tbuckley/cabot-search huggingface dataset:
FOLFIRINOX (F-NOX) followed by individualized radiation for borderline-resectable pancreatic cancer: Preliminary toxicity and R0 resection rates from a prospective phase II study.
Authors: Janet E. Murphy, Jennifer Yon-Li Wo, David P. Ryan, Wenqing Jiang, Beow Y. Yeap, Lawrence Scott Blaszkowsky, Eunice Lee Kwak, Jill N. Allen, Jeffrey W. Clark, Jason Edward Faris, Andrew X. Zhu, Lipika Goyal, Harvey J. Mamon, Keith D Lillemoe, Thomas F. DeLaney, Carlos Fernandez-del Castillo, Cristina Ferrone, Theodore S. Hong
Journal: Journal of Clinical Oncology (2017)

368 Background: F-NOX has been increasingly utilized in borderline resectable pancreatic cancer (BRPC) due to the improved response rate compared to gemcitabine. However, prospective data remains limited, with the largest series being a 22 patient (pt) cooperative group trial (Alliance A021101), in which 14 pts had R0 resection. In this study, we evaluate neoadjuvant F-NOX followed by individualized chemoradiation (CRT) for BRPC. Methods: Pts ECOG PS 0-1 with biopsy-proven BRPC as defined by NCCN criteria (SMV/PV involvement with suitable flow, abutment of SMA &lt; 180 degrees or of hepatic artery) were enrolled in a single institution, NCI-sponsored phase II study (NCT01591733). Pts received F-NOX for 8 cycles. If after chemotherapy, the tumor was radiographically resectable, pts received short course CRT in 5 (protons 25 GyE) or 10 fractions (photons 30 Gy) with capecitabine 825 mg/m2 bid. If the tumor was still abutting vasculature, pts received CRT to 50.4 Gy with a vascular boost to 58.8 Gy. The primary endpoint of the study was R0 resection rate. Results: 50 pts were enrolled from 8/2012 to 8/2016. One pt was ineligible (lung metastases) and 1 pt is still on treatment, thus 48 patients were evaluable for this analysis. Median age was 62y (46-74). Median tumor size was 37 mm (21-56). Tumor location was in the head of pancreas for 36 (75%) pts. Of the evaluable pts, 40 (83%) completed therapy. Reasons for not completing therapy included pt withdrawal (3), physician decision (3), unacceptable toxicity (1) and progression (1). Grade 3 or greater toxicity occurred in 21 (44%) pts, including diarrhea (6, 12%), febrile neutropenia (4, 8.5%), neutropenia (4, 8.5%), elevated AST/ALT (3, 6.2%), thrombocytopenia (2, 4.2%), anemia (2, 4.2%), elevated alkaline phosphatase (2, 4.2%). 27 (56%) had short course CRT, while 13 (27%) had long course CRT. In evaluable pts, R0 resection rate was 28/40 (58%). Conclusions: Preoperative F-NOX followed by individualized chemoradiation results in a high R0 resection rate. Final results including PFS outcomes on the entire cohort will be presented at the meeting. Clinical trial information: NCT01591733.
Multicenter phase I/II trial of topotecan (T) and ifosfamide (I) combination as second-line therapy for pediatric solid cancer: Phase II results.
Authors: Hiroshi Kawamoto, Mari Saito Oba, Ako Hosono, Yuji Ishida, Takashi Taga, Yoshiyuki Kosaka, Jiro Inagaki, Hideo Mugishima, Yasuhiro Okamoto, Atsushi Ogawa
Journal: Journal of Clinical Oncology (2013)

10050 Background: Both of T and I are key drugs for recurrent pediatric solid malignancies but rarely used in combination. Results of the phase I portion of the combination of T and I chemotherapy (TI) which is dose-finding study by CRM method in ASCO 2010. We hereby report the results of efficacy and safety screening of TI conducted as a phase II portion. Methods: Recurrent pediatric solid malignancies with history of chemotherapy no more than 20 cycles (Cs) are eligible. Combination of I (1.2g/m 2 /day) and T (0.6 mg/m 2 /day) were administered day 1 through 5 up to six Cs. In the phase II portion, a Simon optimal two-stage design was adopted using treatment compliance with 4 Cs of TI as primary endpoint. Unacceptable compliance was set at 20% and promising one at 40%. If more than two patients (pts) among initial 13-15 pts successfully complete 4 Cs, patients’ enrollment is allowed to continue until a total of 33 pts in the phase II portion. Complete or Partial Response (CR+PR) was evaluated according to RECIST 1.0 criteria and toxicity, CTCAE v3.0. Results: 35 pts, median age 12 years (range 1-28) has been registered in both phase I and II between March 2008 and January 2013 in 8 centers: 7 neuroblastoma (NB), 8 rhabdomyosarcoma (RMS), 8 osteosarcoma (OS), 6 Ewing’s sarcoma (ES), 2 hepatoblastoma (HB), and 4 others. 13 pts out of total 34 pts (38%) completed 6 Cs. 13 pts out of 28 pts (36%, the phaseII portion) received more than 4 Cs without meeting stopping criteria of protocol treatment. This has reached the predefined efficient level. No Grade 4 non-hematological toxicity occurred. Grade 2-4 fatigue, anorexia, and nausea were 20% or less. Grade 3 or 4 neutropenia was frequent (105/127 Cs, 83%), though only 9 % (12 Cs) developed febrile neutropenia. 2 CR (HB, ES) and 2 PR (RMS, OS) were observed at best response among 22 pts with measurable disease, leading to an estimated OR rate of 18% (95%CI 5-40%). 14 patients had disease stabilization. One year progression-free survival rate and overall survival rate are 21% and 64%. Conclusions: TI achieved very good compliance and favorable toxicity as well as good tumor control rate. This combination is a new promising 2 nd line therapy for pediatric solid malignancies. Clinical trial information: UMIN000001037.
Circulating endothelial cells (CEC) and angiogenic proteins monitoring in patients (pts) with advanced hepatocellular carcinoma (HCC) treated with bevacizumab
Authors: V. Boige, C. Baey, C. Dromain, M. Ducreux, D. Malka, J. Pignon, F. Farace
Journal: Journal of Clinical Oncology (2009)

4597 Objective: The objective of the study was to evaluate prognostic/predictive biomarkers in pts with advanced HCC treated in a phase II trial of bevacizumab monotherapy. Methods: Pts with unresectable HCC received bevacizumab at 5- 10 mg/kg biweekly. CEC and serum proteins (MMP2, MMP9, VEGF, sVEGFR2, IL6, IL8, and PIGF) levels were monitored at baseline (BL) and on days (D) 3, D15 and D60 after beginning of bevacizumab therapy, and correlated with tumor response and survival. CEC were measured in one ml erythocyte lysed whole blood by four-color flow cytometry (FCM) and identified by a CD45-CD31+CD146+ 7-amino- actinomycin (7AAD)- phenotype according to a method we established previously. Serum proteins were measured using standard ELISA. A mixed model was used to compare variations of the values over time according to response and logrank test for prognostic study. Results: Overall, 43 pts (33 men; median age, 65 years [range, 23–84]; Child-Pugh cirrhosis A5/A6/B7/B8:17/21/3/2; CLIP score 0/1/2/3/4/5: 2/8/14/13/2/1) received a median of 7 cycles of treatment with bevacizumab. Among the 38 pts evaluable for efficacy, 6 (16%) had confirmed partial response (PR), and 18 (47%) had stable disease (SD); 16 weeks disease control rate was 42%. BL CEC levels (n=36 pts; median, 14/mL; range, 0–71) were not correlated with tumor size, progression-free survival (PFS), and overall survival (OS), but were higher in pts with PR or SD compared with PD (p=0.02). A significant decrease in VEGF levels at D3 (n=37 pts, p&lt;0.0001) and a trend toward higher VEGF levels in the PD group (p=0.07) were observed. BL IL8 levels superior to median value (n=43 pts, 80 pg/ml) were significantly correlated with shorter PFS and OS (p=0.03, p=0.04, respectively). No significant variation or relation to patient outcome was observed with the other proteins. Conclusions: These results suggest that BL CEC levels might be a useful biomarker to predict bevacizumab antitumor activity and that IL8 might have a strong prognostic value in patients with advanced HCC. Funding: Roche. [Table: see text]
Residual estrogen receptor availability during fulvestrant 500 mg therapy in patients with metastatic breast cancer.
Authors: Michel van Kruchten, Elisabeth De Vries, Myles Brown, Andor W. J. M. Glaudemans, Meta C. van Lanschot, Ido P. Kema, Martijn Van Faassen, Carolien P. Schroder, Erik F. J. De Vries, Geke Hospers
Journal: Journal of Clinical Oncology (2014)

588 Background: Fulvestrant competitively binds the ER and can decrease its expression. However, it is currently unknown whether the standard dose of 500 mg intramuscularly (days 1, 14, 28 and every 4 weeks thereafter) in metastatic breast cancer patients is sufficient for maximal ER downregulation. In a feasibility study we therefore evaluated whether fulvestrant 500 mg completely abolishes ER availability in patients with ER-positive metastatic breast cancer. Methods: Sixteen patients received fulvestrant and underwent positron emission tomography/computed tomography (PET/CT) before therapy initiation (scan 1), on day 28 (scan 2) and day 84 (scan 3) to monitor tumor [18F]fluoroestradiol (FES) uptake. A relative decrease of <75% in the median (background-corrected) tumor FES uptake and a residual standardized uptake value (SUVmax) ≥1.5 was predefined as incomplete reduction in ER availability. Plasma fulvestrant levels were determined concurrently with the scans by liquid chromatography tandem mass spectrometry. Results: All patients had at least one FES-positive (SUVmax ≥1.5) lesion before therapy initiation. A total of 131 FES-positive lesions were identified on FES-PET/CT (median SUVmax in patients = 2.9 [range 1.7 - 6.5]). The relative change in tumor FES-uptake in patients during fulvestrant was -85% at scan 2, but varied widely across individuals (-99% to +60%). Median residual tumor SUVmax was 1.7 (1.1 - 3.8) at scan 2 and remained stable at scan 3. Fulvestrant reduced tumor FES uptake incompletely at scan 2 in 6 of 16 patients (38%). Eight of nine patients with ≥75% decrease in median FES-uptake at scan 2 subsequently experienced clinical benefit from fulvestrant therapy, compared to only one of six with <75% decrease. Plasma fulvestrant levels were 33 (16 to 53) nmol/L at scan 2 and 27 (13 to 42) nmol/L at scan 3 and did not correlate with changes in tumor FES uptake. Conclusions: FES-PET showed significant residual ER availability in tumors during the first 3 months of fulvestrant therapy in 38% of patients, which was related to early progression. FES-PET may be used as an effect sensor for fulvestrant efficacy and may help to identify patients that could potentially benefit from a higher dose. Clinical trial information: NCT01377324.
Effect of cancer-associated fibroblasts on trastuzumab resistance by activating multiple pathways in HER2-positive breast cancer.
Authors: Yan Mao, Qing Qu, Xiaosong Chen, Yuzi Zhang, Junjun Liu, Gen Wang, Gang Xiao, Xiumin Wang, Kunwei Shen
Journal: Journal of Clinical Oncology (2014)

e11587 Background: HER2 positive breast cancer accounts for about 25% of this malignancy, which was characterized by an aggressive clinical course. Trastuzumab, an anti-HER2 targeted agent, has improved the prognosis of this kind of patients. However, almost 50% of them will develop trastuzumab resistance within 1 to 2 years treatment. Cancer-associated fibroblasts (CAFs), one major component of tumor microenvironment, have related to drug resistance, but whether and how they mediate trastuzumab resistance in HER2 positive breast cancer remain unclear. Methods: CAFs and normal fibroblasts (NFs) were isolated from fresh HER2+ breast samples obtained from Ruijin hospital. Conditional medium (CM) were collected from cultured CAFs and NFs. Different secreted proteins were analyzed by RayBio human cytokine antibody Array. Cell proliferation was determined by XTT assay and colony formation assay. Gene expression was analyzed by real-time PCR. Protein expression was determined by western-blotting. Gene transcriptional activity was determined by luciferase reporter assay. Results: CAFs mediated trastuzumab resistance in two HER2+ cell lines, BT474 and SK-BR3.Moreover, higher level of interleukin 6 (IL6) was secreted from CAFs compared with NFs, and induced trastuzumab resistance in both cell lines. Also, this phenomenon was accompanied by PTEN downregulation and JAK/STAT3, AKT, NF-kB and MAPK pathways activation. Interestingly, a neutralizing IL-6 antibody, the PI3K/AKT/mTOR inhibitor BEZ235, BKM120; STAT3 inhibitor STAT3I; NF-kB inhibitor Bortezomib and ERK inhibitor U0126 all partly blocked CAFs-induced pathways activation and reversed trastuzumab resistance. Conclusions: CAFs secrete high level of IL6, mediate trastuzumab resistance through activating multiple pathways, such as JAK/STAT3, AKT, NF-kB and MAPK pathway, and degrading PTEN by decreasing its transcriptional activity. Anti-IL6 and inhibiting these multiple pathways may partly rescue trastuzumab sensitivity in HER2+ breast cancer cell lines, serving as novel therapeutic ways for trastuzumab-resistant breast cancer patients.
Response to Salvage Therapies and Outcome of Patients with Multiple Myeloma Relapsing After Pomalidomide Therapy
Authors: Shirshendu Sinha, Shaji Kumar, Suzanne Hayman, Francis Buadi, Kristen Detweiler Short, Joseph Mikhael, Angela Dispenzieri, Morie Gertz, David Dingli, S. Vincent Rajkumar, Martha Lacy
Journal: Blood (2010)
Stimulant Use and Bone Mineral Density
Authors: Alison Poulton, Karen N. W. Lee
Journal: JAMA Pediatrics (2017)

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Association of EGFR mutation or ALK rearrangement with expression of DNA repair and synthesis genes in never-smoker females with pulmonary adenocarcinoma.
Authors: Xiaoxia Chen, Shengxiang Ren, Peng Kuang, ChunXia Su, Jiayu Li, Xuefei Li, Qiong Hu, Caicun Zhou
Journal: Journal of Clinical Oncology (2012)

10527 Background: Epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement was found not only predict the efficacy of targeted drugs, but also associate with the efficacy of chemotherapy drugs in non-small cell lung cancer (NSCLC) patients. We investigated the relationship of EGFR mutation status or ALK rearrangement and DNA repair or synthesis genes, such as excision repair cross-complementing 1 (ERCC1), ribonucleotide reductase subunit M1 (RRM1), thymidylate synthetase (TS) and breast cancer gene one (BRCA1) gene expression, as a potential explanation for these observations. Methods: In this surgical series, 104 resected lung adenocarcinomas from nonsmoker females were analyzed concurrently for the EGFR mutation, ALK rearrangement status and mRNA expression of ERCC1, RRM1, TS and BRCA1 genes. EGFR mutation detection was performed by the method of ADx-ARMS, ALK rearrangement was detected by PCR and the mRNA expression of different genes were tested using the method of real-time PCR. Results: 73 (70.2%) patients harbored EGFR mutations and 10 (9.6%) had ALK rearrangement. The ERCC1 mRNA level in patients with EGFR mutation was 3.44±1.94×10 -3 , which is significantly lower than in the patients with ALK positive and both negative(4.60±1.95×10 -3 and 4.95±2.33×10 -3 respectively, P=0.010). While the TS mRNA levels were significantly lower in the patients with EGFR mutation(1.15±1.38×10 -3 VS 2.69±3.97×10 -3 , P=0.006) or ALK positive (1.21±0.78×10 -3 VS 2.69±3.97×10 -3 , P=0.020) than in patients with both negative. Conclusions: NSCLC specimens harboring activating EGFR mutations are more likely to express low ERCC1 and TS mRNA levels, while NSCLC patients with ALK rearrangement are more likely to express low TS mRNA levels, which could be helpful to select a proper chemotherapy regimen for NSCLC patients with known EGFR mutation or ALK fusion status.
Assessing tumor response using CT density-volume trajectory in metastatic bladder cancer.
Authors: Les Folio, Vana Derderian, Seth M. Steinberg, Evrim Turkbey, Andrea Borghese Apolo
Journal: Journal of Clinical Oncology (2014)

4539 Background: Automation advances in PACS provide efficient volumetric measurement capability not utilized by existing tumor criteria. We developed a combined density and volume assessment termed Automated Density and Volume Application (ADaVA) to quantify change in viable versus necrotic tumor volumes responding to anti-angiogenic therapy. Volume is not assessed in the Response Evaluation Criteria In Solid Tumors (RECIST) or other criteria such as MASS (Morphology, Attenuation, Size and Structure) and Choi. We compared overall survival (OS) predictive ability in ADaVA with existing and evolving criteria in metastatic bladder cancer. Methods: We assessed 141 lesions using RECIST, MASS, Choi, lesion volumes, and ADaVA at baseline and serial follow-up Contrast Enhanced CT exams (n=55) in 17 patients with metastatic bladder cancer treated with cabozantinib, a tyrosine kinase inhibitor. A semi-automated PACS tool (Carestream Health; Rochester, NY) segmented volumes for density thresholds representing viable (50-180 HU) or necrotic tissue (0-50 HU). RECIST response equivalents (partial response (PR), stable disease (SD) and progressive disease (PD)) were used. For each criterion, Kaplan-Meier curves and two-tailed log-rank test compared OS based on early response determination (PR+SD vs. PD); a Cox proportional hazards model assessed PR at any follow-up exam as a time-varying covariate for OS. Results: There was a statistical association between response determinations and OS (with binary tumor response) in total and low density-volume change in ADaVA (two-tailed, p=0.019); compared to other criteria that showed weak or no association. Low-density ADaVA change had the closest trend towards association (p=0.087; Hazard ratio=0.16; 95% CI on HR: 0.02 to 1.30) with time to developing PR. Conclusions: Our pilot study suggests that ADaVA incorporating lesion density and volume may predict OS as early as the first follow-up CT, potentially outperforming existing criteria. Combined density-volume criteria accurately reflect tumor burden and may predict outcomes earlier, improving therapeutic efficacy. Further study is warranted. Clinical trial information: 9236.
Factors influencing outcomes in patients (Pts) with relapsed/refractory b-precursor acute lymphoblastic leukemia (r/r ALL) treated with blinatumomab in a phase 2 study.
Authors: Hagop Kantarjian, Nicola Gökbuget, Susan Mary O'Brien, Anthony Selwyn Stein, Catherine Jia, Stephen J. Forman, Ralf C. Bargou, Adele K. Fielding, Leonard T. Heffner, Richard A. Larson, Svenja Neumann, Tapan Maniar, Dirk Nagorsen, Max S. Topp
Journal: Journal of Clinical Oncology (2015)

7057 Background: Blinatumomab, a bispecific T-cell engager (BiTE) antibody construct, showed efficacy in r/r ALL in a large phase 2 study (Topp et al. Lancet Oncol 2015;16:57). We evaluated associations of baseline characteristics with outcomes. Methods: Pts (≥18 y) had Ph-negative r/r ALL (1st relapse <12 mo; relapse <12 mo of HSCT; ≥2ndsalvage; refractory). Blinatumomab was given by continuous IV infusion (4 wk/2 wk off) for ≤5 cycles (cycle 1: 9 µg/d days 1–7; then 28 µg/d; subsequent cycles: 28 µg/d). The primary endpoint was complete remission (CR) or CR with partial hematologic recovery (CRh) within 2 cycles. Associations of baseline factors (platelets, prior salvage, bone marrow blasts [BMB], disease stage, age, region, prior HSCT, prior relapse, LDH) with CR/CRh and overall survival (OS) were assessed (Cochran-Mantel-Haenszel test, uni- and multivariate logistic regression). Results: 81 (43%) of 189 pts treated achieved CR/CRh within 2 cycles. Median (95% CI) RFS was 5.9 (4.8–8.3) mo; median OS was 6.1 (4.2–7.5) mo. CR/CRh was seen in all groups, including pts ≥65 yrs (44%), with/without prior HSCT (45%/42%), and pts with ≥3 prior salvages (34%). Pts with ≥50% BMB at baseline had 29% CR/CRh vs 73% in pts with <50% BMB, similar to the 78% minimal residual disease (MRD) response rate in pts with MRD+ ALL in the BLAST study (Goekbuget et al. Blood 2014;124:379), suggesting low biologic resistance to blinatumomab. In multivariate analyses, lower BMB and higher platelet count were associated with CR/CRh; higher platelet count and lower LDH were associated with longer OS (Table). Conclusions: Blinatumomab has antileukemia activity in pts with r/r ALL, including pts with poor prognostic factors. Low baseline BMB count had the strongest association with response, supporting early blinatumomab administration. For pts with higher tumor burden, cytoreduction/higher doses may be options. Clinical trial information: NCT01466179. Odds Ratio for CR/CRh (95% CI) P Hazard ratio for OS (95% CI) P BMB <50% vs ≥50% 5.1 (2.5–10.5) <0.0001 ns Platelet count (109/L) 0.0341 <0.0001 <50 vs ≥100 0.3 (0.1–0.8) 4.2 (2.3–7.8) 50 to <100 vs ≥100 0.3 (0.1–1.0) 2.6 (1.3–5.4) LDH ≥230 vs <230 ns 1.9 (1.2–3.1) 0.0082