julilili42/papers huggingface dataset:
Circulating tumor DNA in patients with metastatic urothelial cancer: concordance of genomic findings with matched tissue biopsies.
2019-05-20

e16036 Background: Patients (pts) with metastatic urothelial cancer (mUC) now have access to many different treatment options. This creates an incentive for molecular profiling of their tumors, with the aim of developing biomarkers. Genomic profiling may leverage the presence of circulating tumor DNA (ctDNA), but it has not been shown whether this recapitulates the findings from tissue samples. Methods: Whole blood samples were collected for next-generation sequencing of leukocyte and cell-free DNA (cfDNA). Deep targeted sequencing was performed across a UC-specific custom 50-gene panel (median depth of 986x). Matched archival tissue was profiled using the same assay for 65 pts. Results: Between 11/2011 and 12/2017, 90 pts developed mUC (87 evaluable). Baseline characteristics: median age 67, 83% male, 14% upper-tract disease, 17% stage IV at initial presentation. Treatments delivered: 76% platinum-based chemotherapy, 47% PD-1/PD-L1 inhibitor. At a median follow-up of 12.8 mo., 45% remain alive. We found ctDNA fractions above 2% in at least one blood collection in 81% of cases. For 17 pts, matched metastatic biopsies and cfDNA collection were available; in those cases 82% of coding somatic mutations identified in tissue were independently detected in cfDNA. Half of discordant findings could be attributed to low ctDNA fraction. Most (89%) mutations detected in primary tissue (cystectomy or nephrectomy) were present in later cfDNA collections. ctDNA detected mutations in TP53 and ARID1A in 64% and 29% of pts, respectively. A tumor mutation burden ≥25 mutation per Mb was observed in 27% of cases. Conclusions: There is a high concordance between genomic findings from ctDNA and matched tissue of pts with mUC. This supports the use of liquid biopsies to study potential biomarkers in this disease.
Investigation of the efficacy of imidazolyl ethanamide pentandioic acid (IEPA) to reduce chemotherapy-induced myelosuppression (CIM) in breast cancer patients.
2019-05-20

e23098 Background: Neutropenia is a major toxicity of myelosuppressive chemotherapy (CTX). Treatment and prophylaxis of CTX-induced neutropenia with granulocyte colony-stimulating factors is mainly recommended in patients with high risk of febrile neutropenia. IEPA, a hemoprotective small molecule for oral use, may constitute a safe alternative. The main objective of the study was to assess the efficacy of IEPA in reducing CIM in breast cancer patients. Methods: Randomized, double-blind, placebo-controlled, parallel group study in female adults diagnosed with invasive breast cancer receiving epirubicin/cyclophosphamide CTX. Patients took one tablet daily of IEPA 100 mg or placebo starting 5 days prior to the first CTX cycle until 3 days prior to the second CTX cycle. Two batches of study medication were used sequentially in the study. Hematologic and other variables were tightly measured during the first CTX cycle. Results: After no significant treatment effect was observed in the total study results, post-hoc analyses revealed a significant batch effect. Treatment with Batch 1 IEPA was superior to placebo in treating CIM (Table). Conclusions: Although the presence of a batch effect precludes final conclusions and calls for a formulation optimization of the compound, the efficacy of Batch 1 IEPA in reducing CIM consistent with prior non-clinical and clinical studies invites further investigation of the hemoprotective properties of IEPA. Area over the curve (AOC) integrates extent and duration of decreased absolute neutrophil counts [(ANC/nL)*days] below thresholds corresponding to grade 1 (ANC &lt; 2.0x10^9/L) and 3 neutropenia (ANC &lt; 1.0x10^9/L); CI: confidence interval; LS: least squares; DN3: duration of grade 3 neutropenia in [days]. Clinical trial information: NCT02692742. [Table: see text]
EUDARIO/ENGOTov-48: A European multicenter randomised phase II trial on the combination of the HSP90 inhibitor ganetespib with carboplatin followed by maintenance treatment with niraparib (+/- ganetespib) compared to platinum-based combination-chemotherapy followed by niraparib in relapsed platinum-sensitive ovarian cancer patients.
2019-05-20

TPS5605 Background: Carboplatin (C) mainly acts by forming interstrand crosslinks (ICL) within the DNA double helix, which can only be removed by the Fanconi Anemia (FA) pathway. HSP90 inhibitors destabilise a number of HSP90 client proteins, such as those governing the FA DNA repair pathway and the G2/M checkpoint (e.g. Chk1 and Wee1). Kramer et al. (Cell Death Differ, 2017) showed that the HSP90 inhibitor Ganetespib (G) virtually eliminates a functional FA DNA repair complex, therewith preventing the repair of DNA ICL in vitro and vivo. In parallel, G abrogated Chk1 and Wee1 expression and circumvented a G2/M arrest. Consequently, cells with unrepaired DNA damage rushed into mitosis, which resulted in massive tumour cell death. Furthermore, HSP90 inhibition has been shown to reduce the amount of BRCA1 in the cell therewith broadening sensitivity towards PARPi and preventing acquired PARP resistance. Our trial approach is tested in ovarian carcinomas with a mutant p53 background. EUDARIO (EUDRACT 017-004058-40) is funded by the European Commission (FP7 project GANNET53). Methods: Eligible patients have relapsed platinum-sensitive ovarian cancer, no limits in prior lines, high-grade (but clear cell) histology or carcinosarcoma, disease measurable or evaluable according to RECIST 1.1. Patients are randomised into 3 treatment arms (1:1:1), a) control arm: C+Gemcitabine or C+Paclitaxel (q3w, 6 cycles, investigator`s choice) followed by Niraparib, b+c) 2 experimental arms: C (AUC5, d1) + G (150mg/m 2 , d1) q3w 6 cycles followed by either Niraparib alone (arm b) or by Niraparib+G (arm c; G at 100mg/m 2 weekly, limited to 9 months). Niraparib (200/300mg/day) is given in case of SD, PR or CR after platinum-based treatment until disease progression. The main analysis will combine both experimental arms b+c and jointly compare them against arm a using log-rank test. Primary endpoint is PFS, secondary endpoints are PFS2, TFST, TSST, safety, ORR, PRO, OS. The first patient was dosed in January 2019. Clinical trial information: NCT03783949.
Analyzing Effects of Goal Competition and Task Difficulty in Multiple-Task Performance: Volitional Action Control within ACT-R
2019-05-20

Commonly, multiple-task performance is empirically investigated by using simple choice reaction time tasks and modeled based on activation mechanisms and executive control productions (e.g., Sohn & Anderson, 2001). Although this has yielded promising insights into basic executive functions it remains unclear whether the assumed mechanisms are applicable to everyday multiple-task behavior involving higher time demands and additional volitional processes.
Angiosarcoma of bone: A European Muscoloskeletal Oncology Society (EMSOS) multicenter, retrospective study.
2019-05-20

11046 Background: Angiosarcoma of bone (B-AS) is an exceedingly rare malignant tumor of vascular origin. The aim of this EMSOS retrospective study is to report on natural history, type of treatment and prognosis of B-AS. Methods: Patient data were collected according to the national rules for observational studies through electronic dataset available on EMSOS WEBsite. Results: 80 patients (51 male and 29 female, median age 54 years, range 17 to 92 years, 56% with localized disease, 44% metastatic) from 8 EMSOS Centers were collected. Surgery of the primary tumor was performed in 76% of patients (amputation in 30%), with intralesional margins in 26%. A surgical complete remission status (SCR) was achieved in 47% of the patients. Radiotherapy (RT) was delivered in 41% of the patients (in 15 patients as definitive local treatment), chemotherapy (CT) in 47% (56% in metastatic and 41% in localized cases). With a median follow-up of 31 months (range 40 to 309 months), 68% of patients died, 16% were disease-free, 12% were alive with disease and 4% dead for other causes. The 5-year overall survival (OS) was 27% (95%CI 16-30): 41% (95%CI 25-56) for localized patients (45% SCR, 17% no SCR, p = 0.03) and 8% (95%CI 0-20) for metastatic patients (p = 0.002). Among metastatic patients, 29/35 have died, with a median time to death of 6 months (1-45), while 6 patients were alive with a median follow-up of 22 months (8-106). Improved survival was observed for male patients (30% vs 8%, p = 0.04), while type of treatment (surgery, chemotherapy, radiation), pattern of metastases and age did not affect outcome. In 18 metastatic patients who underwent chemotherapy partial respo nse (PR) was documented in 1/3 patients after paclitaxel (RR 33%), and stable disease (SD) in 5 patients (2/2 with gemcitabine, 2/8 with doxorubicin/ifosfamide, and 1/4 with osteosarcoma-like chemotherapy). In localized patients, the 5-year OS was significantly better for age ≤ 50 years (68% vs 34%, p = 0.02) and extremity and central tumor as compared with pelvis/sacral location (50% vs 58% vs 0%, p = 0.008), with improved disease-free survival (DFS) after chemotherapy (49% vs 33%, p = 0.04). Conclusions: Metastatic B-AS is a fatal disease and inclusion in experimental trials is warranted. In localized patients, a better probability of survival is expected in younger and surgically treated patients. The use of chemotherapy was associated with improved DFS.
Reducing Cognitive Load and Fostering Cognitive Skill Acquisition: Benefits of Category-Avoiding Instructional Examples
2019-05-20

It is often argued that one important prerequisite for skilled problem solving is the availability of problem-type schemata, i.e., representations of problem categories together with category-specific solution procedures. A ubiquitous answer on how such schemata can be acquired is that studying concrete instances of problem categories (i.e., examples) is necessary for schema acquisition. It is commonly assumed that those instructional worked examples should be designed in a molar way to convey knowledge on problem categories (defined by multiple structural problem features) and category-specific solution procedures (category-focusing examples).
ctDNA as a noninvasive monitoring tool in metastatic melanoma.
2019-05-20

9548 Background: The field of liquid biopsy provides a promising alternative to standard tissue biopsies. Previous work has shown that plasma circulating cell-free DNA (ctDNA) can reflect the heterogeneous spectrum of mutations in cancer including metastatic melanoma. Our project aimed to establish and statistically validate plasma-based assays for tumour load and therapy monitoring in melanoma. Methods: On a large cohort of stage III and stage IV melanoma patients (N = 96) who received signalling targeted or immune checkpoint inhibitors we showed that the most common oncogenic drivers of this disease such as the BRAFV600E, NRASQ61 and the TERTC250T and TERTC228T promoter mutations (termed TERTprom) can be analysed in ctDNA with highly sensitive droplet digital PCR technology (detection of mutant ctDNA down to 0.01% analytical sensitivity). Results: Our research has demonstrated that ctDNA (irrespective of the genotype) significantly correlates with tumour stage (P &lt; 0.05). Using receiver operating characteristics (ROC) analyses thresholds were established for risk stratification and response prediction. Elevated ctDNA at baseline was a significant predictor of disease progression compared to elevated LDH or S100 in multivariable cox proportional hazards model (Hazard ratio [HR] 7.43, P = 0.05). During therapy, patients with low ctDNA load (below the ROC threshold) had significantly better radiological outcomes and prolonged progression free survival (PFS) compared to patients with high ctDNA load (P &lt; 0.0001). Our findings were confirmed on an independent cohort of metastatic melanoma patients (N = 35) treated with immune checkpoint inhibitors, where also during therapy low ctDNA load correlated with prolonged PFS (P = 0.003). An added benefit of ctDNA was demonstrated in about 80% of the patients, where ctDNA analyses preceded the radiological diagnosis of response or relapse. Progression was detected in plasma ctDNA in average 3.5 months earlier as compared to routine imaging techniques. Finally, we demonstrated that the occurrence of NRASQ61 mutation in BRAFV600-inhibitor treated patients at therapy baseline was associated with treatment failure. The sub-clonal NRASQ61 mutation at therapy baseline was an independent predictor of shorter PFS (HR 2.69, P = 0.02) as compared to BRAFV600E patients without the NRASQ61 mutation at therapy baseline. Conclusions: In sum, our results support the value of ctDNA as a sensitive biomarker for real-time therapy monitoring and early detection of disease progression.
First-line (1L) ribociclib (RIB) plus letrozole (LET) for postmenopausal women with hormone receptor-positive (HR+), HER2- advanced breast cancer (ABC): MONALEESA-2 long-term safety results.
2019-05-20

1078 Background: In the phase III MONALEESA-2 study (NCT01958021), 1L treatment (Tx) with RIB (cyclin-dependent kinase 4/6 inhibitor) plus LET significantly prolonged PFS vs placebo (PBO) + LET in patients (pts) with HR+/HER2– ABC (HR 0.56; P&lt;0.0001). In the primary publication (data cutoff, Jan 2016), the median duration of exposure was 13.0 mo (RIB + LET) and 12.4 mo (PBO + LET), and the most common all-grade adverse events (AEs) in the RIB + LET arm were neutropenia (74.3%), nausea (51.5%), infections (50.3%), fatigue (36.5%), and diarrhea (35.0%; Hortobagyi GN, et al. N Engl J Med. 2016;375:1738-48). Here we present long-term safety data from MONALEESA-2. Methods: Pts received either RIB + LET (n=334) or PBO + LET (n=330). AEs were graded per CTCAE v4.03. Results: As of data cutoff (Oct 2018), 79 (24%) pts (RIB + LET) and 39 (12%) pts (PBO + LET) remained on Tx. The median duration of exposure was 20.2 mo (range, 0-54) for RIB + LET and 14.1 mo for PBO + LET, and 30% and 17%, respectively, had ≥ 36 mo of exposure. Neutropenia was the most common exposure-adjusted any-grade AE of special interest (AESI) in the RIB + LET arm (Table). AEs were the most common reason for RIB dose reductions (56.6%) and interruptions (73.4%). Discontinuations due to AEs occurred in 19.2% and 4.2% of pts in the RIB + LET and PBO + LET arms, respectively, and the most common AEs leading to discontinuation in the RIB + LET arm were increased ALT (4.5%), GI disorders (3.3%), and increased AST (2.7%). Prolonged QT led to dose interruption in 0.9% of patients (no discontinuations), and the additional follow-up did not reveal any sudden deaths related to prolonged QT interval beyond the 1 identified in the primary analysis. Conclusions: AEs occurring with 1L RIB + LET in postmenopausal pts with HR+/HER2– ABC were manageable and the safety profile was comparable to that in the primary report. Clinical trial information: NCT01958021. [Table: see text]
A prospective, open label, multicenter, randomized phase II trial: Sequential therapy with bevacizumab, RAd001 (everolimus) and axitinib in metastatic renal cell carcinoma (mRCC) (BERAT study).
2019-05-20

e16097 Background: Inhibitors of the vascular endothelial growth factor (VEGF), its receptor (Ri) or mammalian target of rapamycin (mTORi) are components of systemic treatment in metastatic renal cell carcinoma (mRCC) and are applied in sequence. We compared the efficacy of VEGFRi and mTORi in 2 nd line after failure of bevacizumab/interferon in a phase II trial. Methods: Key inclusion criteria were: measurable mRCC (all histologies), ECOG 0-1, IMDC risk: good or intermediate, adequate organ function. Tumor status was assessed in week 11 and q12 wks., thereafter. Measures of Health-related quality of life (HR-QoL) utilized FKSI-10 and was assessed in week 4, 10 and q12 wks., thereafter. 1 st line consisted of bevacizumab 10mg/kg q2wks. + interferon 9*10 6 IE 3x/week (BEV/IFN). Upon progression or intolerance, patients were re-screened and randomized between VEGFRi (axitinib 5 mg BID, dose-escalation permitted; sunitinib 50 mg OD, 4-2 regimen) and everolimus (EVE) treatment (10 mg OD). Cross-over occurred at time of progression or intolerance. Improvement of 2 nd line PFS-rate at 6 mo. from 50% to 65% was the primary endpoint. Secondary endpoints were PFS, total PFS, ORR, OS, safety and HR-QoL. Results: Between November 2012 and June 2015 a total of 22 of 100 patients were included and at that time stopped for poor accrual. 10 pts. (46%) were randomized to receive 2 nd line treatment with everolimus (n = 5) or VEGFRi (n = 5). At study entry (2/10) 20% had nephrectomy. ECOG 0 was recorded in 20% (EVE) and 60% (VEGFRi), respectively. Objective response rate (ORR) to 1 st line BEV/IFN was 20%. In 2 nd line treatment all patients experienced adverse events (AE). Grade ≥3 AEs occurred in 2/5 (40%) (EVE) and 4/5 (80%) (VEGFRi) pts., respectively. SAEs occurred in 3/5 (60%) in each arm. ORR was 1/5 (20%) for axitinib and 0/5 (0%) for EVE. PFS rate at 180 days was 20% in each arm. Median PFS was 3.7 (EVE) and 2.2 mo. (VEGFRi) HR 1.0 (95%CI 0.26-3.85; p = 0.997). OS was comparable between arms HR 1.12 (95%CI 0.27-4.61; P = 0.872). 7 pts. crossed over to 3 rd line treatment. Conclusions: The small number of pts. randomized to EVE or VEGFRi is a major limitation of our trial, but may mirror the current change of treatment reality. However, no significant difference was detected for the PFS rate at 6 mo., indicating the limited activity of EVE or VEGFRi in 2 nd line treatment. Clinical trial information: NCT01731158.
Prediction of occult axillary metastases in treatment-naïve patients with breast cancer: A transSENTINA analysis.
2019-05-20

566 Background: Prediction of occult axillary metastases through clinical / biological parameters may allow reduction of axillary staging. This is particularly important, as systemic therapies have become more efficient. We have conducted a systematic analysis among patients undergoing axillary sentinel lymph-node biopsy (SLNB) before initiation of primary systemic therapy as part of a clinical trial (SENTINA) with the goal to identify predictors of sentinel lymph node status in a well-defined patient cohort. Methods: Patients with a clinically negative axillary status who underwent SLNB as part of the prospective SENTINA trial were included. Univariate and multivariate analyses were carried out to identify clinical / pathological parameters associated with SLN status, using logistic regression models. Model performance was assessed by ROC analyses. Calculations were performed using R version 3.5.2. Results: Arms A and B of the SENTINA study contained 1022 patients. Among 805 cN0 patients, all parameters considered relevant for this analysis were available. 527 and 278 patients presented with negative and positive lymph nodes upon SLN biopsy, respectively. Univariate regression models identified largest tumor diameter (odds ratio (OR) 1.016, p-value 0.0041), tumor type (ductal vs. lobular, OR 2.004, p 0.00234), tumor grading (low vs. high, OR 0.537, p &lt; 0.001), hormone receptor (HR) status (negative vs. positive, OR 2.668, p &lt; 0.001), HER2 status (negative vs. positive, OR 1.462, p 0.0158) as being associated with SLN status with an a &lt; 0.1. Multivariate analysis resulted in tumor diameter, HR status, HER2 status and tumor type being independently associated. These parameters were combined using stepwise (backward and forward) selection into a prediction model. This model predicted SLN status with an AUC of only 0.65. Conclusions: Using data obtained as part of the SENTINA trial we were able to build a prediction model that was able to predict SLN metastases in treatment naïve cN0 patients with limited accuracy. Additional (biological) parameters, such as response to systemic therapies (i.e. axillary conversion through PST) may be more appropriate to predict presence of occult sentinel lymph node metastases among patients with breast cancer.
Association between tumor biology and occult lymph node metastases before and after primary neoadjuvant therapy (NAT) for patients with early breast cancer.
2019-05-20

518 Background: Scientific efforts aim at a reduction of axillary morbidity through reduced axillary intervention among patients with early breast cancer. However, it is still unclear if this approach is feasible in all subtypes based on their risk of axillary involvement. We analyzed the association of tumor biology and occult axillary involvement with data from arms A and B of the SENTINA trial (Kühn T et al., Lancet Oncol 2013). Methods: Patients were included if they presented with a clinically negative axilla before NAT (arms A and B) and stratified according to tumor biology. All patients received SLNB before NAT, in cases of negative SLNB without further axillary surgery (Arm A) and in cases of positive SLNB (Arm B) with SLNB and axillary dissection after NAT. Logistic and linear regression analyses were carried out to evaluate the association between tumor biology and axillary involvement before and after NAT. Results: Of the 1022 patients in arms A and B of the SENTINA trial 926 were evaluable for this analysis. Of these, 27.9% had triple negative (TN), 16.3% hormone receptor (HR) and HER2 positive (triple positive = TP), 47.6% HR positive and HER2 negative (luminal) and 8.2% HR negative and HER2 positive (HER2) tumors. 39.7% of the luminal, 28.9% of the HER2, 19% of the TN and 47% of the TP tumors had involved SLN before NAT. Subgroup comparisons showed a significant difference between luminal and TN (p &lt; 0.0001), whereas the differences between luminal and TP (p = 0.115) and HER2 (p = 0.077) were not statistically significant. The 317 patients with involved SLN prior to NAT received SLNB and axillary dissection after completion of NAT. The analysis after NAT showed trends for lower rates of involved lymph nodes for the high-risk groups (TN 20% / TP 14.3% / HER2 8.7%) compared to luminal tumors (27.6%) without reaching statistical significance. Conclusions: Our analysis demonstrates that among patients enrolled in the SENTINA trial, patients with triple negative disease have the lowest risk for occult lymph node metastases at initial presentation. Our results do not justify more intense local intervention among patients with triple negative breast cancer.