bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tako-tsubo syndrome and use of paclitaxel.
Authors: Ionescu Dana , Stone Danielle , Stone James , Durand Jean-Bernard , Iliescu Gloria , Karimzad Kaveh , Lopez-Mattei Juan , Iliescu Cezar 
Published: September 2018

e14012 Background: Vasospasm and arrhythmias are the main cardiac toxic effects of cancer treatment with Paclitaxel. Chemotherapy induced stress cardiomyopathy (SC) (Tako-tsubo syndrome) has been linked to antineoplastic agents associated with abnormal vasoreactivity. We aimed to identify if there is a causal relationship between SC and Paclitaxel administration. Methods: All cancer patients who fulfilled the diagnostic criteria for SC at MD Anderson Cancer Center over a 6–year period were included in the study. We selected and retrospectively reviewed the medical records of all the patients who had chemotherapy induced SC. Clinical presentation, ECG, laboratory data, transthoracic echocardiogram and coronary angiography results were reviewed. Results: Out of30 patients who fulfilled the diagnostic criteria for SC, 5 patients (16.6%) had SC triggered by chemotherapy. Three patients (2 females, 1 male, mean age 71.3 yo) had Paclitaxel induced SC (60%); two patients received a combination of Paclitaxel and Carboplatin for ovarian cancer, and one patient had combination of Paclitaxel and Cyclophosphamide for prostate cancer. Two patients had cardiac manifestations in the first day of Paclitaxel administration. All three patients presented with chest pain; T wave inversion was the main finding on the electrocardiography. All patients had changes in the cardiac biomarkers (BNP mean 1459.7 pg/dl, TN I mean 1.36 ng/dl, CK-MB mean 8.6 ng/dl) and significant LV dysfunction (LVEF < 50%). Characteristic apical ballooning pattern was identified in all cases from left ventriculogram. Chemotherapy was interrupted ; aspirin and beta blockers were initiated in all patients. Two patients were rechallenged with chemotherapy after 10 days, respectively 20 days after SC. None of the patients experienced recurrence of SC, nor arrhythmias while on aspirin and beta blockers. Conclusions: To our knowledge there are no published data on the association of Paclitaxel administration and SC. In cancer patients who develop acute chest pain after administration of Paclitaxel, evaluation for SC is important to exclude NSTEMI diagnosis, which can impact further cancer therapy. Cancer patients with SC whom have complete recovery may early resume cancer therapy.
Is metronomic vinorelbine (mVRL) able to inhibit both HUVEC and triple-negative breast cancer (TNBC) cells? The proof-of-concept VICTOR-0 study.
Authors: Cerrito Maria Grazia , Pelizzoni Davide , De Giorgi Marco , Digiacomo Nunzio , Lavitrano Marialuisa , Giovannoni Roberto , Bidoli Paolo , Cazzaniga Marina Elena 
Published: September 2018

e14014 Background: TNBC represents an important clinical challenge because of poor prognosis. One of the emerging strategy to achieve disease control while reducing toxicity is metronomic chemotherapy (mCHT) which targets the endothelial cells (ECs) and inhibits the tumor growth. mVRL is a promising option in patients (pts) with metastatic breast cancer (MBC), resulting in a median PFS of 7.7 months and median OS of 15.9. To better explain the effect of mVRL we studied the effects of metronomic doses of VRL in in vitro models and compared them with standard doses of the same drug. Methods: Cell viability and cytotoxicity assays were performed on TNBC cancer cells (MDA-MB-231) and Human Umbilical Vein Endothelial Cells (HUVEC). Cell lines were exposed to different concentration (0,01nM-1mM) of VRL for 4 and 96 h. To simulate the metronomic dosing schedule, we replaced the drug-enriched medium every 24h, while to simulate the conventional administration protocol (sCHT) cells were exposed to VRL for 4h, then the medium was changed and replaced with fresh medium without drug every 24 h. The IC50was calculated by non-linear regression fit of the mean values of data obtained in triplicate experiments. Results: A significant anti-proliferative activity was observed on both HUVEC and MDA cells treated with VRL in mCHT as compared to sCHT protocol (see Table). These lower drug concentrations did not have remarkable effects on cell death. Conversely, the higher dose utilized in sCHT produced important cell death in MDA as well as in HUVEC, even if in vivo, the higher dose of drug inducing the largest apoptosis of cancer cells also affectd healthy proliferating cells causing toxicity. Our findings suggest that mCHT inhibited the proliferation of both endothelial and tumour cells and can block cancer progression with minor side effects. Conclusions: This study provides the proof-of-concept that metronomic doses of VRL, but not the standard ones, are able to inhibit, at the same concentration, both the ECs and the TNBC cells. The clinical trial TEMPO-BREAST, which compares metronomic vs standard VRL, is ongoing in MBC pts. [Table: see text]
Paclitaxel once weekly (wP) combined with fixed dose of oral metronomic cyclophosphamide (OMC): A dose-escalating phase I trial.
Authors: Pannier Diane , Adenis Antoine , Tresch-Bruneel Emmanuelle , Bogart Emilie , El Hajbi Farid , Dansin Eric , Kotecki Nuria , Ceugnart Luc , Ryckewaert Thomas , Delaine Stephanie Clisant , Lauridant Philippin Geraldine , Lesoin Anne , Ducornet Sandrine , Vanseymortier Marie , Decoupigny Emilie , Le Deley Marie-Cecile , Penel Nicolas 
Published: September 2018

e14015 Background: OMC, as continuous administration of low doses of chemotherapy acts as direct cytotoxic as well as antiangiogenetic agent. wP also induces antiangiogenic effects in mouse models. The aims of this trial were to determine the recommended Phase 2 dose (RP2D) of wP given in combination with OMC, and estimate activity and safety of the combination. Methods: Methods This is a single-center, phase 1 trial. Patients (pts) > 18 years with refractory metastatic cancers were eligible if no standard curative measures existed. Paclitaxel was administered IV weekly (D1, D8, D15; D1 = D28) in combination with a fixed dose of OMC (50mg x2/day). A 3+3 design was used for Dose-Escalation of wP (40 mg/m² to 75 mg/m²), followed by an expansion cohort at RP2D. The primary endpoint was the dose-limiting toxicity (DLT), defined as grade > 3 non-hematological or grade 4 hematological toxicity (NCI-CTCAE v4.0) occurring in the first 28 days, or any toxicity leading to a dose reduction. Results: 28 pts (18 in dose-escalation phase and 10 in expansion cohort) were included between May 2011 and December 2013. The sex ratio was 2:1, the median age was 54.5 (range, 26-67); the most common primary tumors were colorectal cancers (n = 9), sarcomas (n = 4), Head & Neck (n = 3). 16/18 pts enrolled in the dose-escalation phase were evaluable for DLT. DLT occurred in 0/3, 1/6 (neuropathy), 0/3 and 2/4 pts (hematological toxicity) at dose 40, 60, 70 and 75 mg/m² of wP, respectively. The RP2D of wP was 70 mg/m2; 1/10 pts in the expansion phase had an hematological DLT. At RP2D (n = 14), the maximal grade of adverse events (AE), regardless of causality, was Gr2 in 3 pts, Gr3 in 7 pts, Gr4 in 3 pts and Gr5 in 1 pt; the maximal grade of treatment-related AE was Gr1 in 1 pt, Gr2 in 8 pts, Gr3 in 3 pts and Gr4 in 1 pt (no AE in 1 pt). At RP2D, the median PFS was 2.8 mo and Growth Modulation index was ≥1.33 in 4/14 pts (29%). There was 1 objective response (1/14; 7%): 1 pt with lung adenocarcinoma achieved a partial response. Conclusions: The combination of OMC and wP resulted in an acceptable safety profile. Further evaluation of this combination with wP at 70mg/m² could be warranted in a phase 2 trial. Clinical trial information: NCT01374620.
Evaluation of cardiovascular status in clinical trials in breast cancer.
Authors: Oren Ohad , Oren Michal 
Published: September 2018

e14038 Background: With the expansion of treatment options in oncology, patients are now increasingly exposed to potentially cardio-injurious compounds. Nevertheless, many clinical trials do not assess the cardiac status of participants, from time of enrollment to study completion. Methods: We reviewed the landmark clinical trials of each of the single-agent chemotherapies specified by the NCCN for use in locally advanced/metastatic breast cancer. We analysed the cardiovascular exclusion criteria, baseline cardiac evaluation as well as cardiac surveillance of patients in each study. We then investigated the literature in the years following each index publication, scrutinising for evidence of cardiac toxicity. Results: 14 phase 2/3 studies were analysed. The total number of patients was 2,522. 42.8% (6/14) of the studies excluded patients with clinically-determined cardiovascular disease, 66.6% (4) of which specified normal EF as a pre-requisite for enrollment. 42.8% (6/14) of the studies evaluated the baseline cardiovascular function of participants using EKG or TTE. 35.7% (4/14) of the studies included a more rigorous monitoring that included serial EKGs and/or TTEs. New Heart Failure (HF) occurred in 1.63% (20/1226) and 0.87% (9/1024) of patients in the more- and less- rigorous trials, respectively (P value = 0.11). Subsequent follow-up studies (published a mean of 8.5 years later) disclosed significantly higher incidence of symptomatic HF (range 2.3-28.0%) with 3 (of 4) chemotherapies in the more-rigorous study group (doxorubicin, cyclophosphamide, epirubicin) and 1 (of 10) chemotherapies in the less-rigorous group (docetaxel). Conclusions: The majority of clinical studies in breast cancer do not prospectively assess cardiac status beyond a pure clinical assessment. The discrepancy between the toxicity profile shown by original studies and that detected in subsequent investigations implies that the tools currently used to evaluate the cardiovascular status of enrollees may be insufficiently sensitive in predicting the development of HF. Novel tools (circulating markers, imaging) and longer follow-up periods are needed to ascertain the cardiotoxic profile of new chemotherapies.
Clinical efficacy of icotinib in patients with advanced non-small cell lung cancer harboring EGFR exon 18, 20 and 21 uncommon mutations.
Authors: Xu Chunwei , Wang Wen-xian , Fang Meiyu , Zhuang Wu , Lin Gen , Chen Xiao-hui , Zhu You-cai , Du Kai-qi , Huang Yun-jian , Xu Hai-peng , Chen Yan-ping , Chen Gang , Lv Tangfeng , Song Yong 
Published: September 2018

e14050 Background: EGFR gene mutations were discovered in some of NSCLC patients. Two major EGFR mutations include 19del and L858R. These mutations account for more than 90% of all mutations related to EGFR TKIs sensitivity. Icotinib, an EGFR TKI, showed equivalent response rates and better tolerability compared with gefitinib, double blind trial (ICOGEN) with advanced NSCLC previously treated in China. In addition, other uncommon mutations have been identified. The efficacy of icotinib in patients harboring these mutations to icotinib is still unknown. This study investigated the efficacy of icotinib in patients carrying G719X/E709X/G724S in exon 18, S768I/20 insertions/T790M/V769M in exon 20 and L861Q/L833F in exon 21. Methods: Retrospectively analysed 24 cases of 18 exon, 58 cases of 20exon and 17 cases of 21 exon uncommon mutation NSCLC patients until the progress of the disease or the emergence of the side effects and clinical efficacy was observed after months followed-up. Results: 99 patients with G719X/E709X/G724S/S768I/20 insertions/T790M/V769M/ L861Q/L833F mutations were enrolled. The patient response rate and disease control rate were 31.58%, 66.66%, 0, 25.00%, 11.11%, 4.76%, 0%, 23.53%, 0% and 73.68%, 66.66%, 100%, 80.00%, 44.44%, 47.62%, 100%, 64.71%, 100%, respectively. The mPFS were 2.7 months, respectively. Patients with L833F mutation manifested the longest mPFS(4.2 months), followed by those with G724S mutation(3.5 months), S768I and V769M(3.2 months), E709X(3.1 months), G719X(2.8 months), L861Q(2.2 months), exon 20 insertions(1.9 months) and T790M(1.6 months). Patients with complex mutations show a better PFS than those with single mutations(G719X mutations 3.3 months vs 2.6 months, P = 0.029; E709X 7.2 months vs 2.7 months, P = 0.225; S768I mutations 2.2 months vs 3.3months, P = 0.174; T790M 2.45 months vs 2.9 months, P = 0.845; L861Q mutations 2.1 months vs 5.6 months, P = 0.065 ).Conclusions: Icotinib is less effective in patients with uncommon mutations than in those with common mutations. Patients with complex mutations benefited more from icotinib than those with single mutations.
Apatinib for EGFR-TKIs resistant NSCLC patients: Initial clinical experience.
Authors: Zhou Na , Zhang Chuantao , Jiang Man , Hou Helei , Zhao Lantao , Liu Dong , Cong Jing , Zhu Hua , Zhang Xiaochun 
Published: September 2018

e14059 Background: The 3rd generation TKI is still not available for Chinese NSCLC patients with EGFR-mutant who develop acquired resistance following treatment with 1st EGFR tyrosine kinase inhibitors (EGFR-TKIs). Apatinib, a novel small molecule TKI targeted VEGFR2, recommended as third-line treatment for metastatic gastric cancer patients, might be used as an alternative strategy for these patients. This study is an initial clinical experience about Apatinib for EGFR-mutant NSCLC patients with 1stTKI resistance. Methods: Eight patients pathological diagnosed as adenocarcinoma with EGFR mutant were enrolled between January, 2016 and January, 2017. All patients had undergone TKI treatment and disease progression. They had an ECOG performance status (PS) of 0–1. 250 mg-500mg/day of Apatinib was continuously administered for two months, during which we observed the curative effect and adverse events closely. Informed consent was obtained from each patient before enrollment. Results: Computed tomography (CT) scan evaluation revealed that partial response (PR) occurred in 25% (2/8) patients and other 75% (6/8) showed stable disease (SD). There was no progressive disease (PD) occurred. Hypertension is one of the most frequent adverse reactions, which appeared in 50% (4/8) patients who were getting to be normal under antihypertensive agent. Others like hand-foot syndrome, anergy and temple elevated urine protein also appeared and could be better controlled. Conclusions: Apatinib is a safe and effective oral targeted drug on EGFR-mutant NSCLC patients with TKI resistance. It could provide a new therapy strategy for them before taking osimertinib. To further investigate the role of Apatinib in drug resistant EGFR-mutant NSCLC, large sample and additional clinical trials are needed. Table1. Clinicopathologic Characteristics of Patients. [Table: see text]
Dose-exposure-response relationship between AZD6738 and peripheral monocytes.
Authors: Pierce Andrew , Berges Alienor , Cheung S Y Amy , Standifer Nathan , Ross Graham , Smith Simon , Hollingsworth Simon J , Krebs Matthew , Postel-Vinay Sophie , Bang Yung-Jue , El-Khoueiry Anthony B. , Abida Wassim , Sundar Raghav , Carter Louise , Castanon-Alvarez Eduardo , Im Seock-Ah , Lopez Juanita Suzanne , Yap Timothy Anthony , Harrington Kevin , Soria Jean-Charles 
Published: September 2018

e14063 Background: AZD6738 is a potent, selective inhibitor of the ataxia telangiectasia and Rad3-related (ATR) serine/threonine-specific protein kinase with good selectivity against other phosphatidylinositol 3-kinase-related kinase (PIKK) family members. To support dose/schedule guidance through mathematical modelling of clinical pharmacokinetic/pharmacodynamic relationships, we sought to determine quantitative pharmacodynamic effects of AZD6738 in peripheral blood with respect to drug exposure. Methods: We assessed peripheral blood cell subpopulations in clinical studies of AZD6738 used either as a monotherapy, a combination with the PARP-1 inhibitor olaparib and in combination with the PD-L1 inhibitor durvalumab through both blood analyser and flow cytometry characterization. Peripheral pharmacokinetics of AZD6738 were also assessed. Results: Levels of peripheral monocytes were suppressed in a dose-dependent manner for the duration of AZD6738 dosing resulting in a decrease of up to 80% within the first 7 consecutive days of AZD6738 treatment; these results were consistent across studies. Upon cessation of an AZD6738 dosing interval monocyte levels return to baseline values within 14 days; in combination with durvalumab there is a trend for the rebound in monocyte counts to surpass baseline levels by up to 20%. Monocyte suppression is specific to AZD6738 and not found with either single agent olaparib or single agent durvalumab, possibly attributable to defective base excision repair in monocytes and lack of PARP-1. Monocytes were found to be the most sensitive cell type to AZD6738 treatment compared with neutrophils, platelets, haemoglobin or lymphocytes. Conclusions: This drug effect of AZD6738 is consistent with natural clearance of peripheral monocytes under suppression of monocyte precursor proliferation in the bone marrow, suggestive of a change in the equilibrium between production and elimination of peripheral monocytes. Used as a surrogate marker of target inhibition, a mathematical model of the AZD6738/monocyte dose-exposure-response relationship is described and has been used to inform AZD6738 Phase 2 dose and schedule.
A new model for estimating glomerular filtration rate in patients with cancer.
Authors: Janowitz Tobias , Williams Edward Hywel , Marshall Andrea , Ainsworth Nicola , Thomas Peter B , Sammut Stephen John , Shepherd Scott Thomas Colville , White Jeff D. , Mark Patrick , Lynch Andy , Jodrell Duncan Ian , Tavaré Simon , Earl Helena Margaret 
Published: September 2018

e14074 Background: The glomerular filtration rate (GFR) is essential for carboplatin chemotherapy dosing, however, the best method to estimate GFR in patients with cancer is unknown. We identify the most accurate and least biased method. Methods: Data on age, sex, height, weight, serum creatinine, and results for GFR from 51Cr-EDTA excretion measurements (51Cr-EDTA GFR) were obtained from Caucasian patients aged 18 years or older with histologically confirmed cancer diagnoses at the University of Cambridge Hospital NHS Trust, UK. We developed a new multivariable linear model for GFR using statistical regression analysis. 51Cr-EDTA GFR was compared to the estimated GFR (eGFR) from seven published and our new model using an internal validation data set and root-mean-squared-error (RMSE) and median residuals. A comparison of carboplatin dosing accuracy based on an absolute percentage error more than 20% (APE > 20%) was undertaken. Results: Between August 2006 and January 2013 data from 2,471 patients were obtained. The new model improved the eGFR accuracy (RMSE 15.00ml/min (95% CI 14.12-16.00)) compared to all published models. Body surface area (BSA) adjusted CKD-EPI was the most accurate published models for eGFR (RMSE 16.30ml/min (95% CI 15.34-17.38)) for the internal validation set. Importantly, the new model reduced the fraction of patients with a carboplatin dose APE > 20% to 14.17% in contrast to 18.62% for BSA adjusted CKD-EPI and 25.51% for the Cockcroft-Gault model. The results were externally validated. Conclusions: In a large data set, from patients with cancer, a new model improves eGFR and carboplatin dose calculations, when compared to BSA adjusted CKD-EPI, the model we identified as the best published model for determination of eGFR in patients with cancer.
Clinical development of 4SC-202, a combined epigenetic inhibitor of HDAC class I and LSD1, to overcome anti-PD-1 refractoriness and increase efficacy of checkpoint inhibition.
Authors: Hermann Frank 
Published: September 2018

e14096 Background: Checkpoint inhibitor (CI) like anti-PD(L)-1 antibodies are a breakthrough innovation, but a high unmet medical need remains for a large proportion of patients not responding. Low mutational load, microsatellite stability and a non-inflamed tumor microenvironment have been described as negative predictive factors. A promising approach to increase the benefit from anti-PD(L)-1 treatment is to alter the tumor microenvironment to a more immune-inflamed phenotype by combination assets. Epigenetic modulation has been reported as one key determining factor in shaping the immune microenvironment and compounds altering these processes, like histone deacetylases (HDAC) inhibitor in particular offer a promising approach. Methods: We report preclinical results from the small molecule compound 4SC-202, an orally available clinical stage epigenetic inhibitor, specifically targeting HDAC class I and lysine-specific demethylase LSD1. Results: 4SC-202 has shown the ability to elicit a variety of immune modulating effects on tumors and their microenvironment by enhancing the expression of tumor associated antigens as well as MHC and co-stimulatory molecules. Combination treatment of 4SC-202 with CI in syngenic mouse models showed a strong synergistic effect leading to enhanced tumor reduction when compared to 4SC-202 or checkpoint inhibitor treatment alone. Importantly, 4SC-202 strongly increased the number of tumoricidal cytotoxic T cells (CTL) without affecting the viability of activated T cells. Conclusions: Anti-PD(L)-1 refractory/non-responding patients remain a population with a high unmet medical need, increasing in number over time. Advanced melanoma is the model tumor for immunotherapy in general and CI in particular. Based on the strong preclinical rationale, we hypothesize that the addition of 4SC-202 to anti-PD-1 treatment may lead to increased immunogenicity of the tumor, an inflamed tumor microenvironment and subsequent clinical benefit in anti-PD-1 refractory/non-responding melanoma patients. The “SENSITIZE” study is intended to proof this concept in a phase Ib/II clinical trial.