bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and biomarker analysis of neoadjuvant carrizumab plus apatinib in patients with local advanced biliary tract cancers.
Authors: Rao Jian-hua , Wu Chen , Zhang Hui , Wang Xuehao , Lu Ling , Cheng Feng , Chen Dongsheng 
Published: June 2021

e16126 Background: Camrelizumab (anti-PD-1 antibody) plus apatinib (VEGFR2 inhibitor) as combination therapy is highly effective in advanced osteosarcoma, hepatocellular carcinoma and extensive-stage SCLC. This study aimed to access the efficacy, safety and explore predictive biomarkers of neoadjuvant carrizumab plus apatinib in local advanced biliary tract cancers (BTCs) (ChiCTR2000034283). Methods: This single-arm, phase II trial enrolled patients with local advanced BTCs. Patients received camrelizumab 200 mg every 2 weeks plus apatinib 250 mg once per day for two cycles, clinical response was then evaluated. Gene expression profiling (GEP), using the 289-gene immune-related RNA panel sequencing, was performed on baseline tumor samples. Differential gene expression analysis was performed between responder (partial response and complete response) and non-responder (stable disease and progressive disease) using Wilcoxon rank-sum test. Results: Across these patients with local advanced BTCs, neoadjuvant camrelizumab plus apatinib demonstrated antitumor activity. Seventeen (n = 13 gallbladder carcinoma; n = 4 cholangiocarcinoma) response-evaluable patients received two cycles of combination therapy, of whom 12 (70.5%) patients achieved objective response, including 2 (11.7%) with complete response, and the DCR was 76.4%. To further assess the impact of the tumor microenvironment on the combination therapy response, we sequenced baseline tumor samples performed biomarker analyses using the 289-gene immune-related RNA panel. Of all enrolled patients with evaluable responses, 16 (94.1%) patients had available GEP data. Baseline tumor samples on differential genes revealed a significantly higher S100A8 (P = 0.004), IL1B (P = 0.002), KIR2DL3 (P = 0.007) expression in non-responders compared with responders. Extensive analyses on immune cell types were also performed. ECMES positive exhausted CD8 T cells (P = 0.009) and SIGLEC5 positive neutrophils (P = 0.0014) were significantly increased in baseline non-responders. In contrast, no significant differences of CD8 positive T cells, B-cells, cytotoxic cells, dendritic cells, macrophages cells or NK cells were found at baseline between groups. Meanwhile, signature scores were calculated using the Gene Set Variation Analysis package with publicly available gene signatures between responder and non-responder groups, and no noteworthy differences were found in TILs score, Cytolytic activity score, IFN-γ signature and Teff score. Conclusions: Neoadjuvant camrelizumab plus apatinib exhibited promising antitumor activity in patients with local advanced biliary tract cancers. Elevated S100A8, IL1B, KIR2DL3 expression levels may indicate resistance in clinical response. Increased ECMES positive exhausted CD8 T cells and SIGLEC5 positive neutrophils were predictive of response in non-responder tumors.
Updated results of the phase II ALTER-H003 trial: Anlotinib plus toripalimab as a first-line treatment for patients with unresectable hepatocellular carcinoma.
Authors: Lin Haifeng , Ma Jie , Zhuo Manyun , Zhang Chengsheng , Luo Jingru , Zhuang Xiaohong , Zeng Zhiming , Yang Lihua 
Published: June 2021

e16130 Background: The combination therapy of anti-angiogenic with anti-PD-1 /L1 agents has represented superior efficacy over sorafenib in the first-line treatment for unresectable HCC (uHCC). There are unmet medical needs due to limited options. Anlotinib is a novel oral multi-targeted tyrosine kinase inhibitor for tumor angiogenesis and proliferation, and has been approved for treatment of several malignancies in China. Toripalimab is a humanized IgG4 mAb against PD-1. Now we present the updated results with more patients enrolled and longer follow-up of ALTER-H003 to evaluate the efficacy and safety of anlotinib plus toripalimab as the first-line regimen for uHCC. Methods: This was a single-arm, multicenter, phase II trial. 30 patients (pts) with uHCC, previously untreated, Child-Pugh ≤7 and ECOG PS <2 will be enrolled. Pts received anlotinib (12 mg, p.o., qd, d1-14, q3w) and toripalimab (240 mg, iv, d1, q3w) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed by investigator according to mRECIST and irRECIST. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DoR) and safety. Results: By the cutoff date of January 21, 2021, 18 pts were enrolled and durations of treatment ranged from 0.1+ to 7.4+ months, 13 pts were still on treatment. 14 pts were evaluable, confirmed ORR and DCR was 21.4% (95% CI 4.7%-50.8%) and 92.9% (95% CI 66.1%-99.8%) respectively according to mRECIST. one patient achieved a complete response (CR), and one additional patient remained on treatment with unconfirmed PR. The median duration of response (DoR) has not been reached and DoRs ranges from 2.4m to 4.9m. 14 of 18 pts (77.8%) experienced treatment-related adverse events (TRAEs), Grade 3 TRAEs occurred in 7 pts (38.9%). Immune-Related TRAEs (irTRAEs) occurred in 10 pts (55.6%), few grade 3 irTRAEs were observed. No grade 4 or higher (ir)TRAEs occurred. More detailed (ir)TRAEs information were shown in Table. Conclusions: Anlotinib in combination with toripalimab showed promising anti-tumor efficacy and manageable toxicity in the first-line treatment for uHCC patients. This study is still ongoing and more data is being updated. Most common (ir)TRAEs in enrolled pts (n=18). Clinical trial information: ChiCTR1900028295. [Table: see text]
Radiological response as a predictor of pathological response to combined tyrosine kinase inhibitor (TKI) and anti-PD-1 antibodies in hepatocellular carcinoma (HCC).
Authors: Sun Hui-Chuan , Huang Cheng , Zhu Xiao-Dong , Shen Ying-Hao , Wu Dong , Ji Yuan , Ge Ning-Ling , Chen Yi , Tan Chang-Jun , Zhou Jian , Fan Jia 
Published: June 2021

e16144 Background: Pathological complete response (CR) and major pathological response (MPR) are associated with long-term survival after neoadjuvant/conversion surgery of HCC. The relationship between imaging and histopathological evaluations of response to combined TKI plus anti-PD-1 antibody treatment is unclear. Methods: This retrospective analysis included 23 patients with an initial diagnosis of unresectable HCC who underwent resection after combined TKI/anti-PD-1 antibody treatment between March 2019 and December 2020 at Zhongshan Hospital of Fudan University. MRI was performed before and after treatment and objective response rate (ORR; CR or partial response [PR]) was evaluated using RECIST 1.1 and mRECIST by investigator assessment (INV) and independent imaging review (IIR). Histopathological response was evaluated in resected tumor tissue using residual viable tumor (RVT; RVT area/total tumor bed surface area under 100X microscopy). MPR was defined as <10% RVT. The relationship between radiological reduction in tumor size and MPR was investigated using a receiver operating characteristic (ROC) curve. Results: Patients had a median age of 54.0 years, 91% were male and the average pre-treatment tumor diameter was 11.5±4.6 cm. Three had Barcelona Clinic Liver Cancer (BCLC) Stage A disease (China Liver Cancer Stage [CNLC] Ib, n=3), six had BCLC Stage B (CNLC IIa, n=1 and IIb n=5) and 14 had BCLC Stage C (CNLC IIIa, n=10 and IIIb, n=4). Patients received lenvatinib (n=19) or apatinib (n=4) plus anti-PD-1 antibodies (pembrolizumab [n=5], sintilimab [n=5], camrelizumab [n=10], treprizumab [n=2] or nivolumab [n=1]) followed by resection. Radiological responses are summarized in Table. An MPR or pathologic CR was achieved by 52.2% (12/23) and 39.1% (9/23) of patients, respectively. A correlation was observed between radiological responses using RECIST 1.1 and mRECIST and MPR (Fisher’s exact test; P=0.089 and 0.037, respectively). Using RECIST 1.1, the optimum diagnostic cutoff for MPR was a 26% reduction in tumor size, by both INV (area under ROC (AUC)=0.780, 95% CI: 0.580–0.981, sensitivity 83.3%, specificity 72.7%) and IIR (AUC=0.739, 95% CI: 0.527–0.951, sensitivity 75.0%, specificity 72.7%). Using mRECIST, the optimum cutoff for MPR was a 78% reduction in tumor size by INV (AUC=0.746, 95% CI: 0.538–0.954, sensitivity 58.3%, specificity 90.9%) and IIR (AUC=0.742, 95% CI: 0.532–0.953, sensitivity 66.7%, specificity 81.8%). Conclusions: Radiological response showed a degree of correlation with MPR in patients with advanced HCC receiving combined TKI and anti-PD-1 antibody therapy. Therefore, imaging evaluation may be used to predict a pathological response and further guide clinical treatment decisions. Response rates (n=23).[Table: see text]
First-in-human phase I, pharmacokinetic (PK), and pharmacodynamic (PD) study of oral GNS561, a palmitoyl-protein thioesterase 1 (PPT1) inhibitor, in patients with primary and secondary liver malignancies.
Authors: Harding James J. , Awada Ahmad , Decaens Thomas , Roth Gael , Merle Philippe , Kotecki Nuria , Dreyer Chantal , Ansaldi Christelle , Rachid Madani , Mezouar Soraya , Menut Agnes , Bestion Eloine , Paradis Valerie , Halfon Philippe , Raymond Eric , Abou-Alfa Ghassan K. 
Published: June 2021

e16175 Background: GNS561 belongs to a novel generation of drug blocking cancer cell proliferation by inhibiting late-stage autophagy and dose-dependent accumulation of enlarged lysosomes by interacting with palmitoyl-protein thioesterase-1 (PPT1). Methods: This phase I, multicenter, open-label, dose-escalation trial (3+3 design) explored two dosing schedules: one single oral intake three times a week and twice daily (BID) continuous oral intake of GNS561 in patients with advanced primary and secondary liver cancers (NCT03316222). The primary objective was to determine recommended phase II dose (RP2D) and schedule for further clinical development. The secondary objectives included a preliminary evaluation of the safety, pharmacokinetic (PK), pharmacodynamics (PD), and antitumor activity of GNS561. Results: Nineteen treatment-refractory patients were enrolled and were evaluable for primary endpoint: intrahepatic cholangiocarcinoma (iCCA) (9), hepatocellular carcinoma (HCC) (7), pancreatic ductal adenocarcinoma (PDAC) (2) and colorectal cancer (CRC) (1). Median age was 60, 89% were male and 37% had received 3 or more lines as prior cancer therapies. Dose escalation ranged from 50 mg three times a week to 200 mg BID. No dose-limiting toxicity were observed. Treatment-related adverse events were grade 1-2 gastrointestinal toxicity, primarily nausea/vomiting, occurring in 8 patients (42%) and diarrhea in 4 patients (21%). Occurrence of nausea/vomiting despite antiemetic prophylaxis prevented increasing doses above 200 mg BID. GNS561 displayed favorable bioavailability with interpatient variability (CV%: 13 to 223% and 21 to 98.2% on plasma concentrations on cycle 1 day 1 and cycle 2 day 1 respectively), and dose proportional exposure in plasma. GNS561 concentrations accumulated after multiple administration (2.60 - 9.00-fold) and exhibited a long half-life. Plasma and liver concentrations at doses ranging 100-200 mg BID were comparable to therapeutic exposures in preclinical models. Five patients (3 HCC and 2 iCCA) experienced tumor stabilization according to RECIST 1.1 criteria, including a minor response (-23%). Conclusions: GNS561 RP2D single agent was set at 200 mg BID based on this favorable safety profile and plasma exposure, GNS561 will be next further evaluated in monotherapy and in combination with checkpoint inhibitors considering the autophagic activity restriction of major histocompatibility complex-1 promotion of immune invasion. Clinical trial information: NCT03316222.
Pancreatic hormones response-generated machine learning model to help distinguish sporadic pancreatic cancer from new-onset diabetes cohort.
Authors: Bao Jiantong , Sun Chenyu , Zhang Yidi , Li Ling , Pandol Stephen Jacob , Kozma Kelly 
Published: June 2021

e16235 Background: Diabetes mellitus (DM), a paraneoplastic phenomenon, can develop earlier than other symptoms in pancreatic cancer (PaC) patients. Enhanced surveillance is encouraged on all elderly patients with new-onset DM. However, it is a challenge to differentiate newly developed PaCDM from type 2 DM (T2DM). Thus, we investigated the differences of pancreatic hormones responses and functions between PaCDM and T2DM patients, and developed discriminative model by machine learning algorithms. Methods: PaC patients with normal blood glucose (PaCNG) or with new-onset DM (PaCDM) were recruited. For each case, age and gender matched newly developed T2DM patients and healthy volunteers were selected as controls. After ≥10 hours fasting, all participants underwent a mixed meal stimulation test (MMTT). Blood samples were collected at 0, 15, 30, 60 and 120 min to measure insulin, C-peptide, glucagon, and pancreatic polypeptide (PP). Indices of insulin sensitivity (HOMA-IS, HOMA-IR) and insulin secretion (HOMA-β, insulinogenic index 30’ and 120’) were calculated. Increases in hormone levels were compared among groups with repeated measure analysis. Four machine learning algorithms (Random Forest, Logistic Regression, Support Vector Machines, Naïve bayes) were used to develop quadri-separated discriminative models of PaCDM based on baseline characteristics, pancreatic hormones and insulin indices listed above. Results: Insulin and C-peptide responses to MMTT were blunted in PaCDM patients compared to T2DM. The AUC of insulin were comparatively lower in PaCDM; between-group differences were observed at the fasting (197.15 ± 16.59 pg/mL to 537.96 ± 118.69 pg/mL; P = 0.040) and 15 min (523.94 ± 81.15 pg/mL to 1182.51 ± 219.35 pg/mL; P = 0.036) time-points. No statistical differences among groups were found for glucagon. The mean peak PP concentration after MMTT in PaCDM group (466.67 ± 79.05 pg/mL) was higher than control group (258.54 ± 31.36 pg/mL, P = 0.034), but not statistically different to T2DM patients (452.34 ± 62.96 pg/mL, P = 0.892). PaCDM patients had lower insulin secretion capacity but better insulin sensitivity compared to T2DM patients. Eight indices (age, HbA1c, CA19-9, peak concentration of glucose, area above basal of PP, HOMA-IR, HOMA-IS, HOMA-β) were recruited for model development. And the discriminative model generated by random forest algorithm obtained best performance (AUC = 1.000, CA = 0.963, F-1 = 0.941, Precision = 0.889, Recall = 1.000, Specificity = 0.947; model verified). Conclusions: PaCDM patients tend to present with lower β-cell function and better insulin resistance compared to T2DM patients. As our model based on machine learning algorithm generates a good result for discrimination, the above findings may help with early screening for sporadic PaC in new-onset DM. Clinical trial information: ChiCTR1800018247.
A phase 1 study of neoadjuvant chemotherapy followed by concurrent chemoradiation with gemcitabine, sorafenib, and vorinostat in pancreatic cancer.
Authors: Poklepovic Andrew Stewart , Fields Emma Charlotte , Bandyopadhyay Dipankar , Tombes Mary Beth , Kmieciak Maciej , McGuire William P. , Gordon Sarah W. , Kaplan Brian J. , Myers Jennifer Lynn , Matin Khalid , Patel Bhaumik , Kothadia Sejal , Dent Paul 
Published: June 2021

e16268 Background: The multi-kinase inhibitor sorafenib (S) and HDAC inhibitor vorinostat (V) demonstrated synergism against preclinincal pancreatic cancer (PaCa) models. The combination of S & V also potently radiosensitized pancreatic cancer cells and enhanced the activity of gemcitabine (G). This led to a phase 1 trial to determine the doses and schedule appropriate for phase 2 study of S & V with weekly G and intensity modulated radiotherapy (IMRT) as neoadjuvant treatment of PaCa following chemotherapy. Methods: Using a 3+3 dose-escalation design, adult patients with resectable, borderline resectable, unresectable, and lymph node positive PaCa were enrolled to 6 dose levels. Enrolled patients had completed at least 8w of neoadjuvant chemotherapy prior to IMRT. The schedule of administration was weekly 200mg/m2 G weekly during IMRT, S & V were dosed either 3x or 5x weekly during IMRT. Primary endpoint was to identify the dose and schedule for S & V with G based chemoradiation. Key secondary endpoints included antitumor activity, R0 resection rate, OS. Correlative studies to evaluate a variety of biomarkers and Nanostring expression analysis on pre- and post-therapy tumor specimens were also performed. Results: 22 patients were enrolled and 21 treated at 6 dose levels. Due to thrombocytopenia limiting drug exposure, the trial was modified to reduce G to 200mg/m2/wk and S & V to 3 d/wk instead of 5 d/wk. 13 patients were eligible for surgery, and 9 had R0 resections. Conclusions: Our findings indicate that the study regimen was well tolerated, typical toxicities of S (hand foot syndrome) were not observed with intermittent dosing. Uncomplicated cytopenias limited drug exposure, which was improved with intermittent S&V dosing. The RP2D of the combination is S (400mg po BID 3d/wk), V (200mg po qd 3d/wk), G 200mg/m2 IV weekly, with IMRT (50.4 Gy over 28 fractions, 5d/wk). Antitumor activity was observed across dose levels, with an encouraging R0 resection rate. These results warrant further investigation of combining S and V with G and IMRT as neoadjuvant treatment of PaCa following chemotherapy. Analyses of correlative studies and OS are underway. Clinical trial information: NCT02349867. [Table: see text]
Efficacy of anti-PD(L)1 therapy for patients (Pts) with advanced urothelial carcinoma (aUC) with primary resistance to platinum-based chemotherapy (PC).
Authors: Stewart Tyler F. , Kotha Nikhil V. , Dzimitrowicz Hannah Elizabeth , Makrakis Dimitrios , Khaki Ali Raza , Simon Nicholas I. , Nelson Ariel Ann , Freeman Dory , Rose Tracy L , Beck Wolfgang , Chawla Neal Shiv , Pal Sumanta K. , Kilari Deepak , Milowsky Matthew I. , Apolo Andrea B. , Grivas Petros , Zhang Tian , Sonpavde Guru P. , McKay Rana R. 
Published: June 2021

e16515 Background: PC remains standard first-line (1L) therapy for aUC. Approximately 15% of pts exhibit primary resistance (P-R) to PC and ∼25% progress by 4 months. PD(L)1 inhibitors yield objective response rates (ORR) of ∼20% in pts with progression after PC; however, it is unclear if this benefit extends to pts with P-R to PC. We examined the efficacy of anti-PD(L)1 in pts with aUC who experienced P-R to 1L PC. Methods: We conducted a multi-institutional retrospective study of pts with aUC who experienced P-R to PC and were subsequently treated with single-agent anti-PD(L)1 therapy. Eligibility included pts with unresectable or metastatic disease diagnosed after January 1, 2017. P-R to PC was defined as radiographic progression by RECISTv1.1 within 12 weeks from initiation of PC. Pts who developed metastatic disease while receiving (neo)adjuvant PC were eligible. Clinicopathologic variables were collected. ORR to anti-PD(L)1 was the primary endpoint. Secondary endpoints included time to treatment failure (TTF, defined as time from start of anti-PD(L)1 therapy to next line of therapy, hospice or death) and overall survival (OS) were estimated using Kaplan-Meier method. Multivariate (MV) analysis using Cox regression evaluating factors associated with OS was performed. Results: Overall, 42 pts were included: 74% male, median age 65 (28-90); 79% ever smokers; 21% mixed histology; 31% received definitive locoregional therapy. Metastatic sites at diagnosis of aUC included: lymph node only (19%), liver (29%), bone (38%) and lung (33%). At diagnosis of aUC, ECOG PS was 0 in 26%, 1 in 52% and unknown in 21%. 1L PC included cisplatin (76%) and carboplatin (24%) based regimens. Anti-PD(L)1 was received either 2L (98%) or 3L (2%). Overall, ORR to anti-PD(L)1 was 17%: CR (2%), PR (14%), SD (14%), PD (57%) and unknown (12%). Of the 24 pts with PD as best response to anti-PD(L)1, only 9 (38%) received subsequent therapy. Overall, median TTF was 4.2 mo (95% CI 2.8-6.7 mo) and median OS was 7.4 mo (95% CI 4.2-11.1 mo). ORR in patients with a PDL1 combined positive score ≥ 10% (n=6) was 0%: 1 SD and 5 PD. MV analysis for OS from start of anti-PD(L)1 is shown (Table). Conclusions: P-R to PC portends a poor prognosis in pts with aUC. While a subset of patients may respond to anti-PD(L)1 therapy, the majority of pts do not derive benefit. Alternative agents, e.g. antibody drug conjugates and FGFR inhibitors, and combination-therapy should be investigated for this high risk population.[Table: see text]
Intensity of free-radical reactions in metastasizing cervical cancer.
Authors: Chernikova Natalia V. , Goroshinskaya Irina A. , Frantsiyants Elena M. , Verenikina Ekaterina V. , Poryvaev Yuriy A. , Myagkova Tatiana Yu. , Kachesova Polina S. , Nemashkalova Ludmila A. 
Published: June 2021

e17508 Background: Cervical cancer (CC) is one of the main causes of death among patients with gynecological tumors. As a rule, patients die from relapses and metastases which rates reach 30-45%. According to research data, treatment of patients with distant metastases is ineffective, and half of them die within 9.7 months, while the average survival is 15.9±0.26 months. The development of many pathological processes is considered to be associated with an increase in free-radical reactions leading to oxidative damage to various biomolecules. The purpose of the study was to analyze some characteristics of the free-radical oxidation and antioxidant defence in metastasizing CC. Methods: The study included 56 patients aged 29-73 years with stage IIB-IV CC after antitumor treatment. The main group – 27 patients who developed metastases within 4 months to 8 years after the CC diagnosis; controls – 29 patients with non-metastatic CC; donors – 19 healthy women aged 27-61 years. The accumulation of carbonyl derivatives in blood plasma proteins was detected in the reaction with 2, 4-dinitrophenylhydrazine. The induced oxidative modification of proteins was stimulated with Fenton's reagent. Free-radical processes was evaluated by the intensity of peroxide-induced luminol-dependent plasma chemiluminescence and the content of nitric oxide metabolites; the intensity of lipid peroxidation - by the content of malondialdehyde (MDA); the activity of catalase and ceruloplasmin was also studied. Results: CC progression was accompanied by increasing lipid peroxidation and spontaneous oxidation of blood plasma proteins. MDA levels in patients with metastases increased by 57.8% compared to donors and by 34.3% compared to patients without metastases (p < 0.05). The concentration of 2, 4-dinitrophenylhydrozones increased on average by 4 times compared to donors and by almost 2 times compared to patients without metastases. Patients with metastasizing CC demonstrated elevated levels of products of the interaction of nitric oxide and its derivatives with proteins and peptides - 3-nitrotyrosine and nitrosoglutathione, compared to both donors (by 31.4% and 55.3%) and patients in remission (by 38.1% and 34.5%). Chemiluminescence activity increased by 54.5% compared to donors (p < 0.05) and by 93% (p < 0.01) compared to controls. Catalase activity in the blood plasma of patients with metastases increased by 54.1% compared to donors, but was lower than the values in the control group (by 22.1%). Ceruloplasmin activity was increased only in patients without metastases (by 33%). Conclusions: The process of CC metastasis is accompanied by a greater intensity of oxidative processes of both proteins and lipids, as well as depletion of the adaptive capabilities of the body's antioxidant system.