GDF15: Immunomodulatory Role in Hepatocellular Carcinoma Pathogenesis and Therapeutic Implications.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths globally and the sixth most common cancer worldwide. Evidence shows that growth differentiation factor 15 (GDF15) contributes to hepatocarcinogenesis through various mechanisms. This paper reviews the latest insights into the role of GDF15 in the development of HCC, its role in the immune microenvironment of HCC, and its molecular mechanisms in metabolic dysfunction associated steatohepatitis (MASH) and metabolic associated fatty liver disease (MAFLD)-related HCC. Additionally, as a serum biomarker for HCC, diagnostic and prognostic value of GDF15 for HCC is summarized. The article elaborates on the immunological effects of GDF15, elucidating its effects on hepatic stellate cells (HSCs), liver fibrosis, as well as its role in HCC metastasis and tumor angiogenesis, and its interactions with anticancer drugs. Based on the impact of GDF15 on the immune response in HCC, future research should identify its signaling pathways, affected immune cells, and tumor microenvironment interactions. Clinical studies correlating GDF15 levels with patient outcomes can aid personalized treatment. Additionally, exploring GDF15-targeted therapies with immunotherapies could improve anti-tumor responses and patient outcomes.

Pivekimab sunirine (IMGN632), a novel CD123-targeting antibody-drug conjugate, in relapsed or refractory acute myeloid leukaemia: a phase 1/2 study.

BACKGROUND: Pivekimab sunirine (IMGN632) is a first-in-class antibody-drug conjugate comprising a high-affinity CD123 antibody, cleavable linker, and novel indolinobenzodiazepine pseudodimer payload. CD123 is overexpressed in several haematological malignancies, including acute myeloid leukaemia. We present clinical data on pivekimab sunirine in relapsed or refractory acute myeloid leukaemia. METHODS: This first-in-human, phase 1/2 dose-escalation and dose-expansion study enrolled participants aged 18 years or older at nine hospitals in France, Italy, Spain, and the USA with CD123+ haematological malignancies (Eastern Cooperative Oncology Group performance status of 0-1); participants reported here were in a cohort of participants with acute myeloid leukaemia who were refractory to or had relapsed on one or more previous treatments for acute myeloid leukaemia. The 3 + 3 dose-escalation phase evaluated two dosing schedules: schedule A (once every 3 weeks, on day 1 of a 3-week cycle) and fractionated schedule B (days 1, 4, and 8 of a 3-week cycle). The dose-expansion phase evaluated two cohorts: one cohort given 0·045 mg/kg of bodyweight (schedule A) and one cohort given 0·090 mg/kg of bodyweight (schedule A). The primary endpoints were the maximum tolerated dose and the recommended phase 2 dose. Antileukaemia activity (overall response and a composite complete remission assessment) was a secondary endpoint. The study is ongoing and registered with ClinicalTrials.gov, NCT03386513. FINDINGS: Between Dec 29, 2017, and May 27, 2020, 91 participants were enrolled (schedule A, n=68; schedule B, n=23). 30 (44%) of schedule A participants were female and 38 (56%) were male; 60 (88%) were White, six (9%) were Black or African American, and two (3%) were other races. Pivekimab sunirine at doses of 0·015 mg/kg to 0·450 mg/kg in schedule A was administered in six escalating doses with no maximum tolerated dose defined; three dose-limiting toxicities were observed (reversible veno-occlusive disease; 0·180 mg/kg, n=1 and 0·450 mg/kg, n=1; and neutropenia; 0·300 mg/kg, n=1). Schedule B was not pursued further on the basis of comparative safety and antileukaemia findings with schedule A. The recommended phase 2 dose was selected as 0·045 mg/kg once every 3 weeks. At the recommended phase 2 dose (n=29), the most common grade 3 or worse treatment-related adverse events were febrile neutropenia (three [10%]), infusion-related reactions (two [7%]), and anaemia (two [7%]). Treatment-related serious adverse events occurring in 5% or more of participants treated at the recommended phase 2 dose were febrile neutropenia (two [7%]) and infusion-related reactions (two [7%]). Among 68 participants who received schedule A, one death (1%) was considered to be treatment-related (cause unknown; 0·300 mg/kg cohort). At the recommended phase 2 dose, the overall response rate was 21% (95% CI 8-40; six of 29) and the composite complete remission rate was 17% (95% CI 6-36; five of 29). INTERPRETATION: Pivekimab sunirine showed single-agent activity across multiple doses, with a recommended phase 2 dose of 0·045 mg/kg once every 3 weeks. These findings led to a phase 1b/2 study of pivekimab sunirine plus azacitidine and venetoclax in patients with CD123-positive acute myeloid leukaemia. FUNDING: ImmunoGen.

Advances in the Field of Two-Dimensional Crystal-Based Photodetectors.

Two-dimensional (2D) materials have sparked intense interest among the scientific community owing to their extraordinary mechanical, optical, electronic, and thermal properties. In particular, the outstanding electronic and optical properties of 2D materials make them show great application potential in high-performance photodetectors (PDs), which can be applied in many fields such as high-frequency communication, novel biomedical imaging, national security, and so on. Here, the recent research progress of PDs based on 2D materials including graphene, transition metal carbides, transition-metal dichalcogenides, black phosphorus, and hexagonal boron nitride is comprehensively and systematically reviewed. First, the primary detection mechanism of 2D material-based PDs is introduced. Second, the structure and optical properties of 2D materials, as well as their applications in PDs, are heavily discussed. Finally, the opportunities and challenges of 2D material-based PDs are summarized and prospected. This review will provide a reference for the further application of 2D crystal-based PDs.

Treatment With Etirinotecan Pegol for Patients With Metastatic Breast Cancer and Brain Metastases: Final Results From the Phase 3 ATTAIN Randomized Clinical Trial.

Importance: Patients with breast cancer and brain metastases (BM) have a poor prognosis and high clinical need for novel treatments; however, historically, studies have often excluded these patients. Although the BEACON study did not meet its primary end point, treatment with etirinotecan pegol vs chemotherapy of the physician's choice for patients with advanced breast cancer demonstrated a significant improvement in overall survival (OS) for the prespecified patient subgroup with preexisting, pretreated, and nonprogressive BM. Objective: To compare clinical outcomes in patients with BM treated with etirinotecan pegol vs chemotherapy of the physician's choice in a confirmatory trial. Design, Setting, and Participants: This study was a phase 3, open-label, randomized clinical trial (ATTAIN) in patients with metastatic breast cancer and a history of stable pretreated BM who experienced disease progression while receiving chemotherapy in the metastatic setting. The trial took place at 47 sites in 10 countries, and patients were enrolled between March 7, 2017, and November 6, 2019. Interventions: Patients were randomized to receive etirinotecan pegol, 145 mg/m2, every 21 days or chemotherapy (eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel). Main Outcomes and Measures: The primary end point was OS. Key secondary end points included progression-free survival, objective response rate, duration of response, and the clinical benefit rate. Results: A total of 178 female patients (9 [5.1%] Asian, 8 [4.5%] Black or African American, and 123 [69.1] White individuals) were randomized to receive treatment with etirinotecan pegol (92 [51.7%]; median [range] age, 53 [27-79] years) or chemotherapy (86 [48.3%]; median [range] age, 52 [24-77] years). Median OS was similar in both groups (etirinotecan pegol, 7.8 months; chemotherapy, 7.5 months; hazard ratio [HR], 0.90; 95% CI, 0.61-1.33; P = .60). Median progression-free survival for non-central nervous system metastases per blinded independent central review for etirinotecan pegol vs chemotherapy was 2.8 and 1.9 months (HR, 0.72; 95% CI, 0.45-1.16; P = .18) and 3.9 vs 3.3 months, respectively, for central nervous system metastases (HR, 0.59; 95% CI, 0.33-1.05; P = .07). Safety profiles between the groups were largely comparable. Conclusions and Relevance: The results of the ATTAIN randomized clinical trial found no statistically significant difference in outcomes between treatment with etirinotecan pegol and chemotherapy in patients with BM. However, this study represents one of the largest published trials dedicated to patients with breast cancer and BM and may help to inform further research. Trial Registration: ClinicalTrials.gov Identifier: NCT02915744.

Intelligent Error Correction of College English Spoken Grammar Based on the GA-MLP-NN Algorithm.

With the development of neural networks in deep learning, artificial intelligence machine learning has become the main focus of researchers. In College English grammar detection, oral grammar is the most error rate content. So, this paper optimizes MLP based on GA in the deep learning neural network and then studies the intelligent image correction of College English spoken grammar. The main direction is to discuss and analyze GA-MLP-NN algorithm technology first and then predict the error correction model of spoken language grammar by combining the optimized algorithm. The results show that GA-MLP-NN provides excellent accuracy for the prediction of the whole syntax error correction model. Then, the paper studies the deep learning technology to build an intelligent image error correction model of College English spoken grammar. The results show that the effect of intelligent correction of spoken grammar is very fast and accurate.

A Phase Ib study of ruxolitinib + gemcitabine ± nab-paclitaxel in patients with advanced solid tumors.

PURPOSE: Aberrant activation of the Janus-associated kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is associated with increased malignant cell proliferation and survival. This Phase Ib study evaluated ruxolitinib, a potent JAK1/2 inhibitor, in combination with gemcitabine with or without nab-paclitaxel in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received ruxolitinib + gemcitabine (regimen A) or ruxolitinib + gemcitabine + nab-paclitaxel (regimen B). The objective of the dose-finding phase was to identify the maximum tolerated doses (MTDs) of ruxolitinib plus gemcitabine with or without nab-paclitaxel. RESULTS: Among 42 patients enrolled, the median age was 62.5 years, 81.0% had pancreatic cancer, and almost 62% had received prior systemic therapy. Regimen A was tolerated with standard doses of gemcitabine; regimen B was tolerated with reduced doses of gemcitabine/nab-paclitaxel or concomitant granulocyte colony-stimulating factor. The sponsor decided to terminate the study early due to the interim analysis results of the Phase III JANUS 1 study. Discontinuations were mainly due to radiologic or clinical disease progression (81.0% of patients). Median treatment durations were 55.5 days (cohort A0) and 150.5 days (pooled B cohorts). Four patients (pooled B cohorts) had dose-limiting toxicities: grade 3 pneumonia (n=1), grade 4 neutropenia (n=1), and grade 4 thrombocytopenia (n=2). The most common grade 3/4 hematologic adverse events (AEs) were anemia, thrombocytopenia, and neutropenia. Serious AEs occurring in ≥2 patients in cohort A0 or pooled B cohorts were abdominal pain, sepsis (cohort A0), dehydration, anemia, and asthenia (pooled B cohorts). Overall response rates (ORRs) were 12.5% in cohort A0 and 38.5% in pooled B cohorts. Among patients with pancreatic cancer, ORR was 23.5% (14.0% cohort A0 30.0% pooled B cohorts). CONCLUSION: The study was terminated early prior to reaching MTDs per sponsor decision; although ruxolitinib plus gemcitabine with or without nab-paclitaxel was generally safe and well tolerated in patients with advanced solid tumors, this combination will not be pursued further.

Comparing three regularization methods to avoid extreme allocation probability in response-adaptive randomization.

We examine three variations of the regularization methods for response-adaptive randomization (RAR) and compare their operating characteristics. A power transformation (PT) is applied to refine the randomization probability. The clip method is used to bound the randomization probability within specified limits. A burn-in period of equal randomization (ER) can be added before adaptive randomization (AR). For each method, more patients are assigned to the superior arm and overall response rate increase as the scheme approximates simple AR, while statistical power increases as it approximates ER. We evaluate the performance of the three methods by varying the tuning parameter to control the extent of AR to achieve the same statistical power. When there is no early stopping rule, PT method generally performed the best in yielding higher proportion to the superior arm and higher overall response rate, but with larger variability. The burn-in method showed smallest variability compared with the clip method and the PT method. With the efficacy early stopping rule, all three methods performed more similarly. The PT and clip methods are better than the burn-in method in achieving higher proportion randomized to the superior arm and higher overall response rate but burn-in method required fewer patients in the trial. By carefully choosing the method and the tuning parameter, RAR methods can be tailored to strike a balance between achieving the desired statistical power and enhancing the overall response rate.

Simulation study for evaluating the performance of response-adaptive randomization.

A response-adaptive randomization (RAR) design refers to the method in which the probability of treatment assignment changes according to how well the treatments are performing in the trial. Holding the promise of treating more patients with the better treatments, RARs have been successfully implemented in clinical trials. We compared equal randomization (ER) with three RARs: Bayesian adaptive randomization, sequential maximum likelihood, and sequential posterior mean. We fixed the total number of patients, considered as patient horizon, but varied the number of patients in the trial. Among the designs, we compared the proportion of patients assigned to the superior arm, overall response rate, statistical power, and total patients enrolled in the trial with and without adding an efficacy early stopping rule. Without early stopping, ER is preferred when the number of patients beyond the trial is much larger than the number of patients in the trial. RAR is favored for large treatment difference or when the number of patients beyond the trial is small. With early stopping, the difference between these two types of designs was reduced. By carefully choosing the design parameters, both RAR and ER methods can achieve the desirable statistical properties. Within three RAR methods, we recommend SPM considering the larger proportion in the better arm and higher overall response rate than BAR and similar power and trial size with ER. The ultimate choice of RAR or ER methods depends on the investigator's preference, the trade-off between group ethics and individual ethics, and logistic considerations in the trial conduct, etc.