compared with S resulted in lower event rates in all age groups with an absolute reduction for pts &lt;65 yrs of 0.85% (HR 0.98 CI 0.90-1.05), for pts ≥65 yrs of 3.6% (HR 0.89 CI 0.82-0.96), and for pts ≥75 yrs of 8.7% (HR 0.80 CI 0.70-0.90), with interaction P values of 0.09 and 0.005, respectively. Using age as a continuous variable found event rates for EZ/S vs. S were always lower, but the test for interaction between age and treatment effect for the primary endpoint was non-significant (P=0.15). The rate of gallbladder, liver, and muscle-related adverse events was not increased with EZ/S vs. S among older pts or younger pts. Conclusions: In the IMPROVE-IT trial, pts 65 yrs or older and especially pts 75 yrs or older after ACS derived substantial benefit from higher-intensity lipid lowering therapy with EZ/S compared with S alone, with no increase in safety issues among older age subgroups. These results may have implications for guideline recommendations regarding more intensive lipid lowering in the elderly.
Association of the number of natural killer cells and B-cell area ratios in lymph nodes with survival in patients with stage II colon cancer.
Authors: Kazutake Okada, Sotaro Sadahiro, Gota Saito, Akira Tanaka, Toshiyuki Suzuki, Akemi Kamijo, Shinobu Masuda
Journal: Journal of Clinical Oncology (2016)

3541 Background: Patients with many retrieved lymph nodes (LNs) have good outcomes in Stage II colon cancer. We previously reported that the longest diameter of retrieved LNs correlates with the number of LNs and can be used as a prognostic factor (Int J Colorectal Dis 2015). LNs consist mainly of T cells, B cells, NK cells, and histiocytes. We studied the relations of the number of NK cells and the T-cell and B-cell area ratios in longest-diameter LNs to the number of retrieved LNs and outcomes. Methods: The subjects were 320 patients with stage II colon cancer. One LN with the maximum long-axis diameter was selected, and was immunostained with CD56 as an NK-cell marker, CD3 as a T-cell marker, and CD20 as a B-cell marker. The number of CD56-positive cells were examined and the mean number per 0.093 mm2 was calculated by 6 power fields. CD3 and CD20 positive area ratio was determined by image analysis. The relations were evaluated with the use of Spearman’s rank correlation coefficient. The cut-off values were calculated by ROC curve analysis. Results: The number of LNs was 14.8 ± 10.1 (mean ± SD). The number of CD56-positive cells was 10.7 ± 9.6. The CD3-positive area ratio was 0.39 ± 0.08. The CD20-positive area ratio was 0.42 ± 0.10. The correlation coefficients for the number of LNs with the number of CD56-positive cells, CD3-positive area ratio and CD20-positive area ratio were 0.30 (p < 0.001), -0.03 (p = 0.569) and 0.10 (p = 0.072), respectively. The number of LNs positively correlated with the number of CD56-positive cells. The median follow-up period was 118 months. Patients with 12 or more CD56-positive cells (n = 97) had a significantly better survival (HR, 0.64; 95%CI, 0.41-0.97; p = 0.040). Patients with a CD20-positive area ratio of 0.43 or greater (n = 160) had a significantly better survival (HR, 0.64; 95%CI, 0.44-0.92; p = 0.015). Multivariate analysis revealed the number of NK cells is an independent prognostic factor for relapse-free survival. Conclusions: A high number of NK cells in longest-diameter LN was associated with a higher number of retrieved LNs and better survival. NK cells in the longest LNs may reflect the host antitumor immune response in patients with Stage II colon cancer.