The University of Texas MD Anderson Cancer Center (colloquially MD Anderson Cancer Center) is a comprehensive cancer center in Houston, Texas. It is the largest cancer center in the US and one of the original three comprehensive cancer centers in the country. It is both a degree-granting academic institution and a cancer treatment and research center located at the Texas Medical Center in Houston. It is affiliated with The University of Texas Health Science Center at Houston.
PURPOSE This first-in-human, dose-escalation and dose-expansion study evaluated the safety, tolerability, and antitumor activity of datopotamab deruxtecan (Dato-DXd), a novel trophoblast cell-surface antigen 2 (TROP2)–directed antibody-drug conjugate in solid tumors, including advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS Adults with locally advanced/metastatic NSCLC received 0.27-10 mg/kg Dato-DXd once every 3 weeks during escalation or 4, 6, or 8 mg/kg Dato-DXd once every 3 weeks during expansion. Primary end points were safety and tolerability. Secondary end points included objective response rate (ORR), survival, and pharmacokinetics. RESULTS Two hundred ten patients received Dato-DXd, including 180 in the 4-8 mg/kg dose-expansion cohorts. This population had a median of three prior lines of therapy. The maximum tolerated dose was 8 mg/kg once every 3 weeks; the recommended dose for further development was 6 mg/kg once every 3 weeks. In patients receiving 6 mg/kg (n = 50), median duration on study, including follow-up, and median exposure were 13.3 and 3.5 months, respectively. The most frequent any-grade treatment-emergent adverse events (TEAEs) were nausea (64%), stomatitis (60%), and alopecia (42%). Grade ≥3 TEAEs and treatment-related AEs occurred in 54% and 26% of patients, respectively. Interstitial lung disease adjudicated as drug-related (two grade 2 and one grade 4) occurred in three of 50 patients (6%). The ORR was 26% (95% CI, 14.6 to 40.3), and median duration of response was 10.5 months; median progression-free survival and overall survival were 6.9 months (95% CI, 2.7 to 8.8 months) and 11.4 months (95% CI, 7.1 to 20.6 months), respectively. Responses occurred regardless of TROP2 expression. CONCLUSION Promising antitumor activity and a manageable safety profile were seen with Dato-DXd in heavily pretreated patients with advanced NSCLC. Further investigation as first-line combination therapy in advanced NSCLC and as monotherapy in the second-line setting and beyond is ongoing.
Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. Specifically, the biallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive pediatric malignancies. Here, we developed embryonic mosaic mouse models of malignant rhabdoid tumors (MRTs) that faithfully recapitulate the clinical-pathological features of the human disease. We demonstrated that SMARCB1-deficient malignancies exhibit dramatic activation of the unfolded protein response (UPR) and ER stress response via a genetically intact MYC-p19ARF-p53 axis. As a consequence, these tumors display an exquisite sensitivity to agents inducing proteotoxic stress and inhibition of the autophagic machinery. In conclusion, our findings provide a rationale for drug repositioning trials investigating combinations of agents targeting the UPR and autophagy in SMARCB1-deficient MRTs.
The clinical translation of mesenchymal stem cell (MSC) therapies remains limited due to rapid cell clearance and stress-induced viability loss during injection. These limitations emphasize the need to develop delivery systems allowing MSCs to persist in the tissue and exert their biological effect. Cell microencapsulation within alginate (Alg) biomaterials is a promising strategy, where arginine-glycine-aspartic acid (RGD)-coupled alginate (RAlg) hydrogels have recently demonstrated improved bioactivity. However, achieving precise encapsulation and injectability while preserving cell viability remains an ongoing challenge. This study presents an injectable delivery platform using electrosprayed RAlg microcapsules that enhance viability and sustain the release of MSCs. Electrospray parameters were optimized to yield a microcapsule size of 175.4 ± 21.1 μm with high uniformity and consistent spherical morphology. Electron microscopy images of the microcapsules revealed a highly ordered microporous architecture. Physicochemical characterization confirmed that the presence of RGD peptides did not significantly alter the swelling, viscoelasticity, and encapsulation efficiency of Alg. Successful encapsulation of MSCs were observed, with cells assuming a round morphology within the microcapsule. After 14 days, RAlg maintained significantly higher cell viability at 91.3
Sinonasal adenocarcinomas (SNACs) are the second most common carcinoma category in the sinonasal tract after squamous cell carcinomas and include intestinal type adenocarcinoma, non-intestinal type adenocarcinomas and salivary-type adenocarcinomas. Improved morphologic and molecular characterization have established that most non-ITAC are phenotypically seromucinous with several provisional subtypes (BRAF V600E-mutated sinonasal ductal-like tumors, MAPK/PI3-K altered SNAC, CTNNB1-mutated sinonasal carcinoma, fusion-kinase associated SNAC e.g. ETV6::NTRK3, FGFR-rearranged biphasic SNAC). We report two biphasic/ bicellular ("oncocytic" and "basaloid") SNACs, with multimodal omics characterization, to further underscore the biological complexity of these tumors. One oncocytic case showed HRAS and AKT1 activating mutations; the other basaloid case had a FGFR2::SORB3 fusion. Spatial transcriptomics revealed divergent intra- and inter-tumoral signatures emphasizing the transcriptomic heterogeneity within biphasic components.
Background Accurate assessment of bone mineral density (BMD) is crucial for evaluating bone loss in elderly and oncologic patients. Quantitative computed tomography (QCT) enables noninvasive quantification of patient BMD and can be performed opportunistically during routine CT examinations using either conventional or multi-energy CT (MECT). While both methods are used clinically, MECT can address limitations of conventional CT-based QCT. Purpose This study addresses a critical gap in the literature by systematically evaluating commercially available calibration phantoms for use with MECT, assessing the impact of protocol variations, establishing a calcium-based material decomposition workflow for BMD quantification, validating phantom-derived metrics against patient data, and providing recommendations for integrating quality control (QC) into routine clinical workflows. Methods Five CT QC phantoms containing bone-approximating materials, including calcium (Phantom A), dipotassium phosphate (Phantom B), hydroxyapatite (Phantom C), and calcium carbonate (Phantoms D and E), were evaluated by determining the dual-energy ratio (DER) of inserts. Phantoms were scanned on two identical dual-source CTs at 90/150Sn and 100/150Sn kVp with dose levels of 10 and 20 mGy. Images were reconstructed using filtered back-projection and iterative reconstruction. Phantom DERs were compared with retrospective vertebral measurements from a 10-patient cohort. Results Phantom A provided the most suitable representation of patient data, exhibiting a DER of 1.55 [95%CI:1.54-1.57] at 100/150Sn kVp, compared with 1.44 [95%CI:1.37-1.50] in patients. kVp significantly influenced response, whereas radiation dose and reconstruction approach had minimal effect. Conclusions Phantom selection is critical for MECT-based QCT, and calcium-based phantoms are well-suited for clinical QC and BMD quantification workflows.
