bluuebunny/crossref_metadata_2025_split huggingface dataset:
13C-uracil breath test to predict 5-fluorouracil toxicity in gastrointestinal cancer patients.
Authors: Cunha Geraldo Felicio , de Marco Luiz , Bastos-Rodrigues Luciana , Bolina Marina Borges , Martins Flavia Linhares , Pianetti Gerson Antonio , Cesar Isabela Costa , Coelho Luiz Gonzaga 
Published: March 2020

e13008 Background: Up to 30% of patients on 5-fluorouracil (5FU) experience severe toxicity. Dihydropyrimidine-dehydrogenase (DPD) deficiency explains 36-61% of cases. Predicting toxicity is an unmet challenge. Uracil breath test (UraBT) consists of measuring 13CO2 in exhaled breath after ingestion of 2-13C-uracil to evaluate pyrimidine (and 5FU) catabolism. Methods: We studied 33 gastrointestinal cancer patients previously exposed to 5FU: thirteen had grade 3-4 and 20, grade 0-1 toxicity. Groups were well-balanced regarding: age (median, 57 years); gender (males, 35%); primary (colorectal, 90%); ethnicity (Caucasians, 55%); chemotherapy (Mayo clinic regimen, 75%). Main toxicities were febrile neutropenia, diarrhea and stomatitis. Tests used to evaluate pyrimidine catabolism: (1) sequencing of three exons of DPYD; (2) plasma dihydrouracil/uracil ratio (UH2/U); (3) UraBT. We tested the performance of UraBT to discriminate patients who had grade 0-1 toxicity versus grade 3-4 toxicity and patients with and without proven DPD-deficiency. DPD-deficients were defined as having had grade 3-4 toxicity plus either UH2/U < 1.8 or deleterious mutation. Results: 4/13 grade 3-4 toxicity patients proved to be DPD-deficient: three had deleterious mutations (IVS14+1G>A in one; SNP 2846A>T in two), and one had low UH2/U ratio. Mean delta over baseline in 50 minutes (DOB50) significantly differed between groups. DOB50 ≤ 161.4 discriminated individuals with grade 3-4 versus grade 0-1 toxicity (sensitivity= 61.5%; specificity= 85%) and DPD-deficient versus non DPD-deficient (sensitivity= 75%; specificity= 85%). Conclusions: UraBT is a non-invasive and easy to perform method with promising accuracy in discriminating individuals with severe toxicity to 5FU, comparing favorably to most tests available to predict 5FU toxicity. [Table: see text]
Phase I safety and tolerability of once daily oral afatinib (A) in combination with docetaxel (D) in patients (pts) with relapsed or refractory advanced solid tumors.
Authors: Senellart Helene , Bennouna Jaafar , Isambert Nicolas , De-Montserrat Helene , Squiban Patrick J. , Tschoepe Inga , Delord Jean-Pierre 
Published: March 2020

e13010 Background: A is an orally bioavailable, irreversible, ErbB Family Blocker. This open label, Phase I, dose escalation trial investigated the safety, tolerability, and PK of A, in two parallel dose cohort expansion parts, in combination with either gemcitabine (Part A) or D (Part B) in patients with relapsed or refractory solid tumors. Preliminary results from Part B are presented here. Methods: Eligible pts (confirmed diagnosis of advanced solid tumors, ECOG PS 0–1) received once daily, oral dosing of A in combination with D, given iv on Day 1 of every 3 week cycle. Dosing of A started on Day 2 of Cycle 1. Primary objective was to establish the maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicities (DLT) observed in Cycle 1. Dose escalation was performed with cohorts of 3–6 pts using a 3+3 design. Initial starting dose level was A 30 mg/day and D 60 mg /m², escalating up to A 50 mg/day and D 75 mg/m² until the MTD was reached, and followed by a PK expansion cohort of 12 pts at the MTD level. Incidence and severity of AEs were recorded. Results: To date, 21 pts have been treated with A (30–50 mg/day) and D (60–75 mg/m2), with baseline characteristics: mean age (55.4 years), women (42.9%) and number of prior chemotherapies (≤2: 57%; >2: 43%). Fourteen pts received 2–4 cycles of treatment and five patients received 4 or more cycles. In Cycle 1, DLT was experienced by one out of six pts receiving 30 mg afatinib + 60 mg/m² docetaxel (Grade 3 diarrhea). No DLT was observed during the subsequent dose levels up to A 50 mg/day and D 75 mg/m². AEs observed in most pts were diarrhea (76.2%) and asthenia (66.7%). Conclusions: In pts with relapsed or refractory advanced solid tumors, the combination of A and D is well tolerated. AEs were manageable and the MTD was not reached in the tested dose range up to A 50 mg/day and D 75 mg/m². Considering the potential for diarrhea and rash during later cycles, the recommended dose for the expansion cohort was A 40 mg/day in combination with D 75 mg/m². Enrollment is ongoing (nine pts to date) and additional safety data and preliminary evidence of activity are anticipated to be available at the time of presentation.
Response of HER2+ breast cancer patients to allogeneic cell immunotherapy.
Authors: Har-Noy Michael , Lausoontornsiri Wirote , Or Reuven , Katsanis Emmanual 
Published: March 2020

e13013 Background: The immune mechanism of non-myeloablative allogeneic stem cell transplantation has been shown to be effective in debulking chemotherapy-resistant metastatic cancer despite the presence of immunoavoidance mechanisms, but this immune effect is intimately related to GVHD toxicity limiting the clinical application. An allogeneic cell therapy (aCT) with intentionally mismatched, CD3/CD28 microbead-conjugated CD4+ memory cells exhibiting both Th1- and NK-like properties designed to elicit autologous anti-tumor effects in the context of graft rejection was evaluated in a FDA-approved phase I/II clinical trial of 42 refractory metastatic solid tumor patients with a variety of indications. No objective tumor response was observed, however there was evidence of enhanced survival and immune-mediated tumor debulking without GVHD toxicity. RECIST overestimated tumor burden, as responding tumors swelled and appeared larger on CT. Multi-parameter analysis identified serum IL-12 as a predictor of enhanced survival. 50% were IL-12+ and survived a median of 211 days vs. 131 days for IL-12- patients (p<.009). Methods: An analysis of IL-12+ responders was conducted to determine the indication with the highest IL-12 response. Results: 9 of 16 refractory metastatic breast cancer (mBC) patients were IL-12+. The Her2+ subset of mBC were 100% IL-12+ (5 of 5) with a median survival of 416 days, while the 11 Her2- patients had a median survival of only 134 days (p<0.05). Conclusions: Normally, Her2+ tumors are more aggressive and have a poorer prognosis than Her2- tumors. The enhanced response to aCT in Her2+ mBC may be due to high titers of anti-Her2 IgG1 antibodies known to be present in these patients. aCT upregulates host FcgR expression on host monocytes through a CD40L-CD40 mechanism. The FcgR bind IgG1 antibodies and mediate ADCC tumor lysis. We hypothesize that patients expressing tumor-specific IgG1 autoantibodies are more likely to respond to aCT. Serum autoantibodies to tumor-associated antigens thus may be a predictive biomarker for aCT responders. The combination of natural or exogenous tumor-specific IgG1 Abs with aCT may be a platform for refractory metastatic tumor debulking leading to increased overall survival.
Phase I trial of cancer vaccine with multiple peptides derived from novel onco-antigen and anti-angiogenic antigens for patients with advanced non-small cell lung cancer (NSCLC).
Authors: Suzuki Hiroyuki , Hasegawa Takeo , Ohsugi Jun , Hoshino Mika , Higuchi Mitsunori , Shio Yutaka , Yoshida Koji , Tsunoda Takuya , Nakamura Yusuke , Gotoh Mitsukazu 
Published: March 2020

e13015 Background: Two phase I clinical trials were conducted on patients with advanced or recurrent NSCLC to evaluate the safety, immunogenicity and clinical response of a multiple peptide vaccine that incorporates four epitope peptides. This vaccine is comprised of novel HLA-A24-restricted oncoantigens, including two of the following three peptides; up-regulated lung cancer 10 (URLC10), TTK protein kinase (TTK) and cell division associated 1 (CDCA1), in addition to peptides derived from vascular endothelial growth factor receptor 1 (VEGFR1) and 2 (VEGFR2). Methods: Peptides derived from URLC10, TTK, VEGFR1 and VEGFR2 were tested in Trial 1, while peptides derived from URLC10, CDCA1, VEGFR1 and VEGFR2 were tested in Trial 2. Fifteen HLA-24-positive patients with NSCLC who had not responded to standard therapy were enrolled in this classic 3 patient per dose per cohort phase I trial, designed with varying dosages (Trial 1; 0.5mg, 1mg and 3mg, Trial 2; 1mg, 3mg). Vaccines were administered weekly by subcutaneous injection into patients’ axillary region with Montanide ISA-51 incomplete Freund’s adjuvant until progressive disease occurred and/or patients refused further treatment. Immunological responses were evaluated by INF-gamma ELiSPOT assays. Results: Vaccinations were well-tolerated withno severe treatment-associated adverse events. Specific T cell responses were induced in all patients against at least one epitope peptide. However, weak immunological responses were found in the 0.5mg group compared with the 1mg and 3mg groups in Trial 1, therefore the 0.5mg group was excluded in Trial 2. In terms of clinical responses, no complete and partial responses were found, however 9 of 15 patients (60 %) were categorized with stable disease. The median overall survival time was 13.2 months, while 1- and 2-year survival rates were 52.5% and 32.8% respectively. Conclusions: Multiple peptide vaccination therapy using four novel peptides was safe, and could possibly be effective in extending the patients’ survival. These encouraging immunological and clinical responses could provide a case for further stages of clinical trials.
Genetically engineered natural killer (NK) cell immunotherapy for children poor risk b-cell (CD20+) leukemia and lymphoma (L/L).
Authors: Chu Yaya , Ayello Janet , Hochberg Jessica , Van de ven Carmella , Murphy James , Cairo Mitchell S. 
Published: March 2020

e13022 Background: A majority of children with CD20+ L/L at relapse have a chemotherapy resistant phenotype (Cairo et al Blood, 2007; JCO, 2012). Novel, non-chemotherapy-based therapies are desperately needed for this poor risk population. NK cells play an important role in tumor surveillance post allogeneic stem cell transplantation (Beziat V et al, Leukemia, 2009) but cell number and tumor recognition limit adoptive NK cell therapy (Shereck/Cairo, PBC 2007). PBNK cells expanded with genetically engineered K562-mbIL15-41BBL cells (geK562) have been previously reported (Imai C et al, Blood. 2005). Objective: We investigated the functional activities and cytolytic effect of anti-CD20 chimeric antigen receptor (CAR+) engineered PBNK cells expanded with mK562 against CD20+ L/L both in vitro and in vivo. Methods: Peripheral blood mononuclear cells (PBMC) were expanded with mitomycin C treated geK562 cells in culture medium with 10 IU/ml IL-2 for 7 or 14 days. CD56 and CD3 expression were evaluated by flow cytometry. Retrovirus preps that express CAR+ or CAR- were generated independently. The CAR+ was constructed in a MSCV-anti-CD20BB-CD3-zeta-GFP plasmid (generously supplied by Dario Campana, MD, PhD). Expanded PBMC were transduced with retroviruses as described (Imai C et al, Blood. 2005). NK cytotoxicity was assessed by europium release assay at 2:1 E:T ratio against CD20+ Ramos. Results: CD56+CD3- PBNK cells were significantly increased compared to media alone at day7 (60.94+ 3.63% vs 8.05+0.49%, n=6, p<0.001). CD56-CD3+ PBT cells were significantly reduced compared to media alone at day 7 (22.08+2.22% vs 75.73+0.75%, n=6, p<0.001). CAR+ and CAR- retrovirus supernants infected expanded PBMC at 1%-10% range. The anti-CD20 CAR expression was further confirmed by flow cytometry and western blot. We also observe that cytotoxicity was enhanced with CAR+ PBNK compared to CAR- PBNK (41+ 1.1% vs 24.5+ 3.7%) against Ramos at E:T ratio 2:1. Conclusions: PBNK can be expanded with geK562. Anti-CD20 CAR enhances PBNK anti-tumor activity against CD20+ Ramos. Future directions include characterizing the cytotoxicity activity of engineered PBNK against L/L in vitro and survival in xenogafted mice.
Cancer vaccination trial with novel multiple peptides in previously treated advanced non-small cell lung cancer.
Authors: Hirose Takashi , Noda Hidehiro , Okuda Kentaro , Abe Seiji , Oto Yuji , Kusumoto Sojiro , Sugiyama Tomohide , Ishida Hiroo , Shirai Takao , Nakashima Masanao , Yamaoka Toshimitsu , Ohmori Tohru , Yoshida Koji , Nakamura Yusuke , Adachi Mitsuru 
Published: March 2020

e13029 Background: Cell division cycle associated gene 1 (CDCA1) and insulin-like growth factor-II mRNA binding protein 3 (IMP-3) are novel cancer-testis antigen overexpressed in non-small-cell lung cancer (NSCLC). The aim of this study was to evaluate the safety, efficacy, and immunological response of a novel peptide vaccination therapy, CDCA1 and IMP-3, in patients with previously treated advanced NSCLC. Methods: Human histocompatibility leukocyte (HLA)-A2402 positive advanced NSCLC patients who failed to standard therapy were enrolled if they had a performance status of 3 or less, were 80 years or younger, and had adequate organ function. The cocktail of 2 peptides was subcutaneously injected with 1 mL of incomplete Freund’s adjuvant to axillary or inguinal regions weekly. Immunological response was evaluated with enzyme-linked immunospot assay before and after vaccinations every 4 weeks. Results: From November 2009 through December 2011, 20 patients (13 men and 7 women; median age, 65 years; range, 36 to 78 years) were enrolled. CDCA1 and IMP-3 specific cytotoxic T lymphocyte responses were observed after vaccinations in 60% and 73% of patients, respectively. The overall response rate was 5% (95% CI, 0.1% to 24.9%) and stable disease rate was 55% (95% CI, 31.5% to 76.9%). The median survival time from the start of vaccination therapy was 7 months (range 1 to 26 months). The median progression free survival time was 3 months (range 1 to 15 months). One patient with interstitial lung disease (ILD) had acute exacerbation of ILD during vaccination therapy. The other 19 patients did not have any grade 3 or 4 adverse events. Conclusions: This vaccination therapy was effective and well tolerated in patients with NSCLC who failed to standard therapy, and therefore warrants further clinical studies.
Is vinorelbine pharmacokinetics modified in Asian patients when compared to caucasian patients?
Authors: Ferre Pierre , Shao Zhimin , Jiang Zefei , Zhong Dafang , Xiaoyan Chen , Burillon Jean-Philippe , Petain Aurélie , Zorza Grégoire , Zhang Li 
Published: March 2020

e13036 Background: Pharmacokinetics (PK) of vinorelbine (VRL) has been extensively studied through a series of clinical studies, mainly conducted in Caucasian patients. Interethnic differences in drug disposition may however induce interethnic variation in drug exposure. Consequently, the PK of VRL was assessed in Asian patients during two clinical studies conducted in China, and compared to previous knowledge from non-Asian patients. Methods: Two phase II studies were conducted in China using VRL on Day 1 and 8 in combination on Day 1 with iv cisplatin for lung cancer (NSCLC) or with epirubicin for breast cancer (ABC). Patients were randomized within each study to receive either iv VRL (25 mg/m2 on cycle 1) or oral VRL. PK samples were obtained from subgroups of patients, and blood VRL and its active metabolite DVRL were quantified through LC-MS/MS. Bayesian PK parameters were calculated and VRL monotherapy results (iv 25 mg/m²; oral 60 mg/m²) were compared to historical single agent data from Caucasian patients. A population PK analysis (Variol P. et al. Eur J Clin Pharmacol, 2002: 58) was conducted to investigate for a potential effect of ethnicity. Results: VRL PK was evaluated in 38 NSCLC and 43 ABC Asian patients. Blood VRL and DVRL concentrations profiles were consistent with those from European studies. In Asian patients, mean Cltot/F (oral VRL) was 138 ± 56.5 and 179 ± 87.3 L/h for NSCLC and ABC, and mean Cltot (iv VRL) was 34.6 ± 8.82 and 41.2 ± 13.5 L/h for NSCLC and ABC. Those results did not differ from a reference European study (Bourgeois H. et al. Cancer Chemother Pharmacol, 2007: 60) (n = 48), for which mean clearance was 144 ± 66.6 and 42.8 ± 12.2 L/h for oral and iv VRL. The population PK analysis (n = 222 and 111 patients for oral and iv route) did not evidence ethnicity as a significant covariate on both clearance and oral bioavailability. Conclusions: The PK results reported from 81 Asian patients having received iv or oral monotherapy VRL treatment are consistent with previous data from European PK studies. This is in line with the metabolism knowledge of VRL, mainly involving esterase and CYP3A4 enzymes, which are not described as highly functionally polymorphic in Caucasian and Asian population.
A phase I study of oral darinaparsin in patients (pts) with advanced solid tumors (AST).
Authors: Camacho Luis H. , Senzer Neil N. , Harb Wael A. , Barrett John A , Korth Christopher Charles , Astl Dorothea , Jac Jaroslaw , Youssoufian Hagop 
Published: March 2020

e13040 Background: Darinaparsin [Zinapar, ZIO-101(S-dimethylarsino-glutathione)], is a novel organic arsenic compound with in vitro and in vivo anticancer activity in tumor cell lines resistant to arsenic trioxide. An oral formulation is now available. Methods: This study used a 3+3 escalating design, dosing orally for 21 days followed by 7 days off (28 day cycle). Pts with AST refractory to standard therapy, ECOG performance score (PS) ≤ 2 and adequate organ function were treated. Study objectives were safety profile evaluation, pharmacokinetics (PK) and preliminary activity of oral darinaparsin. CTCAE v. 4.0 and RECIST 1.1 were used. Results: A total of 10 pts (8 males, 2 females), with ECOG PS 0=2, 1=8, mean age of 71 years (range: 60-81), median of prior therapies 3 (range: 1-4) were treated. A median of 2 cycles of darinaparsin was administered (range: 1-6). Dose limiting toxicities (DLT) were confusion (n=1; 400 mg), cognitive disturbance (n=1; 400 mg) and encephalopathic syndrome (n=1; 300 mg), reversible with drug discontinuation. The highest tolerable dose was 300 mg per day. Most frequent AEs were: hypokalemia, nausea (40% each), fatigue (30%), anemia, diarrhea, hypophosphatemia, pneumonia, vomiting (20% each). Most frequent grade ≥3 AEs were: hypokalemia, hypophosphatemia (20% each). Best overall response was stable disease (at 2 cycles), observed in 5 pts: adenocarcinoma of colon (2 pts), chordoma, adenocarcinoma of small bowel and carcinoma of tongue. PK analysis of 400 mg cohort (n=4) and 300 mg cohort (n=6) resulted in Tmax at 9 hr post treatment and Cmax slightly greater than dose proportional (p<0.05). Steady-state trough levels were achieved on or before Day 5. Approximately 40 % greater Cmax was observed on D15 compared to D1 for the 300 mg cohort (p<0.05) while unchanged at 400 mg. DLTs were observed when duration of exposure was more than 7 days and serum trough levels were 800 ng/ml or above. Conclusions: Oral darinaparsin is well tolerated at the dosage of 300 mg per day for 21days in a 28 day cycle in pts with AST. Preliminary evidence of clinical activity and a predictable PK profile justify further evaluation of darinaparsin in selected indications.
Lack of association of genetic variations of deoxycytidine kinase with toxicity or survival of non-small cell lung cancer patients treated with gemcitabine plus cisplatin.
Authors: Ryu Jeong Seon , Shin Eun Soon , Kim Hyun-Jung , Nam Hae-Seong , Lee Jong-Eun , Lim Joo Han 
Published: March 2020

e13065 Background: To determine whether tagging polymorphisms (tSNPs) of deoxycytidine kinase (DCK) have an effect on toxicity or prognosis in patients with non–small-cell lung cancer (NSCLC) treated with gemcitabine plus cisplatin. Methods: Three tSNPs (−201 C>T, rs2306744; IVS2+9846 G>A, rs12648166; IVS6+1392 T>C, rs4694362) were chosen using two databases, the international HapMap Project and Japanese Single-Nucleotide Polymorphisms. Genotyping was performed using the Genome Lab SNPstream Genotyping System and SNaPShot assay kit. We evaluated the associations of the tSNPs with hematologic toxicity or overall survival of 139 NSCLC patients at stages IIIA/IIIB (59) and IV (80). Results: The median survival time of the patients was 11.9 months. Hematologic toxicity such as neutropenia, thrombocytopenia and anemia were not different by the three tSNPs or haplotypes (CGT, CAT and CAC) of DCK. The genetic variations did not affect on survival of the patients (log-rank P: 0.248 for −201 C>T, 0.571 for IVS2+9846 G>A, 0.686 for IVS6+1392 T>C, 0,556 for CGT, 0.453 for CAT and 0.845 for CAC). In Cox model, these tSNPs and haplotypes did not reveal prognostic relevance (aHR and 95%CI: 0.954 and 0.611 to 1.489 for −201 C>T; 1.193 and 0.719 to 1.979 for IVS2+9846 G>A; 1.072 and 0.674 to 1.706 for IVS6+1392 T>C, 0,668 and 0.205 to 2.175 for CGT, 1.043 and 0.713 to 1.525 for CAT and1.043 and 0.701 to 1.550 for CAC). Conclusions: This is the first study to focus on the association of tSNPs and their haplotypes of DCK with toxicity and survival in NSCLC patients. This suggests that genetic variations of DCK have no effect on the outcomes in the patients treated with gemcitabine-based chemotherapy.
In situ distribution of metallic platinum in tumor tissues after intraperitoneal platinum chemotherapy assessed by digital synchrotron-abetted x-ray fluorescence microscopy.
Authors: Taub Robert N. , Leinwand Joshua , Bates Gleneara , Hare Elethea , Borczuk Alain C. , Graziano Joseph , Lanzirotti Antonio , Miller Lisa 
Published: March 2020

e13067 Background: Hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) and catheter-administered intraperitoneal chemotherapy (CAIPEC) are used to treat peritoneal surface-spreading malignancies, including Malignant Peritoneal Mesothelioma (MPM), to maximize local drug concentrations. Previous HIPEC studies showed tissue penetration of cisplatin ~5mm from the peritoneal surface; biodistribution of CAIPEC has not been reported. Methods: Our protocol for MPM includes initial debulking surgery with HIPEC (41°C over 1 hour, drug is then removed), 6 cycles of CAIPEC (room temperature, indefinite dwell-time), and a second debulking surgery with HIPEC. To compare tissue drug penetrations in HIPEC versus CAIPEC, on an IRB-approved protocol we collected peritoneal tissue from 6 MPM patients receiving HIPEC at initial (n=2; both cisplatin) or second surgery (n=4; 2 cisplatin and 2 oxaliplatin) for digital image localization of in situ Pt by synchrotron-abetted (Brookhaven National Laboratory, Upton NY) x-ray fluorescence microscopy at a resolution of 10 microns. Results: Overall Pt levels were highest at second surgery post-HIPEC (median=26.1ppm, range: 2.2-113.4), lowest at initial surgery post-HIPEC (median=5.2ppm, range=4.7-5.8), and intermediate at second surgery pre-HIPEC (median=16.0ppm, range=5.6-21.8). Every sample had higher Pt at the peritoneal surface; also highest at second surgery post-HIPEC (median=40.4ppm, range=4.4-219.7), lowest at initial surgery post-HIPEC (median=11.3ppm, range=8.4-14.2), and intermediate at second surgery pre-HIPEC (median=25.9ppm, range=8.4-29.9). At second surgery, each sample’s overall Pt level was higher than contemporaneous plasma Pt, pre-HIPEC (median=0.27ppm, range=0.08-0.33) and post-HIPEC (median=1.86ppm, range=0.84-2.87). Conclusions: Both CAIPEC and HIPEC effect tissue drug accumulation, greatest at the peritoneal surface. The proportion of peritoneal surface Pt was lowest in second surgery pre-HIPEC samples, suggesting more homogeneous and/or extensive drug distribution in CAIPEC than HIPEC, likely due to longer dwell-time.