bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differences of US-FNA BSRTC class, postoperative pathology, and mutation landscape of thyroid nodules between China and other countries.
Authors: Song Yuntao , Liu Jie , Wang Weiran , Ma Tonghui 
Published: June 2021

3055 Background: Ultrasound and ultrasound-guided fine needle aspiration (US-FNA) are the first choice for judging benign and malignant thyroid nodules. This study will report on the differences of US-FNA BSRTC class, postoperative pathology and mutation landscape of thyroid nodules between China and other countries. Methods: We conducted a prospective study containing 383 FNA samples of thyroid nodules. For most of these FNA samples, genomic DNA and RNA were extracted and sequenced with FSZ-Thyroid NGS Panel V1, and postoperative pathology were followed up. Moreover, we also compared results of this study with those of West China Hospital in China, Yamashita Thyroid Hospital in Japan, and Cleveland Clinic in the United States. Results: Among the 383 FNA samples, the proportions of BSRTC class I to VI were 10.7%, 6.3%, 18.8%, 3.7%, 12.3%, and 48.3% respectively. Compared with study in other countries, the proportion of class II was significantly lower than that in Japan and the United States. Meanwhile, the proportion of class V and VI were significantly higher than the above two countries. Subsequently, 232 thyroid nodules were surgically removed. Postoperative pathology showed that the proportion of malignant tumors (85.3%) was also significantly higher than reported in Japan and the United States. But compared with other studies in China, there was no significant difference. Most of the malignant tumors were papillary thyroid cancer (PTC, 96%), accompanied with 2 follicular thyroid cancer (FTC), 3 medullary cancer (MTC) and 3 anaplastic thyroid cancer (ATC). Compared with study in the United States, the proportion of PTC and FTC were elevated (96% vs. 85.3%) and reduced (1% vs. 9.3%) respectively. At last, we also analysis the mutation landscape of 180 malignant tumors. Compared with TCGA study, the frequency of BRAF V600E in PTC in our study was significantly higher than that of TCGA (73.3% vs. 58%), and the frequency of RAS mutation was significantly lower (1.2% vs. 12.6%). And compared with an institutional experience of ThyroSeq v3 for Bethesda III and IV at the University of Pittsburgh Medical Center, the frequency of BRAF V600E and RAS mutation in Bethesda III-IV malignant tumors was also significantly higher (45.8% vs. 1.4%) and lower (8.3% vs. 47.1%). Conclusions: There were significant differences in BSRTC class and postoperative pathology between China and other countries, such as Japan and the United States. The possible reasons included that the indications for FNA in China were different. For example, most of patients who underwent FNA in this study had suspicious clinical/ultrasound features. So the proportion of BSRTC class V and VI as well as the malignant rate were elevated. On the other hand, more BRAF V600E and less RAS mutations were detected in malignant tumors in this study which might result from racial differentiation and discrepancy in proportion of PTC and FTC.
First-in-human study of PM14 in patients with advanced solid tumors.
Authors: Vieito Maria , Ponce Aix Santiago , Paz-Ares Luis G. , Bahleda Rastilav , Massard Christophe , Agreda Leyre , Banus Eva , Fernandez Cristian Marcelo , Cristoveanu Elena Y , Corral Gema , Llanero Lourdes , Lubomirov Rubin , Kahatt Carmen Maria , Fudio Salvador , Nieto Antonio , Cullell-Young Martin , Zeaiter Ali Hassan , Oberoi Honey Kumar , Garralda Elena 
Published: June 2021

3078 Background: PM14 is a new chemical entity that forms DNA adducts which specifically inhibit RNA synthesis and block active transcription of protein-coding genes. Antitumor activity has been demonstrated in vitro in several cell lines (e.g. lung, kidney, prostate), and in vivo in mice bearing xenografted human-derived tumors (soft tissue sarcoma, small cell lung cancer, ovarian, gastric, breast and renal cancer). Methods: Open-label, dose-escalating, phase I trial of PM14 administered as a 3-hour infusion i.v. every 3 weeks (q3wk) in patients (pts) with advanced solid tumors, adequate organ function and ECOG PS score of 0-1. Two schedules were explored: Schedule A (Day 1 [D1], Day 8 [D8]) and Schedule B (D1). Results: 37 pts were treated (Schedule A/B: 28/9 pts). Baseline characteristics of pts (A/B): median age 56/47 years; male 57%/56%; ECOG PS 0: 57%/56%; median of prior lines (range): 3 (1-8)/4 (1-10). Most common tumor types (A + B): STS (n=7 pts), ovarian (n=6), pancreatic (n=4), prostate cancer (n=3). The maximum tolerated dose was 4.5 mg/m2 for A (dose-limiting toxicities [DLTs]: D8 omission due to lack of recovery of lab parameters for re-treatment [n=2 pts]) and 5.6 mg/m2 (DLTs: G4 febrile neutropenia [n=1], G4 transaminase increase [n=1]) for B. The recommended dose (RD) was 3.0 mg/m2 on D1,D8 (A), and 4.5 mg/m2 on D1 (B). No DLTs were present at the RDs. Most common toxicities were hematological abnormalities and transaminase increase. Main toxicities at the RDs are shown below. Antitumor activity comprised stable disease ≥4 months in 7 heavily pretreated pts (6 in A; 1 in B) at all dose levels. Linear pharmacokinetics were observed for PM14 at tested doses (0.25-5.6 mg/m²), with geometric mean (CV%) total plasma clearance 5.9 L/h (88%), volume of distribution 128 L (81%) and median (range) terminal half-life 15.9 h (7.5-34.3 h). Less than 1.6% of administered dose was recovered in urine. Conclusions: RDs were determined for two PM14 schedules in pts with advanced solid tumors. At the RDs, PM14 is well tolerated and has a manageable safety profile. An expansion phase in specific tumor types, with an optional Bayesian continual reassessment method for RD fine-tuning, is ongoing with both schedules.[Table: see text]
Phase 1b/2 SEASTAR trial: Safety, pharmacokinetics, and preliminary efficacy of the poly(ADP)-ribose polymerase (PARP) inhibitor rucaparib and angiogenesis inhibitor lucitanib in patients with advanced solid tumors.
Authors: Dumbrava Ecaterina Elena , Shapiro Geoffrey , Bendell Johanna C. , Yap Timothy A. , Jeselsohn Rinath , Lepley Denise M. , Hurley Sabrina , Lin Kevin K. , Liao Michelle , Habeck Jenn , Enke Aaron , Hamilton Erika P. 
Published: June 2021

3102 Background: Lucitanib is an oral, potent tyrosine kinase inhibitor that selectively inhibits VEGFR1–3, PDGFRα/β, and FGFR1–3. In preclinical studies, antitumor activity of rucaparib is enhanced by lucitanib through antiproliferative, antiangiogenic, and immunological mechanisms. We hypothesize that combining lucitanib and rucaparib is tolerable and can induce a higher hypoxic state and homologous recombination repair deficiency that may lead to greater sensitivity to PARP inhibition. Methods: Patients with advanced solid tumors who had ≥1 prior line of therapy were eligible. Patients with BRCA1/2-mutated ovarian cancer must have received prior PARP inhibitor. Rucaparib and lucitanib were escalated using a 3+3 phase 1b dose-escalation design from starting doses of 300 mg BID and 4 mg QD, respectively. Dose-limiting toxicities (DLTs) were assessed during the first 28 days of treatment. Plasma samples were collected for pharmacokinetic analyses. Genomic alterations were identified by local testing, or through central testing of plasma or tumor tissue. Results: As of February 1, 2021, 16 patients were treated with rucaparib + lucitanib and included in the analyses (Table). Patients had a median of 4 prior therapies; 1 patient had prior PARP inhibitor (olaparib) treatment. Median time on treatment was 58.5 days, with 2 patients ongoing as of the data cutoff date. A DLT of grade 3 proteinuria was seen in Cohort 1; no other DLTs have been reported. Across all cohorts, the most common any-grade treatment-emergent adverse events were nausea (n=9; grade ≥3, n=1), hypertension (n=8; grade ≥3, n=2) and ALT/AST increased (n=7; grade ≥3, n=3). Initial pharmacokinetic data indicated no drug interactions between the 2 agents. To date, 1 patient in Cohort 1 with PALB2-mutated advanced endometrial cancer had a confirmed partial response per RECIST v1.1, lasting 30 weeks; 6 patients had RECIST v1.1 stable disease (SD), including 1 patient each in Cohorts 1 and 3 with SD for ≥16 weeks. In addition, 1 patient in Cohort 2 with BRCA2-mutated castration-resistant prostate cancer continued to receive treatment despite initial progressing bone metastases, resulting in a prostate-specific antigen response (≥50% change) lasting 16 weeks and a best change in sum of target lesions of −46.3%. Conclusions: Initial findings suggest that rucaparib + lucitanib has an acceptable safety profile. The safety and efficacy of the combination are being further evaluated. Clinical trial information: NCT03992131. [Table: see text]
WX390, a high-potent PI3K-mTOR dual inhibitor, first-in-human (FIH) phase I study in advanced relapsed or refractory solid tumor, and lymphoma.
Authors: Tang Wenbo , Guo Ye , Xue Liqiong , Peng Wei , Ge Xiaoxiao , Xue Junli , Wei Wei , Xu Juncai , Li Yongguo , Li Jin 
Published: June 2021

3106 Background: WX390 is a high potent PI3K-mTOR dual inhibitor targeting pan-PI3K and mTOR. WX390 exhibited anti-tumor activity and high potency in xenograft models with inhibition of AKT phosphorylation. Methods: Patients (pts) with advanced lymphoma and solid tumors who have failed standard therapies were enrolled in dose escalation cohorts and received WX390 administered daily orally in 28-day cycles until confirmed progressive disease, intolerable toxicity or withdrawal of consent. Plasma samples were collected up to 7 days after the first dose and up to 24 hours at C1D28. Results: As of the cut-off date 2021 Feb 10, 25 patients (median age 52 years) were enrolled in 6 dose levels (0.1mg, 0.2mg, 0.4mg, 0.7mg, 1.1mg and 1.4mg) of the dose-escalation cohorts. Cohorts 0.1 mg to 1.1 mg were completed without dose-limiting toxicities (DLT), cohort 1.4 mg was completed with 1 DLT (Diabetic ketoacidosis combined with grade 3 hyperglycemia) out of 4 evaluable patients. Common treatment-related adverse events (TRAEs) (all grades, ≥20%) included hyperglycemia (20 pts, 80%), proteinuria (10 pts, 40%), creatinine increased (11 pts, 44%), hypophosphatemia (10 pts, 25%), anemia (8 pts, 33.3%), thrombocytopenia (7 pts, 29.2%), and aspartate aminotransferase increased (25%). Grade≥3 TRAEs were hyperglycemia (7 pts, 28%, 1 pt combined with diabetic ketoacidosis), hypophosphatemia (2 pts, 8%), neutropenia (2 pts, 8%), dermatitis (1 pt, 4%), and maculopapular rash (1 pt, 4%). PK showed fast absorption (Tmax 0.5-4 h) and dose proportionality for Cmax and AUC0-∞. The mean multiple dose T1/2 was approximately 12.4 hours across all cohorts with minimum accumulation. Among 14 tumor response evaluable patients, there were 3 patients with confirmed PIK3CA mutation. All 3 patients experienced tumor shrinkage and were still on treatment by the cut-off date. 2 (1 pt with head and neck cancer and 1 pt with cervical cancer) of them have achieved partial response (PR). The head and neck cancer patient (PR) was treated with WX390 0.7mg/day without any severe AE and the duration of response was beyond 15 months. Stable disease (SD) was observed in 6 patients (n = 5 with unknown PIK3CA mutation status and n = 1 with confirmed PIK3CA mutation). Of note, 1 patient (follicular lymphoma) treated with 0.1mg experienced SD for 14 months. Another patient (SD, head and neck cancer with PIK3CA mutation) experienced tumor shrinkage for more than 8 months and was still receiving WX390 treatment by the cut-off date. Conclusions: the PI3K-mTOR dual inhibitor WX390 was well tolerated with manageable safety profile, and showed encouraging antitumor activity. A RP2D of 1.1 mg qd is selected to be explored for different indications in solid tumor clinical studies. Clinical trial information: NCT03730142.
The mutational landscape of the sensitivity of cancer to ionizing radiation.
Authors: Gopal Priyanka , Yard Brian , Petty Aaron , Castrillon Jessica , Patel Jyoti D. , Abazeed Mohamed E. 
Published: June 2021

3129 Background: The impact of common or rare gene mutations on the sensitivity of cancers to ionizing radiation remains largely unknown. We conducted a systematic, arrayed (single variant per well) profiling effort to identify gene mutations that alter cellular sensitivity to radiation and validated some of our findings using a clinical cohort of patients who received thoracic radiotherapy alone. Methods: Candidate mutations were prioritized on the basis of genotype-phenotype associations from our previously completed large-scale cancer cell line irradiation profiling study (doi: 10.1038/ncomms11428), location within conserved protein domains, and functional impact (MutationAssessor). We used site-directed mutagenesis to generate mutant clones (2 clones per variant) and transferred the ORFs into lentiviral vectors in SV40 lung primary immortalized cells (BEAS2B). For clinical validation, an IRB-approved study was used to identify patients treated with lung radiotherapy alone. 197 patients with primary (stage I–IV) or recurrent lung cancer and patients with other cancer types and solitary metastases or oligometastases to the lung were included. Death without evidence of local failure was treated as a competing event, and Fine and Gray regression modeling was used to examine potential predictors of local failure. Results: Over 600 cancer variants were tested in ̃1200 experimental replicates, comprising 91 genes. We identified known and new radioresistant and radiosensitive variants involved in several cellular functional categories including cellular signaling, cytoskeleton, cell cycle, apoptosis, DNA methylation, and DNA repair. Variants that conferred resistance in BEAS2B cells were significantly more likely to confer resistance in TERT-HU1 and NCI-H520 cells, suggesting that most functional variants are cellular context indifferent. Variants under somatic oncogenic selection (hotspot mutants) were significantly more likely to confer resistance to radiation. Several infrequent cancer variants ( < 1% prevalence in cancer), including those in ERBB3, SMAD4, TGFBR1, VHL, CTNNB1, and MAP2K1, conferred radiation resistance. Some genes (e.g. KEAP1) demonstrated significant intragenic allelic variation in the magnitude of conferred resistance and other genes (e.g. CTNNB1) displayed both resistance and sensitivity in a protein domain-dependent manner. KRAS (resistant; HR 2.23; P= 0.02) and CTNNB1 exon 3 (sensitive; HR 0.3; P = 0.04) mutants conferred resistance and sensitivity, respectively, to radiotherapy in our clinical cohort. Conclusions: We report on a large-scale profiling effort to identify mutant alleles that govern radiation survival. Our results reveal new insights into potentially actionable determinants of tumor sensitivity to radiotherapy and accelerate clinical validation of common and rare gene mutations that impact radiation sensitivity.
Multimodal circulating tumor DNA (ctDNA) colorectal neoplasia detection assay for asymptomatic and early-stage colorectal cancer (CRC).
Authors: Lee Jeeyun , Kim Hee C , Kim Seung Tae , He Yupeng , Sample Paul , Nakamura Yoshiaki , Raymond Victoria M. , Jaimovich Ariel , Talasaz AmirAli 
Published: June 2021

3536 Background: To improve average risk CRC screening compliance, additional options are needed, especially options that address patient and provider reported barriers such as time and convenience. LUNAR-2 is a multimodal blood-based colorectal neoplasia detection assay incorporating ctDNA assessment of somatic mutations and tumor derived methylation and fragmentomic patterns, aimed to maximize sensitivity for early stage CRC detection. We evaluated this test in a large patient cohort with newly diagnosed CRC. Methods: Individuals diagnosed with CRC between 2013-2016 consented to provide blood samples prior to surgical resection. Those treated with neoadjuvant chemotherapy were excluded. Isolated plasma samples (median 3mL from EDTA) from 434 individuals were analyzed with LUNAR-2 (Guardant Health, USA) and included in the analysis. Median age at CRC diagnosis was 63 years (range 28 - 89) and 41% were female. Control samples were from 271 age-matched cancer free individuals. “ctDNA detected” and “ctDNA not detected” results were generated by a model trained on a separate sample set (N=614) from both cancer free individuals and those with CRC. Calling threshold was determined based on this held-out set to target 90% specificity. ctDNA results and clinical characteristics were correlated. Results: Overall CRC sensitivity was 91% (393/434), with high sensitivity across all stages; 88% Stage I/II, 93% Stage III (Table). Specificity was 94% (255/271). There was no difference in sensitivity when excluding those with early (<45 years) or late (>84 years) onset CRC (90% sensitivity; 388/429; p=0.95; 88% Stage I/II, 93% Stage III). There were no differences in sensitivity for asymptomatic CRC (88%) compared to symptomatic CRC (91%; p=0.4; Table). However, higher cell-free DNA tumor fractions were observed in the symptomatic cohort. Sensitivity for detection of right-sided and left-sided CRC was similar (93% vs. 90%; p=0.5; Table). Conclusions: In this large early-stage CRC cohort, multimodal ctDNA assessment has high sensitivity for CRC detection with high specificity. Equivalent sensitivity in the asymptomatic cohort suggests this test will have clinically meaningful performance in an average risk screening population. A prospective registrational study is ongoing to evaluate the test in an average risk CRC screening cohort.[Table: see text]
Characteristics of patients (pts) and prognostic factors across treatment lines (TL) in metastatic colorectal cancer (mCRC): An analysis from the Analysis and Research in Cancers of the Digestive System (ARCAD) database.
Authors: Bachet Jean-Baptiste , Chibaudel Benoist , Rakez Manel , Goldberg Richard M. , Tebbutt Niall C. , Van Cutsem Eric , Haller Daniel G. , Hecht J. Randolph Randolph , Mayer Robert J. , Lichtman Stuart M. , Benson Al , Sobrero Alberto F. , Tabernero Josep , Adams Richard , Zalcberg John Raymond , Grothey Axel , Yoshino Takayuki , Shi Qian , De Gramont Aimery 
Published: June 2021

3575 Background: Pts with mCRC frequently receive ≥1 sequential treatment TL. Approximately 50%-60% of pts receive second-line (L2) and 20%-30% third-line (L3) regimens in routine practice. We investigated the pts clinical/tumor characteristics and their prognostic impact across TL. Methods: Data from 37,560 pts enrolled in 48 randomized trials (34 in first (L1), 9 in L2, and 5 in L3) were analyzed. Candidate variables (VAR) measured at enrollment were sex, age, body mass index, performance status (PS), bilirubin, hemoglobin (Hb), platelets (Pl), derived white blood cells-to-absolute neutrophil counts ratio (WBC/ANC), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), primary tumor location, and number and location of metastatic sites (MS). Missing data were imputed. VAR with significant value at all TL were selected to construct a prognostic score of overall survival (OS) in training set (TS, n=30,050; 80%). For each TL, the score was calculated as the sum on the estimations of the VAR’ coefficients from the common multivariate model; Cox’s model was used to define risk groups. The discrimination capability was assessed using the Harrell’s C-index. External validation was done in the validation set (VS, n=7,510; 20%). Results: A total of 26,974 pts in L1, 7,693 pts in L2 and 2,893 pts in L3 were analyzed. The following characteristics increased continuously over TL: ≥2 MS (57%, 72%, 82%), lung metastases (50%, 74%, 91%), lymph nodes metastases (51%, 61%, 80%), KRAS mutation (37%, 47%, 51%) and elevated ALP (46%, 52%, 61%). BRAF mutation decreased (9%, 7%, 5%). In L1 vs L3 trials, 70% vs 89% of patients had primary tumor resection, 10% vs 80% had at least one metastasectomy and 31% vs 78% had a late metachronous (>12 months) metastasis. 7 independent VAR were retained in the prognostic score (PS, Hb, Pl, WBC/ANC, LDH, ALP, and the number of MS); four pt groups with significantly different prognoses were defined (table). This score remained valid when excluding pts with PS 2. Third-line oral drugs (vs placebo) and subsequent line (L2/L1 or L3/L2) were effective in all prognostic groups. Conclusions: Clinical/tumor pt characteristics significantly varied over subsequent TL in patients included in randomized trials. The same prognostic model using practical clinical and biological variables can be used in all TL.[Table: see text]
A phase 1 first-in-human study of the anti-LAG-3 antibody MK4280 (favezelimab) plus pembrolizumab in previously treated, advanced microsatellite stable colorectal cancer.
Authors: Garralda Elena , Sukari Ammar , Lakhani Nehal J. , Patnaik Amita , Lou Yanyan , Im Seock-Ah , Golan Talia , Geva Ravit , Wermke Martin , De Miguel Maria , Palcza John , Jha Sujata , Chaney Marya F. , Healy Jane Anne , Falchook Gerald Steven 
Published: June 2021

3584 Background: Patients (pts) with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) that progressed on ≥2 prior therapies have limited treatment options, with median OS ranging from 6-9 months (mo). In the dose-escalation phase of this first-in-human multicohort study (NCT02720068), the anti-lymphocyte activation gene (LAG)-3 antibody favezelimab (fave) was well tolerated alone and with pembrolizumab (pembro) across all dose levels (Lakhani, SITC, 2018, abstract O26). Here, we evaluate the safety and efficacy of fave alone or in combination with pembro in pts with advanced MSS CRC from the dose confirmation phase. Methods: Eligible pts with MSS PD-1/PD-L1-treatment-naïve mCRC that progressed on prior standard-of-care (3L+) were enrolled (cohort A) to receive the RP2D of 800 mg fave alone (Arm 1), 800 mg fave + 200 mg pembro (Arm 2C), or 800 mg fave + 200 mg pembro (MK-4280A) co-formulation (Arm 5), all Q3W. Treatment continued for 35 cycles or until progression, unacceptable toxicity, or investigator/pt decision. Pts with confirmed progression per irRECIST v1.1 on fave alone could crossover to 800 mg fave + pembro. Safety was assessed in all treated pts; efficacy in the full analysis set (FAS) of all treated pts with baseline scan. Objectives included safety (primary), ORR (RECIST v1.1 by investigator [secondary]), and DOR, PFS, and OS (exploratory). Interim analysis data cut-off was: Oct. 23, 2020. Results: A total of 20 pts received fave (Arm 1); 89 pts (including 9 crossover) received fave + pembro (Arms 2C+5); 12 pts (Arm 1) and 36 pts (Arms 2C+5), had PD-L1 CPS ≥1 tumors. At data cut-off, median follow-up was 5.8 months (mo) in Arm 1 and 6.2 mo in Arms 2C+5. Treatment-related adverse events (TRAEs) were 65% with fave (Arm 1) and 65.2% with fave + pembro (Arms 2C+5). Grade ≥3 TRAEs were 15% (Arm 1), and 20% [Arms 2C+5]). No grade 5 TRAEs were reported. Common TRAEs (≥15%) included fatigue (20.0%), nausea (15%) with fave, and fatigue (16.9%) with fave + pembro. Confirmed ORR was 6.3% (4PR, 1CR) with fave + pembro (Arms 2C+5). No pt receiving fave alone responded. In Arms 2C+5, median DOR was 10.6 mo (range, 5.6-12.7). ORR, OS and PFS by PD-L1 status are reported in the Table. Conclusions: Favezelimab alone or in combination with pembrolizumab had a manageable safety profile, with no treatment-related deaths. Promising antitumor activity was observed with combination therapy, including with MK-4280A, compared with monotherapy most notably in pts with PD-L1 CPS ≥1 tumors. Clinical trial information: NCT02720068. [Table: see text]