bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical utility of routine surveillance CT/MRI imaging in patients with localized soft tissue sarcoma (STS) following curative resection.
Authors: Lim Chiew Woon , Harunal Rashid Mohamad Farid Rin , Goh Wei Lin , Tan Sze Huey , Wong Steven Bak Siew , Chan Lai Peng , Hennedige Tiffany Priyanthi , Selvarajan Sathiyamoorthy , Sittampalam Kesavan , Teh Jonathan Yi Hui , Chin Francis Kuok Choon , Tan Mann Hong , Soo Khee Chee , Teo Melissa Ching Ching , Quek Richard Hong Hui 
Published: September 2018

11069 Background: Guidelines recommend routine surveillance imaging in patients (pts) following curative resection of STS. However the benefit of such an approach is unclear. We sought to evaluate the utility of a surveillance imaging strategy in pts with localized STS treated with curative intent. Methods: Pts with localized non-indolent STS, seen between 2010 – 2016, who had undergone surgery with R0/R1 surgical margins were included. Epidemiology, treatment and relapse data were collected as was the mode of detection. We defined optimal surveillance as CT/ MRI performed at least 6-mthly following surgery; suboptimal surveillance was defined as CT/ MRI imaging performed less frequently than 6mthly. Results: Of 294 pts included, 31% (n = 92) vs 34% (n = 100) vs 35% (n = 102) had optimal, suboptimal and no routine CT/MRI surveillance imaging respectively. At a median follow-up of 27mths (range 0-79), 36% (n = 105) experienced a relapse; 43% (n = 45) local and 57% (n = 60) had metastatic relapse. More relapses were noted in the optimal surveillance group, 57% (n = 52) vs 28% (n = 28) and 25% (n = 25) in the suboptimal and no surveillance groups respectively (p < 0.001). Within each cohort, relapses detected directly by routine surveillance imaging vs outside of surveillance imaging were as follows: 35% (n = 32) / 22% (n = 20) in the optimal, 17% (n = 17) / 11% (n = 11) in the suboptimal and 0 / 25% (n = 25) in the no surveillance arms respectively. Comparing the 3 strategies, the proportion of pts who then went on to receive curative resection/ metastacectomy was not significantly different, 38% (n = 20), 57% (n = 16) and 32% (n = 8) of relapses, in the optimal vs suboptimal vs no surveillance cohorts respectively (p = 0.1). Notably, routine surveillance imaging directly leading to curative resection occurred only in 15% (n = 14) of pts in the optimal and 9% (n = 9) in the suboptimal surveillance groups. Conclusions: While an intensive routine CT/MRI surveillance imaging strategy detected more recurrences, the impact it has on subsequent resection is less certain. Optimal frequency of surveillance imaging remains unclear.
Sensitivity to chemotherapy of low-grade endometrial stromal sarcoma (LGESS) versus high-grade endometrial stromal sarcoma (HGESS).
Authors: Sanfilippo Roberta , Colia Vittoria , Fumagalli Elena , Bertulli Rossella , Morosi Carlo , Carcangiu Maria Luisa , Lorusso Domenica , Raspagliesi Francesco , Dei Tos Angelo Paolo , Casali Paolo Giovanni 
Published: September 2018

11072 Background: LGESS and HGESS are rare uterine neoplasms of endometrial stromal origin. The activity of hormonal therapy in LGESS is reported, whilst no data are available in HGESS. The activity of chemotherapy is unknown in both. We focused on LGESS and HGESS to explore their sensibility to chemotherapy Methods: Cases diagnosed with LGHSS and HGESS from 1997 at Istituto Nazionale Tumori, Milan, or within the Italian Rare Cancer Network (RTR), were reviewed. Results: We identified 39 patients (pts), 28 with LGESS (median age:43) and 11 (median age: 54) with HGESS. Seventeen LGESS pts received systemic therapy for advanced disease (1-5 lines). Eight received an aromatase inhibitor, with 2 PR, 5 SD and 2 PD; 8 received oral progestins, with 4 PR, 5 SD and 2 PD. Nine patients (6/9 in first line, 1/9 in second line and 1/9 in third line) received antracyclines +/- ifosfamide and were evaluable for response: 2 had a CR, 4 a PR and 3 a SD. Median PFS was 7,6 months. Five patients received high-dose ifosfamide (HDIFX), obtaining 2 PR and 3 SD. Five pts received trabectedin, with 1 PR, 3 SD and 1 PD. All eleven pts with HGESS received systemic therapy for advanced disease (1-5 lines). Three patients received oral progestins, with PD. Ten pts received an antracycline-based combination chemotherapy and were evaluable for response: 5 had SD and 5 had PD. Median PFS was 3 months. Four pts received HDIFX and all progressed. Four pts received gemcitabine-based chemotherapy, obtaining 1 SD and 3 PD. Five pts received trabectedin, obtaining 1 SD and 4 PD. One pt received Pazopanib, with a PR lasting 5 months. Conclusions: In this series of endometrial stromal tumor pts treated with medical therapy, chemotherapy with antracycline-based combinations resulted in some objective responses in LGESS, while it was essentially inactive in HGESS. An observational clinical study is ongoing to expand this series.
Genomic profiling of resistant tumor samples following progression on EGF816, a third generation, mutant-selective EGFR tyrosine kinase inhibitor (TKI), in advanced non-small cell lung cancer (NSCLC).
Authors: Tan Daniel Shao-Weng , Kim Dong-Wan , Leighl Natasha B. , Riely Gregory J. , Yang James Chih-Hsin , Wolf Juergen , Seto Takashi , Felip Enriqueta , Ponce Aix Santiago , Jonnaert Maud , Pan Chun , Dolan Sinead , Barretina Jordi , Moody Susan Elizabeth , Sequist Lecia V. 
Published: September 2018

11506 Background: Up to 60% of patients (pts) with NSCLC harboring an activating EGFR mutation (mut) and treated with a 1st generation EGFR TKI develop a secondary gatekeeper T790M mut. EGF816 is an irreversible EGFR TKI that is highly potent against activating mut (L858R, ex19del) and T790M mut, while sparing wild-type EGFR. As previously reported, in a Phase I dose escalation study, the overall response rate to EGF816 in pts with advanced EGFR T790M mut NSCLC was 47% and the disease control rate was 87%. However, pts ultimately develop disease progression. Tumor biopsies were obtained from pts who had progressed on EGF816 to identify mechanisms of resistance. Methods: Pts with NSCLC with locally or centrally confirmed T790M status were enrolled in this multicenter, dose escalation study to determine the safety, tolerability and antitumor activity of EGF816 (NCT02108964). EGF816 was administered at 7 dose levels ranging from of 75-350 mg QD. Following disease progression, a tumor sample was obtained and was analyzed by the Foundation Medicine next-generation sequencing (NGS) T7 panel, which interrogates 395 cancer-related genes for base substitutions, insertion-deletions, and copy number changes, as well as introns of 31 genes involved in rearrangements. Results: Tumor samples taken following disease progression on EGF816 were analyzed from 9 pts. Of the 8 pts whose tumors were T790M+ at baseline, this was detected in only 3 pts’ post-EGF816 progression samples. One patient developed an EGFR C797S mut and concurrent deletion in mTOR. Other identified alterations include BRAF fusions (n = 2) and c-MET amplification (n = 1). Only one patient was found to have concurrent TP53 mutation and RB1 truncating mutation. Individual patient response data, including duration of response, will be presented along with detailed genomic parameters. Conclusions: NGS analysis of tumors that developed resistance to EGF816 revealed multiple potential mechanisms of resistance. These data are hypothesis-generating and could lead to rational combination studies with EGF816 to improve the depth and/or duration of response to EGF816. Clinical trial information: NCT02108964.
Characterization of tumor mutation load (TML) in solid tumors.
Authors: Salem Mohamed E. , Xiu Joanne , Lenz Heinz-Josef , Atkins Michael B. , Philip Philip Agop , Hwang Jimmy J. , Gatalica Zoran , Xiao Nianqing , Gibney Geoffrey Thomas , El-Deiry Wafik S. , Tan Antoinette R. , Kim Edward S. , Shields Anthony Frank , Raghavan Derek , Marshall John 
Published: September 2018

11517 Background: Rapid advances in immunotherapy have created a need for biomarkers to improve patient treatment selection. TML is proposed as a potential predictive biomarker due to its association with tumor immunogenicity. Methods: TML was assessed in 8020 tumors from 14 different cancers using somatic nonsynonymous missense mutations sequenced with a 592-gene panel. High TML was set at ≥ 17 mutations per megabase (mt/MB) based on an established concordance ( > 99%) with MSI-High in colorectal cancer (CRC). Results: Mean TML was highest in melanoma (Mel; 21 mt/MB), NSCLC (11 mt/MB), and bladder cancer (BLC; 11 mt/MB), whereas prostate cancer (PC), pancreas adenocarcinoma (PA), and renal cell carcinoma (RCC) had the lowest levels (all 6 mt/MB). High TML was seen most frequently in Mel (36%), NSCLC (15%), BLC (15%), and anal cancer (SCCA; 9%); and least frequently in PA (1.6%) and RCC (0.5%). Primary NSCLC carried lower TML than its brain metastases (11 vs. 16 mt/MB, p < 0.001). Older age was associated with higher TML in Mel (p = 0.001), CRC (p = 0.009), breast cancer (BC; p = 0.01), and NSCLC (p = 0.02). Higher TML was seen in males than in females for Mel (p = 0.002) and NSCLC (p < 0.001). Presence of mutations in oncogenic driver genes such as EGFR, ALK, ROS1 RET fusions, cMET exon 14 skipping correlated with lower TML in NSCLC (6.9 vs. 12 mt/MB, p < 0.001), as did BRAF and NRAS mutations in Mel (17 vs. 26, p = 0.003). Conversely, mutations in tumor suppressor genes such as ARID1A (CRC, NSCLC, and BLC) and NF1 (BC, CRC, Mel, BLC, and NSCLC) were associated with higher TML (p < 0.05). MSI-high was correlated with high TML in CRC and gastric cancers (p < 0.05). Conclusions: TML varied significantly among different cancers. High TML was associated with older age, absence of oncogenic mutations and presence of tumor suppressor gene mutations. Future studies will assess the impact of TML on clinical outcome and establish its role in selecting patients for immunotherapy. [Table: see text]
Change in metabolic tumor activity on 18F-FDG PET after a single dose of cetuximab to predict for treatment benefit, PFS, and OS in patients with advanced colorectal cancer.
Authors: Van Helden Erik Jacobus , Menke Catharina Wilhelmina , Boon Eline , van Es Suzanne , Huisman Marc C. , De Groot Derk Jan , Boellaard Ronald , Van Herpen Carla M.L.- , De Vries Elisabeth , Hoekstra Otto S. , Verheul Henk M.W. 
Published: September 2018

11519 Background: Despite RAS selection, one third of patients with metastatic RAS wild-type colorectal cancer (mCRC) do not benefit from anti-EGFR inhibitors. Therefore, an additional or more accurate predictive biomarker is needed to identify patients with primary resistant mCRC. Methods: In the IMPACT-CRC trial (NCT02117466) patients with chemotherapy refractory mCRC received 500 mg/m2 cetuximab every 2 weeks. Before the first dose and just before the second dose, patients underwent a 18F-FDG PET/CT (FDG PET). PET scans were quantitatively assessed by manual tumor delineation of ≤ 5 lesions, 2 per organ. Outcome is reported in total lesion glycolysis (TLG), defined as metabolic tumor volume times mean standard uptake value of the tumor. An optimal threshold to assess metabolic response was defined as decrease in TLG ≥15%. Quantitative data were correlated with CT evaluation after 8 weeks of treatment according to RECIST v1.1. Results: Out of 35 patients, 1 was excluded due to an infusion reaction. Median age was 64 years, 74% was male, 4 patients had a BRAF mutated tumor and 9 patients had right-sided primary tumors. 62% of patients had stable disease or partial response on CT after 8 weeks. At the time of this analysis, 88% of patients had progressive disease and 71% had died. Of the patients with right-sided tumors 11% had treatment benefit, compared to 80% in the left-sided group (p = 0.001). None of the 9 metabolic non-responders had treatment benefit, whereas 83% of the metabolic responders had treatment benefit according to RECIST v1.1. After adjustment for age, WHO score, BRAF mutation, sex and primary tumor site, FDG PET response remained correlated with PFS and OS (p = 0.002 and p = 0.014). Conclusions: Early evaluation of metabolic response after 1 dose of cetuximab is highly and independently predictive for treatment benefit with a 100% negative predictive value. Implementation of early FDG-PET evaluation in daily clinical practice can prevent unnecessary toxicity, costs of ineffective treatment and allows timely treatment adjustment for patients with mCRC undergoing anti-EGFR treatment. Clinical trial information: NCT02117466.
Correlation of cell-free circulating DNA, RNA, and PD-L1 from plasma with clinical response in patients with metastatic lung and breast cancers.
Authors: Raez Luis E. , Danenberg Kathleen , Castrellon Aurelio Bartolome , Usher Joshua L. , Jaimes Yolanda S , Hunis Brian , Velez Michel E. , Habaue Cheryl , Danenberg Peter 
Published: September 2018

11550 Background: There is an unmet need to evaluate tumor response by other means than radiology tests. Changes in gene expression, allele-fractions of mutations, PDL-1 expression and levels of cell free DNA [DNA] or RNA [RNA] in plasma might be useful for monitoring disease state and predicting outcome to anti-tumoral therapy. Methods: We measured serial levels of plasma DNA/RNA in metastatic patients (pts) with NSCLC and breast cancers undergoing treatment and correlated them with response (CR/PR/SD/PD) seen by CT scans. We also monitored PD-L1 expression in NSCLC pts treated with immunotherapy. DNA/RNA were extracted from plasma. RNA was reverse transcribed with random primers to cDNA. Levels of DNA/RNA were determined by RT-qPCR. Results: 52 pts were enrolled (28 breast/24 NSCLC). Breast group: 39% (11/28) were Caucasian (NHW) and 36% (10/28) Hispanic (H). 20 pts completed first two cycles of therapy: 2 pts had PR and showed no change (NC) or decrease (DEC) in levels of DNA/RNA. 11pts achieved SD, 9 had NC levels of DNA/RNA. Pts with PD: 5/6 underwent significant increase (INC) in DNA/RNA levels. Overall, among breast pts, there was an 84% (16/19) agreement between response and levels of DNA/RNA. These were correlated with one another ( r = 0.7002, p< 0.0001). NSCLC group: 71% (16/24) were NHW and 25% (6/24) H. Non-SQCC were 87% (21/24). 20 pts had CT scans. One pt had PR with DEC levels of DNA/RNA. 10 pts achieved SD, all showed DEC or NC levels of DNA/RNA. 8 pts had PD, 6 of them had INC in DNA/RNA levels even 7 weeks prior to PD. Among NSCLC pts, there was a 90% (17/19) agreement in response and levels of DNA/RNA. These were correlated with one another ( r= 0.6231, p< 0.0001). In 5 pts PD-L1 expression remained stable when CT scans showed SD or PR. Conclusions: There is a strong correlation between clinical responses with changes in plasma levels of DNA/RNA in pts with NSCLC (90%) and breast cancer (84%). Some of these were documented weeks before imaging was done. cfRNA is as effective as cfDNA as predictive tool for response. Plasma PDL-1 expression is a new tool to monitor immunotherapy response.
Metabolic barriers to immunotherapy in renal cell carcinoma.
Authors: Beckermann Katy , Siska Peter , Mason Frank , Rathmell Kimryn , Rathmell Jeffrey C 
Published: September 2018

11560 Background: Cancer cells can inhibit effector T cells through both immunomodulatory receptors and alteration of the tumor microenvironment as a result of cancer metabolism. A majority of patients treated with immune checkpoint inhibitors recently approved by the FDA fail to exhibit a clinical response. The extent to which metabolic conditions within the tumor impede T cell activation and anti-tumor effector function in renal cell carcinoma (RCC) are unknown. Methods: Under the IACUC protocol M1600005-00, BALB/c or Rag mice were subcutaneously injected with 100,000 Renca cells obtained from ATCC and growth monitored by caliper measurements in 3 dimensions every 3 days. In vivoPD-1 blockade was performed by 200 mcg/i.p. injection every 3 days using purified mPD-1 (BioXcell, J43). Deidentified tissue donations from patients with RCC were collected under the IRB protocol #151549 and processed into single cell suspensions following mechanical dissociation for the functional assays indicated below. Results: Through work with Rag deficient mice lacking functional B and T cells, we have established that tumor growth is regulated in a T cell dependent manner as evidenced by earlier formation and faster tumor growth. In a syngeneic mouse model of RCC (RenCa), we find that inhibition of PD-1 delays tumor growth and size. Tumor infiltrating lymphocytes (TILs) were abundant in patient-derived RCC, but are phenotypically distinct and are impaired both functionally and metabolically from healthy control. Instead of efficient use of aerobic glycolysis, TILs fail to increase glucose metabolism, and instead display increased reactive oxygen species (ROS) and mitochondrial dysfunction. CD8 effector cells found in tumors have notable differences in mitochondrial morphology compared to healthy control CD8 T cells by electron microscopy and immunofluorescence where CD8 TIL are punctate and dispersed throughout the cell while healthy control CD8 mitochondria are fused in networks. Thus bypassing metabolic defects may partially restore TIL activation. Conclusions: Preclinical data suggests that improved understanding of metabolic dysfunction in TILs of RCC may allow for combined therapies to improve response rates of checkpoint inhibition in this disease.
Baseline cell-free DNA (cfDNA) and metabolic tumor volume (MTV) independently predict outcome in metastatic chemorefractory colorectal cancer (mCRC).
Authors: Woff Erwin , Kehagias Pashalina , Vandeputte Caroline , Kamoun Tarek , Guiot Thomas , Ameye Lieveke , Geboes Karen Paula , Delaunoit Thierry , Demolin Gauthier , Peeters Marc , D'Hondt Lionel A. , Janssens Jos , Carrasco Javier , Holbrechts Stephane , Goeminne Jean-Charles , Van Laethem Jean-Luc , Vergauwe Philippe , Paesmans Marianne , Flamen Patrick , Hendlisz Alain 
Published: September 2018

11569 Background: No validated prognostic biomarker is currently available for mCRC. This trial assessed cfDNA and MTV before treatment with regorafenib as prognostic biomarkers for progression-free survival (PFS) and overall survival (OS) in mCRC. Methods: After signed informed consent, mCRC patients were enrolled in a prospective non-randomized trial aiming to define unlikelihood to benefit from regorafenib (EudraCT number: 2012-005655-16) and assessed for cfDNA and FDG PET/CT MTV at baseline. cfDNA was extracted from 3mL of plasma and quantified using the Qubit 2.0 fluorometer. All target lesions were delineated on FDG PET/CT using a PERCIST-based threshold and their volumes were summed to obtain total MTV. MTV and cfDNA optimal cutoffs for OS and PFS prediction were determined by the Contal and O’Quigley’s method. MTV, cfDNA, age, gender, Body Mass Index (low, normal, high, obese), ECOG PS, number of chemotherapy lines (NCL), previous use of bevacizumab and presence of a KRAS mutation were included in a multivariate analysis. Results: MTV and cfDNA of 132 evaluable/141 eligible patients were well correlated (Spearman’s correlation coefficient = 0.70; p < 0.001) and risk groups for both PFS and OS were identified on the basis of cfDNA (cfDNA < 1 µg/mL; cfDNA≥1 µg/mL) and MTV (MTV < 100 cm³; 100-300 cm³; > 300 cm³). The multivariate analysis retained cfDNA, MTV, NCL, and obesity as independent parameters for PFS prediction, and cfDNA, MTV, NCL, BMI, and previous use of bevacizumab as independent parameters for OS prediction. Prognostic scores for PFS and OS were developed based on regression coefficients from the final Cox proportional hazards models. Prognostic scores for PFS (1.8 vs 5.3 months, HR: 3.15 for score ≥-3 vs < -3, (95% CI, 2.08-4.76); p < 0.001) and for OS (4.2 vs 13.9 months, HR: 4.59 for score ≥-6 vs < -6: (95% CI, 2.92-7.21); p < 0.001) both identified patients with much contrasted outcomes. Conclusions: Baseline cfDNA and MTV along with BMI parameters predict outcome in patients with mCRC before regorafenib onset. These parameters not related to treatment should be considered, if validated in further studies, as stratification factors in future clinical trials. Clinical trial information: 2012-005655-16.
Contribution of microarrays of gene expression (MAGE) to the definition of PET/CT as a qualified biomarker of early response in metastatic patients.
Authors: Sureda Manuel , Crespo-Jara Aurora , Gonzalez Manzano Ramon , Redal Maria del Carmen , Garcia-Cases Francisco Javier , Martinez Navarro Elena Mª , Brugarolas Antonio 
Published: September 2018

11573 Background: Proliferating cancer cells consume elevated quantity of glucose, converted into lactate regardless the presence of oxygen (Warburg effect). This effect has been useful for imaging metabolically active tumors with FDG-PET, although its use in early response is controversial. Molecular mechanisms of FDG uptake are not fully understood. We have used MAGE to determine the most relevant genes involved in FDG uptake. Methods: Fresh-frozen tumor biopsies and quantitative basal FDG-PET/CT were obtained from metastatic lesions in cancer patients. Total tumor RNA was hybridized to a whole human genome oligonucleotide microarray. Gene expression signature-based prediction, using the most relevant genes involved in FDG uptake measured by SUV, was finally determined by Partial Least Squares (PLS). The interpretation of biological phenomena (IBP) derived from the selected genes was made by means of different public statistical bioinformatics resources. Results: 71 patients with different histological diagnosis were included in the training cohort and 13 in the validation one. 909 probes correlated significantly with SUV: 333 positively and 576 negatively. A predictive signature based on these 909 probes was built using PLS-3, with an RMSE in the validation set of 0.645 (within the 95% CI of RMSE determined in the training set). In IBP, other biological processes were more relevant than glycolysis in FDG uptake: RNA processing, ribosome biogenesis, protein processing, cell adhesion, cytoskeleton organization, angiogenesis and autophagy. Conclusions: This PLS-3-built signature is the first reported one that can accurately predict SUV. FDG uptake is a complex phenomenon that involves multiple biological processes, confirming the value of PET/CT in early response.