bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of a diagnostic PD-L1 immunohistochemical assay for nivolumab therapy in urothelial carcinoma.
Authors: De Los Santos Rose Ann , William Josette , Hanks Debra Ann , Northrup Adam , Jaiswal Dipeshkumar , Jansson Malinka , Phillips Therese , Cleveland Rachel , Satnick Ilana , Pierce Coree , Wynne Bethany , McDonald Hendrick , Carnahan Josette , Reddy Swarnalatha Y. , Phillips Christine , Brooks Dania , Inzunza H. David , Taylor Clive R. , Novotny James , Oroudjev Emin 
Published: September 2018

e14585 Background: PD-L1 IHC 28-8 pharmDx is a qualitative assay developed by Agilent Technologies for the Autostainer Link 48 platform and is based on EnVision FLEX visualization technology and monoclonal rabbit anti-PD-L1, clone 28-8 antibody. The assay has been co-developed with the immunotherapeutic agent nivolumab; initially as an aid in assessing PD-L1 expression in non-squamous non-small cell lung cancer (NSCLC) and melanoma patients. Here we describe the efforts to validate this assay for urothelial carcinoma (UC). Methods: IHC staining was performed on Autostainer Link 48 platform using an automated staining protocol stated per the assay’s instruction for use (IFU). Specimens were coverslipped and interpreted for % PD-L1 positive tumor cells. The assay was analytically validated on commercially acquired formalin-fixed, paraffin-embedded (FFPE) human UC invasive tumor specimens at ≥1% and ≥5% PD-L1 positive tumor cells expression levels. Results: A wide range of % PD-L1 positive tumor cells at all staining intensity levels have been detected. Assay in-house precision was validated for inter-operator, inter-instrument, inter-day, inter-run and intra-run as well as inter-observer and intra-observer agreement. Robustness studies evaluated the assay under multiple conditions for target retrieval pH, temperature and incubation time, slide type as well as tissue section thickness. Assay reproducibility was evaluated at three external sites by testing samples for intra-site/inter-day and inter-site agreement measures. Specimens were also evaluated by an observer at each site, with three reads for each observer to assess intra-observer and inter-observer agreement. All validation studies demonstrated agreement estimates above 85% with values for lower bound 95% confidence intervals calculated above 84%. Conclusions: Results of all conducted studies show high robustness and reproducibility of the assay on UC.
Observational study of the efficacy of nivolumab (Nivo) as 2+ line treatment and quality of life (QoL) in advanced refractory non-small cell lung cancer (NSCLC) patients: Interim analysis.
Authors: Laktionov Konstantin K , Arzumanyan Alla L , Bolotina Larisa V , Breder Valeriy Vladimirovich , Buevich Natalia N , Danilova Anastasia , Filippova Elena A , Kornietskaya Anna , Kramchaninov Mikhail M , Kushniruk Eugenia K , Latipova Dilorom Hamidovna , Lipatova Daria A , Moiseenko Fedor Vladimirovich , Nikitina Tatiana P , Orlov Sergey , Orlova Rashida , Protsenko Svetlana , Sarantseva Ksenia A , Stroyakovskiy Daniil , Ionova Tatyana I 
Published: September 2018

e14593 Background: Therapy with immune checkpoint inhibitors (ICI) changed the paradigm of treatment in many solid tumors including NSCLC. Recently several ICI were approved for NSCLC second and first line. By now data on Nivo benefits/risks in NSCLC is quite limited. The aim of this study was to evaluate clinical and patient-reported outcomes on Nivo in second plus line within the expanded access program in NSCLC. We report interim analysis on response rates, safety and QoL. Methods: Adult pts with advanced refractory NSCLC received Nivo 3 mg/kg q2w. Tumor response was assessed using RECIST v. 1.1., adverse events (AEs) with NCI CTCAE v3.0. and QoL by RAND SF-36. Group comparisons were made using Wilcoxon test. Results: From July of 2015 to January of 2017, 157 pts were enrolled in 7 centers in RF. Median follow-up time was 14 weeks. Clinical characteristics: 66% – males; median age – 62 (29−80); ECOG PS 0-1/2-3 – 81%/19%; former/current smokers – 73%; non squamous NSCLC – 64%; ≥2 lines of previous systemic treatment – 51%. We observed 1.5 increase of Integral QoL index in 53% of pts at 4 weeks; significant improvement was observed for emotional functioning (33.3 vs 50.0; p < 0.05). Efficacy was evaluated in 56 pts: PR – 6/56, SD – 35/56, PD – 15/56. Clinical improvement was noticed in 36 pts. Early deaths from cancer occurred in 9 pts; early deaths not related to cancer – 2 pts. 18 pts discontinued Nivo prematurely ( < 8 weeks) because of rapid clinical worsening. 72 pts were not evaluated for response on cut-off. More pts with quick worsening as compared with responders were with non squamous NSCLC (75% vs 50%) and had brain mets (20% vs 0%). Among responders 33% were with PS > 1 and were > 65 y.o; pts in this group had no brain mets. AEs were registered in 40 pts (median of Nivo treatment – 6 weeks); among them 11 with grade 3-4 AEs. Conclusions: Early data from this study supports thata large number of pts benefits fromNivo treatment. Nivo is well tolerated by this population, with 7% of grade 3 or 4 toxicities. Nivo treatment is accompanied with significant QoL improvement in 53% pts.
Immunotherapy releated cardiomyopathy.
Authors: Sonmez Ozlem , Sever Ozlem Nuray , Oyan Basak , Demir Osman Gokhan 
Published: September 2018

e14601 Background: Side effects of immunotherapies also differ from classical cytoxic chemotherapy agents such as effects. Cardiomyopathy is a relatively rare complication. Studies have shown that the risk of developing myocarditis is higher when the ipilimumab / nivolumab combination is used than when the single agent nivolumab is used. ImmunoCheckpoint inhibitors are associated with an increase in immunologic response and immunosuppressives such as corticosteroids, TNF-alpha antagonists and mycophenolate acetate are used in treatment.In this study, we aimed to report cardiac toxicity in patients who treated with immune checkpoint inhibitors. Methods: Forty patients who were treated with immunocheckpoint inhibitors were screened retrospectively at two centers in Turkey between August 2015 and January 2017 . Results: Twenty-eight of the patients were male (70%), 12 were female (30%); The median age was 61 (32-81) years. 23 (57.5%) patients received nivolumab and 16 (40 %) patients received pembrolizumab and 1(2.5%) patient received pembrolizumab/ipilimumab combination. Seven of the cases had immuno-related side effects (17.5%).In two of our patients, after the second cure of the treatment, diffuse edema and shortness of breath due to heart failure was detected. Echocardiography revealed a low ejection fraction. Methylprednisolone was started by cessation of treatment. One week after the symptoms improved rapidly and control ejection fractions normalized. One of these patients was diagnosed with malignant melanoma and the other with RCC , they using pembrolizumab and nivolumab respectively. Conclusions: In conclusion, side effects that may occur may lead to fatal outcomes, while immunotherapy, which is increasingly used in oncology practice, may result in satisfactory success in treatment. Patients and their relatives should be adequately informed about side effects caused by these agents, complaints should be carefully evaluated and treatment should be started without spending time.
Dosing immunotherapy combinations: Analysis of 3,526 patients in cancer clinical trials.
Authors: Nikanjam Mina , Patel Harsh , Kurzrock Razelle 
Published: September 2018

e14620 Background: Immunotherapy combinations are used to improve outcomes in metastatic cancer, but knowledge of appropriate starting doses for novel combinations is lacking. Methods: Phase I-III adult combination clinical trials (≥1 drug was immunotherapy; anti-PD1, PDL1, or CTLA4) were reviewed (PubMed Jan 1, 2010 to Sep 1, 2016; ASCO 2014-2016, ASH/ESMO 2014-2015 abstracts). The safe dose used in each combination was divided by the single agent recommended dose to calculate dose percentage. Additive dose percentage was the sum of each dose percentage. Results: 84 studies (N=3,526 patients, 60 combinations) were analyzed (see Table). Eight studies had unacceptable safety: ipilimumab with cytoxan, vemurafenib, dacarbazine, dabrafenib/trametinib, or carboplatin/etoposide; nivolumab or pembrolizumab with pazopanib; and tremelimumab with sunitinib. Lowest additive dose percentages evaluated in these studies were: 160, 175, 175, 217, 300, 167, 175, and 167%; it is unclear if lower doses would have been tolerable. Combinations with ipilimumab had lower additive dose percentages. Response rates (median [interquartile range]) were higher for 3 than 2 drug combinations (53% [33%-63%] (N = 23 studies) vs. 23% [14%-39%]) (N = 60 studies) with similar rates seen for targeted, cytotoxic, or dual immunotherapy combinations. Conclusions: In 63% of studies not including ipilimumab, full doses of combinations could be given. Triplet combinations had median response rates of 53 vs. 23% for doublets (p<0.001). These findings can help inform safe starting doses for novel immunotherapy combinations in clinical trials and practice. [Table: see text]
Comparison of an FAP-targeted, CD137 activating DARPin drug candidate with a non-targeted, CD137 activating antibody in a human PBMC transplanted HT-29 mouse tumor model.
Authors: Hepp Julia , Link Alexander , Fiedler Ulrike , Reichen Christian , Metz Clara , Titz Alexander , Tosevski Ivana , Juglair Laurent , Schildknecht Patricia , Kaufmann Yvonne , Fontaine Simon , Bessey Ralph , Arany Zita , Zitt Christof , Dawson Keith M. , Steiner Daniel , Snell Dan , Levitsky Victor , Stumpp Michael T. 
Published: September 2018

e14626 Background: Urelumab (BMS-663513) is a humanized monoclonal antibody binding to CD137 which, upon Fc-clustering, leads to activation of T-cells. Urelumab is currently in Phase 2 clinical development and has been reported to cause significant hepatotoxicities (around 15% Grade ≥2 ALT and AST elevation) when given as infusion every 3 weeks at doses ≥0.3 mg/kg. Currently ongoing clinical trials report decreased systemic toxicity but limited efficacy at lower doses of urelumab. We hypothesized that more effective triggering of CD137 without associated systemic toxicity may be achieved by targeting a CD137 agonistic engager without Fc to fibroblast activation protein (FAP) which is abundantly expressed in the stroma of many solid tumors. To achieve this, a targeted molecule belonging to the DARPin family of binding proteins was composed of one FAP- and two CD137-binding domains in a “beads on a string” format and tested in a mouse model with human PBMCs. Methods: Human PBMCs were used to reconstitute the immune system in NOG mice implanted subcutaneously with HT-29 human colon cancer cells. Mice were monitored for survival, body weight, and tumor size during the treatment phase of two weeks. Results: None of the mice in the control group died and no significant body weight loss was observed. Six of ten (60%) mice in the CD137 antibody group showed strong signs of graft vs. host disease and either died or reached the termination criterion of ≥20% body weight loss and were sacrificed. One of 30 (3%) mice died in the DARPin drug candidate groups but none of the animals showed body weight loss of ≥20% (p < 0.001, Log-rank test). Tumor growth inhibition was comparable for all treatment groups (around 20-30% at Day 18, p < 0.05 vs. control, Mann Whitney Test). Conclusions: This study confirms the hypothesis that systemic toxicities caused by the urelumab mode of action can be circumvented by FAP-targeting of a CD137 agonistic DARPin drug candidate while achieving comparable tumor growth inhibition. Consequently, higher clinical doses of tumor stroma-targeted agonistic DARPin drug candidates might be possible, and may result in stronger tumor growth inhibition.
Phase I study of oncolytic virus (OV) MG1 maraba/MAGE-A3 (MG1MA3), with and without transgenic MAGE-A3 adenovirus vaccine (AdMA3) in incurable advanced/metastatic MAGE-A3-expressing solid tumours: CCTG IND.214.
Authors: Jonker Derek J. , Hotte Sebastien J. , Abdul Razak Albiruni Ryan , Renouf Daniel John , Lichty Brian , Bell John C. , Powers Jean , Breitbach Caroline J , Stojdl David F , Stephenson Kyle B , Bramson Jonathan L , Hummel Jeff , Lemay Chantal G , Cutz Jean-Claude , Wells Julie , Eady Robin , Sun Xiaoqun , Tu Dongsheng , Dancey Janet 
Published: September 2018

e14637 Background: OVs display oncolytic activity and boost adaptive cell immunity. MG1MA3 is a Maraba virus modified to express tumour antigen MAGE-A3. MG1MA3, both alone and after immune priming with a MAGE-A3 modified adenovirus (AdMA3) may trigger anti-tumour T-cell responses. Methods: N = 41 patients (pts) with MAGE-A3 expressing solid tumours were evaluated in 3 groups (A) Dose escalation of MG1MA3 iv d1+4, q8w (n = 9); (B) Single fixed dose AdMA3 1e10 pfu IM d1 (n = 6); (C) AdMA3 priming d(-14) followed by dose escalated MG1MA3 (d1+4, q8w) (n = 25). Arm A and C had a 3+3 design. Pre + post treatment blood and tissue biopsies were evaluated for viral and immune markers. Endpoints included MTD/MFD, RP2DL, safety, tolerability, pharmacokinetics, viral delivery and replication. Results: Dose limiting toxicities (hypoxia/dyspnea, vomiting, headache) occurred in 4 pts (2 each Arm A +C). RP2DL for arm C was AdMA3 1e10 pfu IM d(-14) then MG1MA3 1e11 pfu iv d1+4. Common treatment related toxicities on Arm C occurring hours to a few days after MG1MA3 included diarrhea, nausea, vomiting, anorexia, chills, fatigue, fever, flu-like symptoms, hypophosphatemia, headache, and hypotension. Preliminary tumour gene expression results reveal induction of pro-inflammatory genes, including chemokines (CCL2, CCL5, CX3CL1, CXCL10), acute phase response proteins (IL-6, TNF), antigen presenting cell (APC) activation markers (CD80, HLA-A, HLA-B), markers of APC and Natural Killer cell infiltration (CD56, CD68, TLR3), as well as a co-incident decrease in the suppressive cytokine TGF-β. MG1MA3 replication was observed in some pts, inferred by detection of circulating genomes on days 4, 8 and 15 after clearance of the input dose. Induction of anti-tumour immune responses (CD8 T cells and antibodies vs MAGE-A3) was demonstrated in 3 of 6 Arm C pts evaluated to date. In one patient, over 1% of circulating CD8 T cells were directed against MAGE-A3. Conclusions: AdMA3 prime followed by MG1MA3 OV boost is feasible with a defined RP2DL, and capable of inducing potent anti-tumour immune response. Alternate schedules will be evaluated. Clinical trial information: NCT02285816.
The efficacy and safety of apatinib in patients with metastatic colorectal cancer refractory to standard therapies.
Authors: Lv Wangxia , Yuan Meiqin , Yang Yunshan , Shi Zhong , Zhong Haijun 
Published: September 2018

e15003 Background: Colorectal cancer is the third most frequent cancer and the fourth most frequent cause of cancer-related death worldwide.25% of patients with colorectal cancer have metastatic disease which leads a clinically significant detrimental effect on prognosis. After failure of standard treatments, regorafinib will be recommended to patients, but it has not been approved in China now. Apatinib is a novel, small-molecule tyrosine kinase inhibitor of VEGFR-2 which has shown a survival benefit in gastric cancer in a Phase III trial. This study is an initial clinical experience about the efficacy and safety of apatinib in patients with metastatic colorectal cancer refractory to standard therapies. Methods: Patients with refractory metastatic colorectal cancer received apatinib 500mg once daily. A treatment cycle was defined as 28 days (4 weeks). Response was assessed using RECIST 1.1 criteria. Toxicity was recorded using CTCAE version 4.0. Results: Between August 2015 to October 2016, seventeen patients were enrolled. One patient had PR (5.9%),twelve patients had SD (70.6%), and four had PD (23.6%). The ORR was 5.9% and DCR was 76.5%. The median PFS was 125 days (4.0months, 95%,CI = 1.1-6.9). The grade3/4 adverse events were hypertension (2/17;11.8%), proteinuria (2/17;11.8%), Hand-foot syndrome (2/17;11.8%), leukopenia(1/17;5.9%), neutropenia(1/17;5.9%), hyperbilirubinemia(1/17;5.9%), and diarrhea(1/17;5.9%),respectively.There were no treatment-related deaths. Conclusions:Apatinib is active for the treatment of refractory metastatic colorectal cancer with a manageable tolerability profile. Further investigations of apatinib in mCRC are needed.
Comparative effectiveness and safety of monoclonal antibodies (bevacizumab, cetuximab and panitumumab) in the treatment of metastatic colorectal cancer: Systematic review and metanalysis.
Authors: Silva Wania Cristina , Abreu Lima Ellias Magalhaes , Araújo Vânia Eloísa , Santos Jéssica Barreto Ribeiro , Silva Michael Ruberson Ribeiro , Acúrcio Francisco Assis , Cherchiglia Mariangela Leal , Andrade Eli Iola Gurgel 
Published: September 2018

e15008 Background: Biological agents have presented variable results in the treatment of metastatic colorectal cancer. This study aim to evaluate the effectiveness and safety of the monoclonal antibodies bevacizumab, cetuximab and panitumumab associated or not to chemotherapy in this scenario. Methods: A systematic review and metanaysis was performed based on observational cohort studies published in the following databases: MEDLINE/ Pubmed, LILACS, COCHRANE Library and EMBASE, up to march 2016. The effectiveness outcomes assessed in this trial were overall survival (OS), progression free survival (PFS), pos-progression survival (PPS), response rate based on RECIST criteria and metastasectomy rate. The safety outcome assessed was adverse events. Review Manager 5.3 software was used to perform the data metanalysis and the Newcastle-Ottawa scale evaluated the methodological quality of the observational trials included. Results: 16 trials were included in this metanalysis, 11 evaluating effectiveness and 8 assessing safety. Their methodological quality were considered moderate according to the Newcastle-Ottawa Scale. Basically, this study compared bevacizumab based therapies with no bevacizumab based therapies, once there was no enough data regarding cetuximab and panitumumab. Overall, the group treated with bevacizumab based therapies did better than those in the no bevacizumab group, with OS mean difference (MD) of 4,41 (95% CI 1.75 to 7.07; p = 0.001; I² = 86%) and PFS MD of 3.19 (95% CI 0.42 to 5.96; p = 0,02 I² = 96%). The PPS MD was also statistically significant (MD = 5.90; 95% CI 2.59 to 9.21; p = 0,0005; I² = 82%). When safety was the outcome concerned, the group treated with bevacizumab had more hypertension and gastrointestinal perforation. There was no statistical difference between the groups regarding others side effects. Conclusions: This study showed a potential benefit in using bevacizumab as a part of the treatment of mCRC. Bevacizumab improved PFS, OS and PPS and these differences were statistically significant. However, the drug also increased treatment related toxicities.
Compassionate use program with FDT-TPI (trifluridine-tipiracil) in pre-treated metastatic colorectal cancer patients: Spanish real world data.
Authors: Garcia-Alfonso Pilar , Ruiz Ana , Carrato Alfredo , Vieitez Jose M , Gravalos Cristina , Pericay Carles , Benavides Manuel , Delgado Mayte , Argiles Guillem , Garcia-Carbonero Rocio 
Published: September 2018

e15019 Background: Trifluridine/tipiracil (FTD-TPI) is comprised of an antineoplastic nucleoside analog, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil. Compassionate use programs (CUPs) provide a treatment option for patients with unmet medical needs and an early opportunity to obtain data on efficacy, safety and use in a real-world setting. Methods: Patients were registered and approved to receive 2 cycles of trifluridine/tipiracil treatment, which could be renewed as necessary, we analysed baseline characteristics, safety results and exposure to the treatment with trifluridine/tipiracil (FTD-TPI) in the Spanish CUP. Results: A total 636 were registered in Spain and 538 received treatment with trifluridine/tipiracil. Median age was 64 years, of which 25% were older than 70 years old and 60% were male, 67% of pts were ECOG PS 1. Oral trifluridine/tipiracil was initiated at 35 mg/m2 bid. Most pts had received 2, 3, or ≥4 lines of prior treatment for metastatic disease (27%, 28%, and 38%, respectively); and 4% unknown. 275 (47%) patients had KRAS mutated and 209 (36%) had KRAS wild type. 35% received adjuvant chemotherapy and 20% of the patients were treated with regorafenib in previous lines. The main reasons for not initiating treatment included cancellation of request due to worsening condition and progressive disease. Treatment was generally well tolerated. A total of 173 AEs were reported in the Spanish CUP, the majority were myelosuppressive AEs; febrile neutropenia (grade ≥3) was reported in 6 pts (1.3%), grade _ > 3 neutropenia was reported in 56 (33%), grade 4 neutropenia in 16 (9%). Grade 3 anemia was reported in 8 (15% of the total AEs reported).The majority of pts 306 (56%) were allocated 3-4 cycle of treatment, 95(17.3%) 5-6 cycles, and 30(5. 5%) between 7-8 cycles. Conclusions: Thisreal-world data analysis is consistent with those reported in phase 3 trials of trifluridine/tipiracil (FDT-TP)in pretreated mCRC. The efficacy analyses of this population is planned.
The effect of bundle of warmth care for patients with advanced colorectal cancer undergoing chemotherapy on reduction of oxaliplatin-related peripheral sensory neuropathy.
Authors: Lin Jin-Xiang , Chen Zhan-hong , Chen Xiang-Wei , Fan Zu-Yan , Huang Xiu-Yan , Li Xing 
Published: September 2018

e15031 Background: FOLFOX is the one of the most selected chemotherapy regimens for advanced colorectal carcinoma (aCC) patients, which includes oxaliplatin, 5-fu and leucovorin. However, oxaliplatin often causes chemotherapy-induced peripheral sensory neuropathy (CIPN) which is a common treatment-related adverse effect and affects long- term quality of life. The aim of the study is to observe the effect of warmth intervention on patients with advanced colorectal cancer undergoing chemotherapy. Methods: A total of 60 aCC patients were recruited. They were randomized into an intervention group (30 patients) and a control group (30 patients). The intervention group accepted the bundle of warmth care which included wearing cotton gloves and socks, washing hands and taking a bath with warm water, soaking hands and feet before sleep with warm water, reducing exposure to cold and avoiding cold food. The control group was treated with conventional health education which including how to reduce exposure to cold. CTCAE-4.0 was used to evaluate patient, s peripheral sensory neuropathy at baseline, 3 months, 6 months and 6 months after chemotherapy terminate. Results: At baseline, there was no peripheral sensory neuropathy in two groups. In 3 months, incidence of peripheral sensory neuropathy of intervention group and control group were 26.67%(Ⅰ:20.00%,Ⅱ:6.67%) VS 83.34% (Ⅰ:46.67%,Ⅱ:30.00%,Ⅲ:6.67%)(χ2= 22.289,p = 0.000). In 6 months, incidence of peripheral sensory neuropathy of two group were 36.67% (Ⅰ: 26.67%,Ⅱ: 10.00%) VS 93.34%(Ⅰ:46.67%,Ⅱ:30.00%,Ⅲ:16.67%) (χ2= 23.398,p = 0.000). 6 months after chemotherapy terminate, incidence of peripheral sensory nerve damage of two group were 13.33%(Ⅰ:10.00%,Ⅱ:3.33%) VS 33.34%(Ⅰ:6.67%,Ⅱ:10.00%,Ⅲ:6.67%) (χ2= 4.283,p = 0.233). Conclusions: Bundle of warmth care reduced oxaliplatin-related peripheral sensory neuropathy on patients with advanced colorectal cancer undergoing chemotherapy.