bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of tumor responses in patients (pts) with unresectable hepatocellular carcinoma (uHCC) treated with lenvatinib in REFLECT.
Authors: Kudo Masatoshi , Qin Shukui , Piscaglia Fabio , Vogel Arndt , Evans T.R. Jeffry , Knox Jennifer J. , López López Carlos , Ramji Zahra , Ren Min , Mody Kalgi , Finn Richard S. 
Published: June 2022

4078 Background: In REFLECT, lenvatinib was noninferior to sorafenib based on overall survival in pts with uHCC (median 13.6 vs 12.3 mos; hazard ratio [HR] 0.92, 95% CI 0.79–1.06). The objective response rate (ORR) with lenvatinib was 18.8% by blinded independent imaging review (IIR) per RECIST v1.1; ORR was 40.6% by blinded IIR per mRECIST. Here we further characterize the tumor responses in pts with uHCC who were treated with lenvatinib in REFLECT. Methods: Assessments of ORR included all pts randomly assigned to lenvatinib treatment (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg). Time to first objective response (TTR) and duration of response (DOR) were calculated among pts who achieved a partial or complete tumor response. Tumors were assessed by IIR per RECIST v1.1 or mRECIST. Median DOR was estimated with the Kaplan-Meier product-limit method; 95% CI was estimated with a generalized Brookmeyer and Crowley method. Results: 478 Pts were randomly assigned to receive lenvatinib. Among the 90 pts (18.8%) who achieved an objective response by IIR per RECIST v1.1, median TTR was 2.8 mos (range 1–29) and median DOR was 7.4 mos (95% CI 5.6–9.2). Of the 194 pts who had an objective response by IIR per mRECIST, median TTR was 1.9 mos (range 1–15) and median DOR was 7.3 mos (95% CI 5.6–7.4). ORRs by selected baseline characteristics are reported in the Table. Notably, among responders by IIR per RECIST v1.1 (n=90), median overall survival (by Simon-Makuch method) was 23.4 mos (95% CI 17.6–26.3), median duration of treatment was 10.3 mos, and 65.6% of pts experienced grade ≥3 treatment-related adverse events. Conclusions: Pts with uHCC treated with lenvatinib achieved objective responses with a similar frequency to those seen with single-agent immune checkpoint inhibitors. These responses occurred irrespective of baseline characteristics. Tumor responses occurred early and were durable. Clinical trial information: NCT01761266. [Table: see text]
FGFR2 fusion detection in plasma: A new era in the clinical monitoring of iCCA.
Authors: Gonzalez-Medina Alberto , Verdaguer Helena , Vila-Casadesús Maria , Sierra Alexandre , Castillo Gloria , Fabregat-Franco Carles , Gómez-Rey Marina , Aymar Josep Maria Miquel , Macarulla Teresa , Vivancos Ana 
Published: June 2022

4085 Background: Actionable genetic alterations can be identified in over 50% of intrahepatic cholangiocarcinoma (iCCA). Since EMA approved Pemigatinib, a selective Fibroblast growth factor receptor 1-3 (FGFR1-3) inhibitor for the treatment of CCA with FGFR2 fusions or rearrangements, the screening of patients who may benefit from such targeted therapies is especially relevant. In addition, novel FGFR inhibitors that are effective for treatment of resistant mutant clones are under development. In patients with no available tissue for genomic profiling or at different timepoints after targeted therapy, NGS testing of circulating cell-free DNA (ccfDNA) would be the most convenient option. Hence, two important issues must be addressed: i) technical set-up and validation of detection of FGFR2 rearrangements in plasma, and ii) patient shedding in iCCA, in order to consider liquid biopsy for routine clinical care. Methods: We conducted a retrospective study in a cohort of 18 iCCA patients with known FGFR2 fusion or rearrangement events previously identified in tumor FFPE by NGS (FoundationOne CDx test). A custom-designed capture-based NGS panel for use in plasma or tissue (VHIO-iCCA test) was developed to detect FGFR2 rearrangements and other common altered genes in iCCA. After validating our VHIO-iCCA panel with fusion positive FFPE samples, a concordance study was conducted to evaluate the detection of FGFR2 fusion and rearrangements in matched-to-tissue timepoint plasmas. Finally, additional serial plasma samples taken during FGFR inhibitor treatment were also analyzed. Results: From the 18 rearrangement events previously detected with FoundationOne CDx, we were able to identify all 18 in FFPE samples and 15 in the paired plasma using our VHIO-iCCA panel, representing a 100% and 83% concordance, respectively. In the 3 discordant cases, no additional alterations were detected in plasma, indicating a lack of circulating tumor DNA (ctDNA) shedding. Serial sampling of these patients indicated persistent non-shedding. The analysis of fusion allele fraction (FAF) in serial plasma samples revealed that detection of fusion FGFR2 changed during treatment and correlated with best response. In general, patients with a stable FAF showed a SD, while patients which reduced FAF presented a PR. Conclusions: This extremely valuable set of cases has allowed us to validate our VHIO-iCCA panel to be used in tissue and plasma, and to determine that the sensitivity in plasma is >80%, making this a feasible option to avoid tissue biopsies, whenever patients cannot undergo the procedure and even to aid in cancer monitoring. Patient shedding is high in iCCA, yet a fraction of patients may not find a useful resource in liquid biopsy. For those who shed ctDNA, monitoring through the FAF may guide clinical management of iCCA.
Discovery and clinical validation of cost-effective noninvasive early detection of hepatocellular carcinoma (HCC) through circulating tumor DNA (ctDNA) methylation signature.
Authors: Yang Xin-Rong , Liu Rui , Zhou Jian , Fan Jia , Guo De-Zhen , Huang Ao , Wang Yingchao , Cai Zhixiong , Wang Hui , Yang Qichang , Su Zhixi , Ma Chengcheng , Xu Minjie , Li Wei 
Published: June 2022

4103 Background: Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide, especially in Asian counties. Patients can be treated more effectively if detected earlier, however the current screening strategies with alpha-fetoprotein (AFP) or ultrasound it is largely suboptimal. We aimed to develop non-invasive and cost-effective assay to improve HCC early detection. Methods: HCC-specific DNA methylation markers were screened from tissue and plasma samples through a modified reduce representation bisulfite sequencing assaay,and optimized by a targeted methylation sequencing assay. The most informative markers were then integrated in a multi-locus qPCR assay, HepaQ. Results: Profiling DNA methylation pattern on 61 tissue samples (31 HCC tumor and 30 normal tissues) and 663 plasma samples (276 HCC and 393 control plasma samples) achieved an AUC of 0.99, which corresponds to 91% sensitivity at 94% specificity. The best-performance markers were further screened and analytically verified in additional tissues and plasmas after several rounds of marker selection. A multi-locus qPCR assay, designated as HepaQ, was then developed to incorporate the most effective markers. A cohort of 559 plasma samples including 293 HCC (84% of them at stage 0/A), 60 liver cirrhosis (LC), 36 chronic hepatitis B (CHB) and 170 healthy controls (CTRL), were used to train a classifier for HCC early detection. HepaQ classifier enables to detect 85.3% of HCC under a specificity of 88.3%, 91.7% and 92.4% in LC, CHB and CTRL, respectively. Finally, HepaQ classifier was validated in 374 plasma samples independently collected from multiple clinical centers to confirm its performance of 87.2% sensitivity in HCC and 86.8%,90.5% and 93.4% specificities in LC, CHB and CTRL respectively. Conclusions: We have developed and demonstrated a blood-based ctDNA methylation assay, HepaQ, that can detect early-stage HCC at high sensitivity and specificity. We proposed that HepaQ assay, a cost-effective qPCR assay, has the great potential to benefit the population at-risk for HCC early detection and screening.
A pooled analysis of surufatinib safety from phase 3 trials in advanced NETs.
Authors: Li Jie , Xu Jianming , Shen Lin , Bai Chunmei , Zhou Zhiwei , Li Zhiping , Chi Yihebali , Yu Xianjun , LI Enxiao , Xu Nong , Liu Tianshu , Lou Wenhui , Bai Yuxian , Yuan Xianglin , Wang Xiuwen , Yuan Ying , Chen Jia , Zhang Tao , Xiu Dianrong , Su Weiguo 
Published: June 2022

4126 Background: Surufatinib is a small-molecule inhibitor of VEGFR1, 2, & 3, FGFR1, and CSF-1R. Surufatinib demonstrated prolonged PFS and tolerable safety in two phase 3 studies in advanced neuroendocrine tumors (NETs) of pancreatic (SANET-p; NCT02589821) and extrapancreatic (SANET-ep; NCT02588170) origin (Xu, 2020 Lancet Oncology). Detailed outcomes on safety from these 2 studies are reported here as a pooled analysis. Methods: Data is pooled from SANET-p and SANET-ep studies which have similar designs including a 2:1 randomization of surufatinib to placebo in patients ≥18 years with advanced, well differentiated NETs, progressing on or after ≤2 prior therapies. Surufatinib 300 mg or placebo, was administered once daily until disease progression or unacceptable toxicity. Safety outcomes for each pooled treatment group are reported as treatment-emergent adverse events (TEAE) assessed by NCI-CTC 4.03. Patients were included if they had received study treatment during the double-blinded phase of the studies. Results: As of 30th June 2020, 396 patients were assigned to the surufatinib (n = 263) and placebo (n = 133) groups. Median treatment duration was longer with surufatinib 7.4 months (range 0.1–41.4) compared with placebo 4.6 months (range 0.1–39.9). 29% of patients reached more than 12 months of treatment with surufatinib group compared to 11% with placebo. The mean relative dose intensity was 87.56% in the surufatinib group and 97.01% in the placebo group. Most common TEAEs (surufatinib vs placebo) were proteinuria 68.8% vs 54.9%, hypertension 68.4% vs 27.1%, and diarrhea 49% vs 22.6%. Most common grade ≥3 TEAE were hypertension 38.8% vs 13.5%, proteinuria 14.8% vs 0.8% and hypertriglyceridaemia 5.3% vs 0%. Deaths due to TEAEs were comparable between groups 2.7% vs 2.3%. TEAEs led to dose reductions in 43.0% vs 6.8% of patients and dose interruptions in 47.1% vs 29.3% of patients. The majority of patients (83.3% vs 93.2%) were managed without discontinuation because of TEAE. Median onset of proteinuria and hypertension were < 1 month in both groups. Median (range) onset was 0.95 months (0.16–30.36) vs 0.95 months (0.23–16.95) for proteinuria and 0.49 months (0.03–31.18) vs 0.89 months (0.03–14.75) for hypertension. Among patients with hypertension, 59% (n = 111) vs 28% (n = 11) received antihypertensive medication. Conclusions: Surufatinib was generally well tolerated in this pooled analysis and the safety profile was consistent with its previously reported data. The monitoring and management of hypertension and proteinuria are important for patients receiving surufatinib. Clinical trial information: NCT02589821; NCT02588170. [Table: see text]
Landscape of homologous recombination reversion mutations in pancreaticobiliary malignancies.
Authors: Decker Brennan James , Domchek Susan M. , Nathanson Kate , Bailey Shannon , Danziger Natalie , Thornton James , Hartman Mark , Cui Chenming , Yang Lei , Sivakumar Smruthy , Madison Russell , Sokol Ethan , Schrock Alexa Betzig , Yilmazel Bahar , Mata Douglas A , Vietz Christine , Ross Jeffrey S. , Elvin Julia Andrea , Oxnard Geoffrey R. , Reiss Kim Anna 
Published: June 2022

4156 Background: Homologous recombination (HR) pathway reversion mutations (REV) are emerging treatment resistance biomarkers for platinum and PARP inhibitor therapy. The wide diversity of REV presents a diagnostic challenge. We implemented an automated computational approach to detect REV and examined the genomic features of REV-positive pancreaticobiliary cancers. Methods: Retrospective study of tissue (n = 31,124) and liquid biopsy (n = 3,870) samples from patients undergoing hybrid-capture comprehensive genomic profiling during routine clinical care 11/2012-03/2021. A proprietary algorithm tested samples for seven distinct REV mechanisms in BRCA1, BRCA2, or PALB2. For subjects with multiple samples, the earliest REV-positive sample was used for downstream analyses. Results: 5.3% (1,866/34,994) of biliary and pancreatic primary tumors harbored one or more pathogenic variants (PV) in BRCA1 (1.4%, n = 499), BRCA2 (3.2%, n = 1,119), or PALB2 (0.81%, n = 282). Among patients with at least one PV in these genes, 2.4% (45/1,866) had REV. The majority of REV involved BRCA2 (82%, 37/45), significantly higher than the proportion of BRCA2 PV in the cohort overall (59%, 1,119/1,900; p = 0.022). The remainder of REV involved either BRCA1 (8.9%, 4/45) or PALB2 (8.9%, 4/45). A total of 63 REV pairs were identified. The most frequent REV mechanism was an exonic non-frameshift deletion completely encompassing a PV (36%, 23/63), followed by a frameshift restoring the reading frame of a pathogenic frameshift (23%, 15/63), a benign missense replacing a PV at the same codon (17%, 11/63), and deletion with intronic breakpoints causing loss of a PV (17%, 11/63). REV were approximately equally prevalent in liquid biopsy (2.8%, 5/178) and tissue samples (2.4% 40/1,688; p = 0.72). A range of 1-9 REV were found per sample (liquid biopsy = 1-9, tissue = 1-2), and liquid biopsy samples had a higher median REV per sample compared to tissue (2.0 vs. 1.0; p < 0.001), as well as a higher prevalence of multiple REV per sample (60% [3/5] vs 7.5% [3/40]; p = 0.013). These differences likely reflect stage of disease and sampling of multiple subclones. Conclusions: Although REV are uncommonly detected in pancreaticobiliary carcinomas, the presence of REV in BRCA2, BRCA1, and PALB2 in patients with pancreaticobiliary neoplasms supports HR as a therapeutic target in these cancers. Diverse REV mechanisms highlight a need for robust detection to incorporate REV in identifying treatment resistance and guiding therapy selection.
Patient-derived explant model of appendiceal cancer.
Authors: Strach Madeleine Cornelia , Yeung Nicole , Lin Hui-Ming , Ansari Nabila , Koh Cherry , Shin Joo-Shik , Kench James , Centenera Margaret , Butler Lisa , Horvath Lisa , Mahon Kate 
Published: June 2022

4160 Background: Appendiceal cancers (AC) are rare with 5-year survival of 15% for high grade (HG) adenocarcinomas and 75% for low grade (LG) mucinous neoplasms. There is limited literature on the AC tumour microenvironment (TME) in disease progression and drug resistance. Ex vivo cultures, such as patient derived explants (PDEs), have been used for other solid tumours to test anticancer agents, explore the TME, and are being developed as personalised models. The aim of our study was to develop a PDE model of AC, preserve the TME, study the biological profile of AC and test novel therapies. Methods: Fresh tissue was collected during cytoreductive surgery (CRS) from consenting patients with AC with peritoneal disease, Jul 2020-Mar 2021. Tissues from 10 patients were dissected and cultured as PDEs under varying conditions of tissue size, media, matrix support and duration (Table). Uncultured Day 0 tissues and PDEs were fixed in formalin prior to paraffin embedding (FFPE). Immunohistochemical staining was performed on sections of FFPE tissue to assess viability with antibodies against the tumour marker, Cytokeratin-20 (CK20), and cell death marker, cleaved caspase 3 (CC3). Tissue architecture was rated on a 4-point scale (MS, J-SS). Cancer cells were counted in 6 Day 0 samples and PDEs from 3 patients using QuPath v0.3.2. Apoptotic index (AI) was calculated as the proportion of cells positive for CC3 divided by the number of total CK20 positive cells. Results: The mean proportion of tumour and mucin in the tissues was 3% (0-60%) and 39% (0-95%) respectively. Day 0 samples were viable with mean AI of cancer cells 7% (0-4%). Tissue architecture was maintained, as compared to Day 0 control, for varying sizes of PDE and culture durations up to 4d. More small or medium-sized PDEs had improved architecture compared to large sized PDEs (Table). PDEs at 4d had poorer architecture compared to at 1-3d. There was improved architecture in PDEs using enriched media with support factors compared to base media, and in specimens with matrix support compared to none. The mean AI of PDE cancer cells was 21% (0-92%) and 51% of PDEs had no cancer cell death. Conclusions: This is the first study demonstrating that AC tissue is amenable to ex vivo culture as PDEs. The optimal PDE model was <10mm tissue placed on a gelatine sponge in enriched media for 1-3d. PDEs had preserved tissue architecture and viability compared to uncultured tissue. Protein expression was in keeping with the original tumour. We plan to use this model to test anticancer agents and explore the TME of AC.[Table: see text]
Cell-free DNA methylation as a predictive biomarker of response to neoadjuvant chemotherapy for patients with muscle-invasive bladder cancer in SWOG S1314.
Authors: Lu Yi-Tsung , Plets Melissa , Morrison Gareth , Cunha Alexander T. , Cen Steven Y. , Rhie Suhn K. , Siegmund Kimberly , Daneshmand Siamak , Quinn David I. , Meeks Joshua J , Lerner Seth P. , Petrylak Daniel P. , McConkey David James , Flaig Thomas W. , Thompson Ian M , Goldkorn Amir 
Published: June 2022

4506 Background: Neoadjuvant chemotherapy is the standard of care in muscle-invasive bladder cancer patients. However, treatment is intense, the overall benefit is small, and there is no established marker to identify patients who benefit most. The aim of the study is to characterize cell-free DNA (cfDNA) methylation from patients receiving neoadjuvant chemotherapy in SWOG S1314, a prospective cooperative group trial, and to correlate the methylation signatures with pathologic response. Methods: Blood samples were collected prospectively from 73 patients before and during standard neoadjuvant chemotherapy. At radical cystectomy, pathologic response was documented. Plasma cfDNA was profiled using Infinium MethylationEPIC BeadChip array. Differential methylation between pathologic responders (≤pT1N0M0) and non-responders was analyzed, and a Random Forest model was used to generate a classifier predictive of treatment response. Results: Using pre-chemotherapy plasma cfDNA, we developed a methylation-based response score (mR-score) predictive of pathologic response. The mR-score also could be calculated using plasma samples collected after the first cycle of neoadjuvant chemotherapy, resulting in a similar predictive ability. Furthermore, we used cfDNA methylation data to calculate the circulating bladder DNA fraction, which had a modest but independent predictive ability for treatment response. When we combined the mR-score and circulating bladder DNA fraction, we successfully predicted pathologic response outcomes in 79% of patients based on their plasma collected before chemotherapy and after 1 cycle of chemotherapy. Conclusions: Our study provides proof of concept that cfDNA methylation may be used to predict treatment response in bladder cancer patients receiving neoadjuvant chemotherapy. Clinical trial information: NCT02177695.
TRUCE-02: An open label, single-arm, phase II study of tislelizumab combined with nab-paclitaxel for high-risk non-muscle-invasive urothelial bladder carcinoma.
Authors: Wang HaiTao , Hu Hailong , Niu Yuanjie , Tian Dawei , Shen Chong , Da La , Wu Zhouliang , Zhao Gangjian , Zhou Diansheng , Bai Yiduo , Chen Houyuan 
Published: June 2022

4507 Background: Pts with multiple or tumors with large invasion areas which are un-completely-resectable through TURBT would be recommended radical cystectomy in the clinical treatment. The KEYNOTE-057 study has illuminated the efficiency of immune checkpoint inhibitors monotherapy in HR-NMIBC pts, with acceptable adverse events (AEs). However, the role of PD-1/PD-L1 inhibitor in combination with chemotherapy in NMIBC pts remains unclear. We report preliminary treatment efficiency, safety data, and exploratory work of TRUCE-02 trial. Methods: TRUCE-02 is a phase II study for NMIBC pts with uncompletely resectable tumour by TURBT. The primary endpoint was complete response(absence of non-muscle-invasive bladder cancer or progressive disease). Pts that meet the criteria would receive tislelizumab 200mg on days 1 plus paclitaxel 200mg on days 2 every 3 weeks (Q3W) x 3 or 4 cycles followed by a comprehensive assessment including pathology, urine cytology, and imageology. Meanwhile, biomarker analyses included programmed death-ligand 1 (PD-L1) expression using the combined positive score (CPS; Dako 22C3 pharmDx assay) and whole transcriptome RNA sequencing of the tumor. Results: Between July 2020 and January 2022, 54 pts were enrolled. 42 pts have completed whole 3 or 4 treatment cycles and reached the primary endpoint. 23 pts achieved CR condition (56%, 95%CI, 43.6% and 74.4%). ORR of 60% (N=25/42, 95%CI, 45.2% and 74.8%). As a secondary endpoint, 33 pts remain cystectomy-free condition (78.6%, 95%CI, 66.2% and 91%). Grade 3-4 AEs were lower than 2%. Urine cytology showed its diagnostic efficiency of 68.42% (95%CI, 61.3% and 75.6%), urine FISH showed a diagnostic efficiency of 45.71% (95%CI, 37.7% and 53.4%) before pathological assessment. As for PD-L1 expression, 47.3% (N = 9/19) of response pts (CR+PR) showed positive, 50% (N = 5/10) of un-response pts (PD+SD) showed positive. We also found out through sequencing results that AR, TCF7L2 might be underlying markers that predict adverse outcomes for pts in this crew. HRR mutation may predict a positive prognosis and mutations in NMIBC which might predict the prognosis of this treatment plan. Conclusions: Tislelizumab with nab-paclitaxel represents a novel treatment option with a satisfactory benefit in treating NMIBC. PD-L1 expression has no obvious correlation with the efficiency of this treatment plan. WGS result also showed that there are mutation markers that may predict whether pts would benefit from this treatment plan. Clinical trial information: NCT04730232. [Table: see text]