PANoptosis-related long non-coding RNA signature to predict the prognosis and immune landscapes of pancreatic adenocarcinoma.

Background: Cancer growth is significantly influenced by processes such as pyroptosis, apoptosis, and necroptosis that underlie PANoptosis, a proinflammatory programmed cell death. Several studies have examined the long non-coding RNAs (lncRNAs) associated with pancreatic adenocarcinoma (PAAD). However, the predictive value of lncRNAs related to PANoptosis for PAAD has not been established. Methods: The Clinical Genome Atlas database was used to obtain the transcriptome 、clinical data and the corresponding mutation data of the patients with PAAD in this study. The least absolute shrinkage and selection operator regression analysis was employed to obtain prognosis-related lncRNAs for constructing a risk signature. According to the median risk score of the signature, patients with PAAD were grouped into low- and high-risk groups to further compare the survival prognosis of different risk groups. Time-dependent receiver operating characteristic curves, c-index analysis, nomograms, principal component analysis and univariate Cox and multivariate Cox regression were performed for the internal validation of the signature. In addition, enrichment analysis of different genes was performed using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Lastly, differences in tumor mutation burden (TMB), immune function, tumor immune dysfunction and rejection (TIDE), and drug response were determined for the two risk groups. Results: The signature was constructed with six PANoptosis-related lncRNAs (AC067817.2、LINC02004、AC243829.1、AC092171.5、AP005233.2、AC004687.1) that predicted the prognosis of the patients with PAAD. Survival curves showed that patients in the two risk groups had statistically significant differences in prognosis (P < 0.05), and multi-cox regression analysis identified risk score as an independent risk factor for PAAD prognosis, and internal validation of nomograms showed high confidence in the signature. GO and KEGG enrichment analysis showed functional and pathway differences between the high- and low-risk groups. TMB evaluation demonstrated that patients in the high-risk group had a higher frequency of mutations. The TIDE score indicated that the high-risk group had a lower risk of immunotherapy escape and better immunotherapy outcomes. Additionally, the two risk groups revealed significantly different responses to 11 anticancer drugs. Conclusion: We identified a novel risk signature for PANoptosis-related lncRNAs, which is a standalone prognostic indicator for PAAD. The PANoptosis-related lncRNA risk signature may be relevant for immunotherapy and a therapeutic target for PAAD.

Construction of a cancer-associated fibroblasts-related long non-coding RNA signature to predict prognosis and immune landscape in pancreatic adenocarcinoma.

Background: Cancer-associated fibroblasts (CAFs) are an essential cell population in the pancreatic cancer tumor microenvironment and are extensively involved in drug resistance and immune evasion mechanisms. Long non-coding RNAs (lncRNAs) are involved in pancreatic cancer evolution and regulate the biological behavior mediated by CAFs. However, there is a lack of understanding of the prognostic signatures of CAFs-associated lncRNAs in pancreatic cancer patients. Methods: Transcriptomic and clinical data for pancreatic adenocarcinoma (PAAD) and the corresponding mutation data were obtained from The Cancer Genome Atlas database. lncRNAs associated with CAFs were obtained using co-expression analysis. lncRNAs were screened by Cox regression analysis using least absolute shrinkage and selection operator (LASSO) algorithm for constructing predictive signature. According to the prognostic model, PAAD patients were divided into high-risk and low-risk groups. Kaplan-Meier analysis was used for survival validation of the model in the training and validation groups. Clinicopathological parameter correlation analysis, univariate and multivariate Cox regression, time-dependent receiver operating characteristic (ROC) curves, and nomogram were performed to evaluate the model. The gene set variation analysis (GSVA) and gene ontology (GO) analyses were used to explore differences in the biological behavior of the risk groups. Furthermore, single-sample gene set enrichment analysis (ssGSEA), tumor mutation burden (TMB), ESTIMATE algorithm, and a series of immune correlation analyses were performed to investigate the relationship between predictive signature and the tumor immune microenvironment and screen for potential responders to immune checkpoint inhibitors. Finally, drug sensitivity analyses were used to explore potentially effective drugs in high- and low-risk groups. Results: The signature was constructed with seven CAFs-related lncRNAs (AP005233.2, AC090114.2, DCST1-AS1, AC092171.5, AC002401.4, AC025048.4, and CASC8) that independently predicted the prognosis of PAAD patients. Additionally, the high-risk group of the model had higher TMB levels than the low-risk group. Immune correlation analysis showed that most immune cells, including CD8+ T cells, were negatively correlated with the model risk scores. ssGSEA and ESTIMATE analyses further indicated that the low-risk group had a higher status of immune cell infiltration. Meanwhile, the mRNA of most immune checkpoint genes, including PD1 and CTLA4, were highly expressed in the low-risk group, suggesting that this population may be "hot immune tumors" and have a higher sensitivity to immune checkpoint inhibitors (ICIs). Finally, the predicted half-maximal inhibitory concentrations of some chemical and targeted drugs differ between high- and low-risk groups, providing a basis for treatment selection. Conclusion: Our findings provide promising insights into lncRNAs associated with CAFs in PAAD and provide a personalized tool for predicting patient prognosis and immune microenvironmental landscape.

Surgical Resection of Pancreatic Hepatoid Carcinoma Followed by Combined Transarterial Chemoembolization and Immunotherapy: A Case Report.

Pancreatic hepatoid carcinoma (HC) is a heterogeneous tumor with high degree of malignancy and poor prognosis, which display cytological and/or structural features of focal hepatocellular carcinoma (HCC). For the low incidence and atypical clinical symptoms, it is possible to be diagnosed as pancreatic cancer before operation, and mainly depending on the pathological examination. To the best of our knowledge, surgery combined with radiotherapy and chemotherapy is the common treatment of pancreatic HC. However, the curative effect and prognosis is poor. We report a case of 44-year-old woman with pancreatic HC treated with PD-1 receptor inhibitor and transarterial chemoembolization, whose clinical symptoms and laboratory indexes are significantly improved after treatment.

U.S. Phase I First-in-human Study of Taletrectinib (DS-6051b/AB-106), a ROS1/TRK Inhibitor, in Patients with Advanced Solid Tumors.

PURPOSE: Taletrectinib (DS-6051b/AB-106) is an oral, tyrosine kinase inhibitor of ROS1 and NTRK with potent preclinical activity against ROS1 G2032R solvent-front mutation among others. We report the first-in-human U.S. phase I results of taletrectinib. PATIENTS AND METHODS: Patients ≥18 years old with neuroendocrine tumors, with tumor-induced pain, or tumors harboring ROS1/NTRK rearrangements were eligible. Accelerated titration followed by modified continuous reassessment method and escalation with overdose control was used (50-1,200 mg once daily or 400 mg twice daily). Primary objectives were safety/tolerability, and MTD determination. Secondary objectives were food-effect pharmacokinetics and antitumor activity. RESULTS: A total of 46 patients were enrolled. Steady-state peak concentration (C max) and exposure (AUC0-8) increased dose dependently from 50-mg to 800-mg once-daily doses. The ratio of the geometric mean of AUC0-24 between low-fat-diet-fed/fasted state was 123% (90% confidence interval, 104%-149%). Dose-limiting toxicities (grade 3 transaminases increase) occurred in two patients (1,200-mg once-daily dose). MTD was 800 mg once daily. Most common treatment-related adverse events were nausea (47.8%), diarrhea (43.5%), and vomiting (32.6%). Pain score reductions were observed in the 800-mg once-daily dose cohort. Confirmed objective response rate was 33.3% among the six patients with RECIST-evaluable crizotinib-refractory ROS1+ NSCLC. One patient with TPM3-NTRK1 differentiated thyroid cancer achieving a confirmed partial response of 27 months at data cutoff. We identified a cabozantinib-sensitive ROS1 L2086F as an acquired taletrectinib-resistance mutation. CONCLUSIONS: Taletrectinib has manageable toxicities at the MTD of 800 mg daily. Preliminary efficacy was observed in patients with crizotinib-refractory ROS1+ NSCLC.

Safety and pharmacokinetics of PF-04360365 following a single-dose intravenous infusion in Japanese subjects with mild-to-moderate Alzheimer's disease: a multicenter, randomized, double-blind, placebo-controlled, dose-escalation study.

OBJECTIVE: PF-04360365 is a humanized IgG(2)Δa anti-amyloid ß (Aß) antibody designed to improve outcome in Alzheimer's disease (AD). Single doses of 0.1 - 10 mg/kg were safe and well tolerated in Western (mostly Caucasian) subjects with mild-to-moderate AD. This Phase 1, multicenter, randomized, double-blind, dose-escalation study was the first to evaluate the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of PF-04360365 in Japanese subjects. MATERIALS AND METHODS: 30 subjects with mild-to-moderate AD were enrolled. In each cohort, 3 subjects received PF-04360365 (0.1, 0.5, 1, 5, or 10 mg/kg) and 1 subject received placebo as a single 2-hour intravenous infusion. Subjects were monitored as inpatients for 24 hours and then as outpatients for 1 year. RESULTS: All subjects completed the study. There were no serious or National Cancer Institute Common Terminology Criteria for Adverse Events grade ≥ 3 adverse events, hypersensitivity reactions, or antidrug antibodies. No clinical or MRI evidence of brain microhemorrhage, cerebral edema, or encephalitis was observed. PF-04360365 plasma concentrations increased with dose, and pharmacokinetics were consistent with a small steady-state volume of distribution, slow clearance, and long elimination half-life. Cerebrospinal fluid (CSF):plasma ratios were < 0.5%. Plasma Aß species showed dose-dependent increases in C(max) and AUC(∞), but CSF biomarkers did not differ clearly between treatment arms. CONCLUSIONS: PF-04360365 was safe and well tolerated in Japanese subjects. Pharmacokinetics and plasma pharmacodynamic responses in Japanese subjects were comparable to those in Western subjects. *No longer affiliated with Pfizer.