Citations

Abstract Context There are limited head-to-head trials comparing pharmacological treatments for acromegaly. Objective Systematically review the efficacy and safety of pharmacological treatments for acromegaly and conduct a network meta-analysis (NMA) enabling indirect comparisons. Methods MEDLINE and Embase were searched to identify randomized controlled trials (RCTs) of acromegaly therapies. Screening and data extraction followed PRISMA guidelines. Feasibility assessment evaluated homogeneity and consistency assumptions required for NMA. Bayesian NMAs estimated relative treatment effects and ranking probabilities. Results Twenty-two records covering 18 RCTs were included. Biochemical control rates were comparable among long-acting injectable somatostatin receptor ligands (SRLs), including lanreotide autogel (LAN-ATG), octreotide long-acting release (OCT-LAR), pasireotide, the GH receptor antagonist pegvisomant, oral octreotide (O-OCT), octreotide subcutaneous depot (SC-OCT-D), and the once-daily oral SRL paltusotine. Paltusotine demonstrated significantly higher biochemical control vs O-OCT and SC-OCT-D (odds ratios [ORs], 95% credible intervals [CrIs]: 7.34 [1.48-36.07] and 7.85 [1.72, 36.25]). Pasireotide showed significantly higher biochemical control vs OCT-LAR (OR: 2.03 [1.29-3.23]). Paltusotine had significantly lower discontinuations due to adverse events (AEs) vs O-OCT and SC-OCT-D, (ORs: 0.022 [0.001-0.424] and 0.022 [0.001-0.343]), with similar rates to other treatments. Treatment-emergent AEs (TEAEs) and serious TEAEs were comparable across treatments. Rankings suggested paltusotine as the treatment with the highest probability of ranking as the most effective (or tolerable) treatment across all endpoints studied. Conclusion This systematic review and NMA consolidate recent high-quality RCT evidence for acromegaly treatments. Paltusotine emerges as a promising alternative to injectable SRLs, with favorable efficacy, safety, and AE-related discontinuation patterns. These findings may inform clinical decision-making and guideline development, if confirmed by clinical experience.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is unresponsive to immune checkpoint therapies largely due to immunosuppression mediated by myeloid and lymphoid cells. Effective treatment strategies require, in addition to immune stimulation, the depletion of these immunosuppressive cells and their interactions. Here, we demonstrate for the first time, that a single verteporfin-based photodynamic therapy (PDT) treatment triples median survival in a KPC-PDAC model when combined with anti-PD1 therapy. Mechanistically, apart from reducing CK19 + tumor cells, PDT depletes immunosuppressive myeloid (CD11c+) and lymphoid (FOXP3+) cell populations, by ~ 4- and ~ 18.4-folds, respectively. PDT further disrupts interactions between these immunosuppressive cells, attenuating a key immune-tolerance axis. At the systemic level, PDT reduces splenic immunosuppression through modulation of tumor-derived cytokines. Within this reprogrammed immune-landscape, anti–PD-1 therapy elicits robust CD8 + T-cell responses, reflected by an ~ 6.7-fold increase in the intratumoral CD8+/Treg ratio. Collectively, these findings establish verteporfin-PDT as an immune-priming strategy that complements anti–PD-1 therapy by alleviating immunosuppression in PDAC.

Abstract Metabolic reprogramming is a fundamental determinant of immune cell fate and effector function during inflammation, yet how distinct metabolic pathways regulate pathogenic lung macrophage activity and contribute to fibrotic remodeling remains incompletely understood. Here, we integrated single-cell RNA sequencing, lineage-specific genetic mouse models, and fate-mapping approaches to define the metabolic pathways that regulate the pro-fibrotic activity of lung macrophages. We found that such cells undergo pronounced aerobic glycolysis in the bleomycin-induced mouse model of pulmonary fibrosis. Myeloid cell-specific depletion of lactate dehydrogenase A (Ldha), but not of mitochondrial pyruvate carrier (Mpc), markedly attenuated lung fibrosis and improved survival. Mechanistically, enhanced glycolytic flux increased lactate production, which promoted histone lysine lactylation and facilitated Arginase 1 (Arg1) expression in lung macrophages, thereby driving fibrotic progression. Using monocyte fate-mapping, we further demonstrated that Arg1 expression is largely restricted to recruited monocyte-derived macrophages rather than lung-resident macrophages. Notably, selective deletion of Ldha in granulocyte-monocyte progenitors and their progeny was sufficient to suppress Arg1 expression and reduce fibrosis severity. In human lung samples, we observed significantly elevated expression of ARG1 and key glycolytic enzymes in patients with idiopathic pulmonary fibrosis, despite species-specific differences in the immune cell types expressing ARG1. Together, these findings identify an aerobic glycolysis–lactate–histone lactylation axis that regulates pro-fibrotic myeloid cell function and represents a potential therapeutic target in pulmonary fibrosis.

Abstract Objective: This study aimed to develop a machine learning model for the diagnosis of chronic renal failure (CRF) with spleen–kidney qi deficiency (SKQD) syndrome by investigating facial chromatic biomarkers based on traditional Chinese medicine (TCM) theory. Materials and Methods: This cross-sectional study analyzed TCM-defined facial regions in 303 patients with CRF (166 SKQD and 137 non-SKQD) and 25 healthy controls using active appearance models and RGB/Lab color spaces. Key chromatic features were selected using Chi-square automatic interaction detection (CHAID) decision trees to construct a multibranch deep convolutional neural network (CNN), nomogram, and hybrid model. The model performances were compared using the DeLong test. Results: The SKQD group showed a higher glomerular filtration rate, albumin level, and facial R-value with a lower serum creatinine level (all P < 0.05), accompanied by a higher prevalence of shortness of breath with reluctance to speak, and cold extremities ( P < 0.05) compared with the non-SKQD group. Chromatic analysis revealed elevated R/a values in the kidney region using the natural facial color region method ( P < 0.05), and distinctively higher R -values in the bladder-uterus region and a -values in the right small intestine region using the Mingtang facial color region method ( P < 0.05). The CHAID algorithm selected four diagnostic determinants, including the overall facial R -values. The CNN achieved superior discriminative performance (test area under the receiver operating characteristic curve = 0.74 vs. nomogram 0.68, DeLong test P < 0.001) with no added benefit from model integration ( P > 0.05). Conclusions: Facial chromatic biomarkers effectively differentiated SKQD in patients with CRF when analyzed using TCM-defined regions. The superior performance of the CNN validates AI-driven TCM diagnostics as a clinically actionable tool for precise syndrome classification.

Abstract Polycomb group (PcG) proteins form the Polycomb Repressive Complexes 1 and 2 (PRC1/2), which regulate gene expression through histone modifications. Their dysregulation is implicated in cancer. Genomic analysis of prostate cancer datasets revealed a striking divergence: PRC1 genes are frequently amplified in metastatic disease (SU2C), correlating with poor survival, higher tumor mutational burden (TMB), and enhanced androgen receptor (AR) signaling. In contrast, primary prostate cancer (PRAD) is characterized by recurrent deletion of the 3p13 locus, which harbors the gene for the non-canonical PRC1 subunit RYBP. Transcriptomic analysis indicated that RYBP loss derepresses gene expression, consistent with its role in transcriptional repression. Functionally, RYBP expression positively correlates with AR activity and negatively associates with neuroendocrine (NEPC) differentiation. Spatial and single-cell transcriptomics further show that RYBP is enriched in normal epithelial cells but downregulated in tumor cells. Besides, tumors with lower RYBP expression exhibit an immunosuppressive microenvironment, characterized by increased regulatory T cells. Collectively, these findings position RYBP deletion not only as a novel DNA-based biomarker for primary prostate cancer but also as a pivotal epigenetic deregulation event that coordinates oncogenic signaling and lineage plasticity.

We searched for oncogenes activated by copy number increases using whole-genome sequencing data of 535 pancreatic ductal adenocarcinomas (PDACs). We found that gains of 1q were the second most common gain, occurring in 213 (39.8%) of PDACs. Single-cell analysis via fluorescence in situ hybridization on 33 cancers confirmed these results. A portion of 1q, rather than the entire 1q arm, was gained in 75 (14.0%) PDACs, allowing us to pinpoint two ~3-megabase regions of 1q that were nearly always gained. These two regions contained NCSTN and PSEN2 , genes that code two subunits of the γ-secretase complex. Evaluation of 267 precancerous lesions revealed that extra copies of NCSTN and PSEN2 were common (49%) in noninvasive neoplasms (high-grade pancreatic intraepithelial neoplasms), which are at relatively high risk for progression to PDACs, but uncommon (6%) in low-grade pancreatic intraepithelial neoplasia lesions, which have low malignant potential. We hypothesize that γ-secretase genes are genetically activated oncogenes in the early phases of pancreatic neoplasia.

Abstract Background: Up to 68% of patients will experience CIPN. There are no FDA or ASCO recommended therapies. The pain (P), numbness (N), and tingling (T) can persist for month, years or even lifetime. Duloxetine reduces pain scores by 0.6-1.0 on the 0-10 scale but does not help N or T. Scrambler therapy (ST) is a novel form of neuromodulation that uses EKG electrodes on the dermatomes to capture the pain c-fiber receptors, and generate an action potential of “non-pain” information to replace the pain information. It appears to reset central sensitization by altering cerebral blood flow and re-establishing the balance of neuropeptides (e.g., NGF, GDNGF) in the blood (Smith et al NEJM 2023). Yet many professionals and patients are unaware of it. Methods: We reviewed all available studies. Results: Smith et al (2010, VCU) noted a 59% P reduction (5.8 to 2.4 at the end of 10 days (P&lt;0.0001)) in 16 subjects, and 4 had 0 pain at day 10. Pachman et al (2015, Mayo) in 37 subjects showed a 53% P reduction by day 10; a 44% reduction in T; and a 37% reduction in N. In a randomized trial of 50 patients using ST versus TENS (transcutaneous electrical nerve stimulation), Loprinzi et al (2020, Mayo), in a randomized trial, showed more than twice as many ST patients reported a 50% improvement (36-56%) vs. TENS (16-28%). At 8 weeks the reductions were important: 33%P, 28%N, 41%T. In a subsequent crossover trial (Childs 2021) of the TENS patients to ST, 6 of 12 ST patients achieved a 50% reduction in P and T. Smith et al (2021 Hopkins) did a randomized sham-controlled trial with 35 patients but observed no lasting effect; in retrospect, the electrodes and electrode placement were incorrect in this trial. Abdi et al (2024, MDACC) did a Phase II trial of ST in 10 patients and found symptoms of N, T, trouble walking, and disturbed sleep had significant improvements at 6 months. Worst pain was reduced at 6 months by 3 points. Pain medication use decreased by 70% at the end of treatment and by 42% at 6 months. Patient satisfaction was high (82%) and no adverse events with ST treatment were reported. Wang Z. et al (Hopkins, unpublished data 2025) showed a 60% reduction in pain (6.2 to 2) in twelve subjects, with one achieving complete remission. Strouse et al (2025, UCLA) will soon report similar results in over 60 patients. Wang E. et al (2023, Hopkins) reviewed 1152 patients treated with ST and found just 3 adverse events: one hematoma and two red spots under the EKG electrodes. The only other therapy that reduces all the symptoms of CIPN is spinal cord stimulation (Gupta 2024) but that is invasive, expensive, and can cause a multitude of adverse events. Conclusions: Scrambler Therapy is a safe and effective treatment for the P, N, and T of CIPN with rare and minimal side effects in a syndrome with no other effective treatment. It is hindered by reimbursement ($32/30 minutes, the same as TENS even though the technology is completely different). Scrambler Therapy should become more available in the future. Citation Format: Z. Wang, C. L. Loprinzi, S. Abdi, T. B. Strouse, T. J. Smith. Scrambler Therapy: a safe and effective way to treat chemo-induced neuropathy [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-02-17.