The treatment landscape of metastatic prostate cancer is evolving rapidly. Here, we highlight several ongoing clinical trials that may reshape the future management of metastatic disease, including novel escalation and de-escalation strategies, as well as emerging therapies in both the hormone-sensitive and castration-resistant settings.
Background: There is no standard systemic therapy for unresectable chondrosarcoma. The purpose of this study is to explore the efficacy of combination therapy with an anti-PD-1 antibody and anlotinib in patients with advanced chondrosarcoma.
Methods: Patients with dedifferentiated or high-grade conventional chondrosarcoma were eligible. Anlotinib was administered at 12 mg orally once a day from day 1 to 14 every 3 weeks in all participants. In the combination treatment arm, patients received an additional anti-PD-1 antibody at 200 mg every 3 weeks. The primary endpoint was the 6-month progression-free survival rate (PFSR). Biomarker analyses for therapeutic effectiveness were conducted.
Findings: 70 patients (32 with dedifferentiated and 38 with conventional chondrosarcoma) were enrolled in the study. After a medium follow-up of 15.6 months, combination treatment showed significantly improved outcomes compared to anlotinib alone in the entire population, with a higher 6-month PFSR (60.0% versus 31.4%). The PFS-event inverse probability weighting adjusted Cox model evaluation also revealed a significant benefit of combination treatment (hazard ratio = 0.14, 95% confidence interval [CI]: 0.07-0.30, p < 0.001). Patients with dedifferentiated chondrosarcoma benefited the most from the combination treatment, with improvements in objective response rate (33.3% versus 9.1%), 6-month PFSR (57.1% versus 9.1%), median PFS (7.0 months versus 3.8 months), and 1-year overall survival rate (42.9% versus 18.2%). Effector memory T cells were significantly associated with treatment response (p < 0.001).
Conclusions: The combination treatment demonstrated promising efficacy in advanced chondrosarcoma, particularly for dedifferentiated cases (ClinicalTrials.gov: NCT05193188).
Funding: This trial was supported by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
The Essence-TIMI 73b trial demonstrated that monthly injections of olezarsen, an antisense oligonucleotide targeting hepatic APOC3, over 6 months increased HDL cholesterol and significantly decreased the concentrations of triglycerides, apolipoprotein C-III, apolipoprotein B, non-HDL-C, VLDL cholesterol, and remnant cholesterol in adults with moderate hypertriglyceridemia.1 Studies assessing the long-term safety of olezarsen are ongoing. Whether olezarsen decreases cardiovascular outcomes remains undetermined.
Background: All three dengue vaccines that have completed phase 3 clinical trials have shown greater efficacy in dengue-seropositive compared to dengue-seronegative individuals. This includes the live-attenuated tetravalent dengue vaccine TAK-003, where immunogenicity in baseline seronegative individuals remains lower after two doses, despite seroconversion after the first dose, compared to baseline seropositive individuals after one dose.
Methods: A whole-genome microarray was used to analyze the host response to TAK-003. Bulk whole-blood RNA sequencing was used to confirm pre-vaccination baseline gene expression differences between seronegative and seropositive individuals.
Findings: We found that the host response to TAK-003 in baseline seropositive individuals was driven, at least in part, by reprogrammed innate immune response from prior dengue virus (DENV) infection. Indeed, three independent cohorts of volunteers showed differential immune gene expression between dengue-seropositive compared to dengue-seronegative individuals at baseline. Gene modules related to the cell cycle were positively enriched, while innate immune gene modules were negatively enriched, in dengue-seropositive compared to dengue-seronegative subjects in all 3 cohorts. Remarkably, while a single DENV infection reprogrammed the gene expression of innate immune markers, including those implicated in dengue pathogenesis and disease severity, vaccination did not show evidence of similar innate immune reprogramming.
Conclusions: Our findings suggest a lasting effect of DENV infection on the innate immune system that potentially impacts vaccination outcome and secondary dengue pathogenesis.
Funding: The DEN-210 clinical trial and gene expression analyses were funded by Takeda Vaccines. The cohort studies in Singapore were funded by the National Medical Research Council.
Parkinson's disease (PD) is one of the most devastating neurodegenerative disorders, influenced by a complex interplay of genetic, epigenetic, and environmental factors. Genetic studies and neuropathological evidence suggest that there may be two main forms of early-onset PD driven centrally by either alpha-synuclein aggregation (Lewy bodies) or mitochondrial dysfunction. While numerous studies have utilized omics approaches to investigate the pathogenesis of PD, the role of mitochondrial DNA remains to be fully resolved, in part due to the finite resolution of short-read sequencing technologies. Integrating variations in nuclear and mitochondrial DNA is critical to understanding the etiology of PD and assessing the potential contribution of mitochondrial variation and age-related accumulation of mutations to disease risk. In this review, we explore the role of mitochondrial genetics in PD utilizing long-read sequencing, highlighting its unprecedented versatility in resolving difficult genomic regions and providing critical insights into complex cases of PD.
Background: Early diagnosis of cholangiocarcinoma (CCA) remains challenging, but liquid biopsy is emerging as a promising detection strategy. Here, we identified a novel bile biomarker for CCA and developed an optic fiber biosensor integrated with digestive endoscopy for real-time diagnosis in vivo.
Methods: A total of 583 subjects and two proteomic analyses were used to screen and validate biomarkers for CCA, and then the corresponding antibodies were generated to construct a surface plasmon resonance (SPR)-based optic fiber biosensor. The diagnostic performance of the biosensor was validated in 120 patients in vitro, and its biological characteristics were assessed under various physiological conditions. Finally, its real-time detection and biosafety in vivo were verified in pigs and patients.
Findings: Clusterin (CLU) has been identified as a promising biomarker for CCA. Anti-CLU antibodies can specifically bind antigens with a KD value of 0.231 nM, and the diameter of the antibody-coated biosensor is only 0.488 mm. The optic fiber biosensor can accurately detect different concentrations of CLU with an R2 value of 0.989, and it cannot be disturbed by other free proteins, ions, or different temperatures, pH levels, and colors. The biosensor can identify CCA within 2 s with an area under curve (AUC) of 0.854. Moreover, the biosensor can be easily introduced into porcine bile ducts via digestive endoscopy with excellent biocompatibility. Then, the biosensor was applied to three patients with non-calculous biliary strictures, and the results of real-time detection matched postoperative pathology.
Conclusions: The CLU-based biosensor-endoscopy system enables accurate diagnosis of CCA through real-time in vivo detection, offering significant clinical translational potential.
Funding: Funding information is shown in the acknowledgments.
Background: The therapeutic efficacy and mode of combining immunotherapy with neoadjuvant chemoradiotherapy in proficient mismatch repair (pMMR)/microsatellite stable (MSS) locally advanced rectal cancer (LARC) remain uncertain.
Methods: In this multicenter, randomized, seamless phase 2/3 trial (ClinicalTrials.gov: NCT05484024), eligible participants were randomly assigned (1:1) to receive short-course radiotherapy (SCRT) (5 Gy × 5), followed by 4 cycles of capecitabine and oxaliplatin or 6 cycles of leucovorin, oxaliplatin, and fluorouracil, with (iTNT group) or without (total neoadjuvant therapy [TNT] group) 4 cycles of sintilimab. Following neoadjuvant therapy, participants underwent surgery or a watch-and-wait strategy based on clinical complete response. The primary endpoints were the complete response (CR) rate for phase 2 and the 3-year disease-free survival (DFS) rate for phase 3.
Findings: 218 patients were randomized to the iTNT group (n = 110) and the TNT group (n = 108). All patients completed SCRT, with 88.2% in the iTNT group and 93.5% in the TNT group completing 4 cycles of neoadjuvant treatment. The CR rate was significantly higher in the iTNT group (45.5% vs. 25.0%; p = 0.003). Grade 3-4 treatment-related adverse events were reported in 34.5% of the iTNT group and 19.4% of the TNT group (p = 0.012), with thrombocytopenia, diarrhea, leukopenia, and neutropenia being the most frequently observed. Grade 3-4 immune-related adverse events occurred in 5.5% of patients in the iTNT group.
Conclusions: The addition of the PD-1 inhibitor sintilimab significantly enhances the CR rate compared to SCRT-based TNT, with favorable tolerability in patients with pMMR/MSS LARC.
Funding: This work was funded by the National Natural Science Foundation of China (82473248) and the Shenzhen Medical Research Fund (C2301001).
In patients with locoregionally advanced, Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma, the DIAMOND trial demonstrated that eliminating the concurrent cisplatin radiosensitizer while maintaining PD-1 inhibition throughout a treatment course anchored by gemcitabine-cisplatin induction resulted in non-inferior three-year failure-free survival and significantly lower all-grade vomiting.1 While such a strategy may be considered for cisplatin-ineligible patients, substitution of immunotherapy for concurrent cisplatin in all-comers remains premature.
Background: Hypertension is a significant public health challenge in China, but evidence of current status and trends for hypertension prevalence and management is limited.
Methods: Data were derived from two nationally representative surveys including 750,208 Chinese adults. All analyses accounted for complex sample design weights. Hypertension was defined as a systolic blood pressure ≥140 mmHg and/or a diastolic blood pressure ≥90 mmHg and/or use of antihypertensive medication within 2 weeks.
Findings: The weighted prevalence of hypertension in 2021-2022 was 31.6% (95% confidence interval [CI] 30.1%-33.0%), representing a significantly absolute increase of 8.4% (95% CI 6.5%-10.2%) from 2012-2015 to 2021-2022. The prevalence of isolated systolic hypertension and isolated diastolic hypertension in 2021-2022 was 9.3% and 5.3%, respectively. In 2021-2022, the weighted rates of hypertension awareness, treatment, and control were 43.3% (95% CI 41.5%-45.2%), 38.7% (95% CI 36.9%-40.6%), and 12.9% (95% CI 11.6%-14.4%), respectively. The increases in hypertension prevalence were particularly pronounced among men and rural residents, who also tended to have a lower level of hypertension management. Age-standardized hypertension prevalence was 31.2% (95% CI 31.0%-31.4%) in the 2021-2022 survey and 22.3% (95% CI 22.2%-22.5%) in the 2012-2015 survey, respectively.
Conclusions: Hypertension prevalence in China has risen, while awareness, treatment, and control rates remain relatively low. These findings underscore the urgent need for tailored policies to enhance hypertension management.
Funding: The work was supported by the National Health Commission of the People's Republic of China and Major Science and Technology Special Plan Project of Yunnan Province.
Outcomes of clinical trials are traditionally labeled as positive or negative. Labeling of negative trials may have to be refined to better communicate the observed effects. This will distinguish negative trials with neutral outcomes (no difference between intervention and placebo) from trials with worse outcomes (worse outcome in intervention). We illustrate this concept with examples from recent trials.
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