Precision Therapeutics (United States)

While primary invasive lobular carcinoma (ILC) is well characterized, metastatic ILC remains understudied. Within the post-mortem tissue donation programs, UPTIDER (Belgium) and Hope for Others (USA), we first aimed to explore intra-patient heterogeneity of key prognostic and predictive markers (stromal tumor-infiltrating lymphocytes (sTIL), estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and KI67). Secondly, we compared detection of the metastases by pathology on autopsy samples versus pre-mortem imaging. In total, 306 metastases from 12 patients were collected at autopsy (median: 27 per patient). Both primary tumors (n = 15) and metastases (n = 232) had low sTIL levels, with a median of 2% (range: 0.67-6.67%) and 0.67% (range: 0-13.33%), respectively. Regression models showed lower ER- and PR-expression in metastases (respectively, n = 265 and n = 64) compared to primary tumors (both p < 0.01). KI67 was significantly higher in metastases (n = 262, p = 0.02). HER2-low metastases were found in all but one patient although in varying proportion of metastases (range: 7.5-100%). Central radiology and pathology review had a median concordance of 78% at organ level (range: 33.33-100%) and 71% at patient level (range: 55.88-85.29%). Our findings suggest that a single metastatic biopsy has great limitations to guide treatment and that more adequate methods are needed to detect and monitor ILC metastases.

This study aimed to measure patient exposure dose during kilovoltage (kV) planar imaging in image-guided radiotherapy (IGRT) using a dose area product (DAP) meter and to estimate the DAP under unmeasured imaging conditions using two-dimensional cubic interpolation. Dose measurements during kV planar imaging were performed using a DAP meter (VacuDAP duo; VacuTec Meßtechnik, Dresden, Germany) attached to the kV X-ray tube of the On-Board Imager mounted on a TrueBeam linear accelerator (Varian Medical Systems, Palo Alto, CA, USA). DAP was measured under various imaging conditions, with tube voltages ranging from 60 to 140 kV and tube currents from 2.5 to 20 mAs. A two-dimensional cubic interpolation based on the measured data was implemented to estimate the DAP for unmeasured imaging conditions. The deviation from linearity was relatively larger under low-dose conditions, with a maximum deviation of 1.8% at 100 kV and 2.5 mAs. Nevertheless, the overall DAP for each mAs value exhibited high linearity (R2=1.00). The relative error of the estimated DAP was within 2.0%. The DAP meter was demonstrated to be effective for dose management in kV planar imaging in IGRT, and use of the two-dimensional cubic interpolation enabled accurate dose estimation even under unmeasured imaging conditions.

Evidence on pre-transplant metabolic therapy remains limited. We evaluated whether concurrent glucagon-like peptide-1 receptor agonist (GLP-1 RA) plus sodium-glucose cotransporter 2 inhibitor (SGLT2i) use before solid-organ transplantation was associated with post-transplant outcomes in adults with obesity and type 2 diabetes. A target trial is emulated using de-identified electronic health records from TriNetX US. Dual therapy is compared with GLP-1 RA, SGLT2i, and usual care using 1:1 propensity-score matching. The primary outcome is all-cause mortality at 12 months; kidney graft failure, rejection, complications, and infections are secondary. Sensitivity analyses included the global network,landmark, extensions at 24 and 36 months. Three matched cohorts are constructed, dual versus GLP-1 RA (n = 4718 pairs), dual versus SGLT2i (n = 4282), and dual versus usual care (n = 3787). At 12 months, dual therapy is associated with lower mortality versus GLP-1 RA (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.57-0.85), SGLT2i (0.59, 0.48-0.72), and usual care (0.52, 0.43-0.64).Infection endpoints are neutral or lower. Estimates are consistent across sensitivity analyses. In transplant candidates with obesity and type 2 diabetes, pre-transplant GLP-1 RA+SGLT2i use is associated with lowermortalitythan monotherapy or usual care. Prospective evaluation is warranted.

Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide, with late-stage diagnoses frequently leading to poor outcomes. This underscores the need for effective early-stage gastric cancer (ESGC) diagnostics. We introduce ESGCmiRD, an innovative artificial intelligence-driven strategy that identifies a miRNA signature for ESGC detection by integrating robust expression patterns, ESGC relevance, and regulatory capabilities of microRNA (miRNA) based on multiple networks. Expression and biological roles of miRNAs in GC were validated and explored via bioinformatics analysis and in vitro studies. miRNA-target interaction was confirmed by dual-luciferase reporter assay. Molecular docking predicted miRNA-drug binding affinities, assessing the miRNA signature's therapeutic potential. ESGCmiRD identified a blood miRNA signature (miR-320b, miR-222-3p, miR-181a-5p, miR-103a-3p, miR-107) for ESGC detection, demonstrated high diagnostic accuracy with AUC values of 0.986, 0.977, 0.815, and 0.811 in the test and three validation sets (GSE211692, TCGA-STAD, and our cohort), respectively. The five miRNAs were overexpressed in ESGC plasma and directly target PTEN, promoting GC cell proliferation, migration, and invasion. Molecular docking suggested Paclitaxel had the strongest potential interaction with these miRNAs. This method identifies a robust miRNA signature for ESGC detection and sheds light on gastric carcinogenesis mechanisms, opening doors for potential therapeutic strategies.

Breast cancer affects 1/8 of women throughout their lifetimes, with over 90% of cancer deaths being caused by metastasis. However, metastasis poses unique challenges to research, as complex changes in the microenvironment in different metastatic sites and difficulty obtaining tissue for study hinder the ability to examine in depth the changes that occur during metastasis. Rapid autopsy programs thus fill a unique need in advancing metastasis research. Here, we describe our protocol and processes for establishing and improving the US-based Hope for OTHERS (Our Tissue Helping Enhance Research and Science) program for organ donation in metastatic breast cancer. As of August 2024, we consented 114 patients and performed 37 autopsies, from which we collected 551 unique metastatic frozen tumor samples, 1244 FFPE blocks, 90 longitudinal liquid biopsy samples and developed 14 patient-derived organoid and 8 patient-derived xenograft models. We report in-depth clinical and histopathological information and discuss extensive new research and novel findings in patient outcomes, metastatic phylogeny, and factors in successful living model development. Our results reveal key logistical and protocol improvements that are uniquely beneficial to certain programs based on identifiable features, such as working closely with patient advocates, methods to rescue RNA quality in cases where tissue quality may degrade due to time delays, as well as guidelines and future expansions of our program.

Abstract Background: Colorectal cancer, a prevalent malignancy worldwide, poses a significant challenge due to the lack of effective prognostic tools. In this study, we aimed to develop a functional gene signature to stratify colorectal cancer patients into different groups with distinct characteristics, which will greatly facilitate disease prediction. Results: Patients could be stratified into high- and low-risk groups using the prediction model built based on the functional gene signature. This innovative approach not only predicts clinicopathological features but also reveals the tumor immune microenvironment types and responses to immunotherapy. The study reveals that patients in the high-risk group exhibit poorer pathological features, including invasion depth, lymph node metastasis, and distant metastasis, as well as unfavorable survival outcomes in terms of overall survival and disease-free survival. The underlying mechanisms for these observations are attributed to upregulated tumor-related signaling pathways, increased infiltration of pro-tumor immune cells, decreased infiltration of anti-tumor immune cells, and a lower tumor mutation burden. Consequently, patients in the high-risk group exhibit a diminished response to immunotherapy. Furthermore, the high-risk group demonstrates enrichment in extracellular matrix-related functions and significant infiltration of cancer-associated fibroblasts (CAFs). Single-cell transcriptional data analysis identifies CAFs as the primary cellular type expressing hub genes, namely ACTA2, TPM2, MYL9, and TAGLN. This finding is further validated through multiple approaches, including mIHC (multiplex immunohistochemistry), PCR (polymerase chain reaction), and western blot analysis. Notably, TPM2 emerges as a potential biomarker for identifying CAFs in colorectal cancer, distinguishing them from both colorectal cancer cell lines and normal colon epithelial cell lines. Co-culture of CAFs and colorectal cancer cells identified that CAFs could enhance the tumorigenic biofunctions of cancer cells indirectly, which could be partially inhibited by knocking down CAF original TPM2 expression. Conclusions: This study introduces a functional gene signature that effectively and reliably predicts clinicopathological features and the tumor immune microenvironment in colorectal cancer. Moreover, the identification of TPM2 as a potential biomarker for CAFs holds promising implications for future research and clinical applications in the field of colorectal cancer.

Mosaic loss of chromosome Y (mLOY) is the most commonly detected mosaic chromosomal alteration, and is associated with a range of health outcomes in males. We detected mLOY in 106,054 European (EUR), 13,927 admixed African (AFR), and 6,127 Hispanic (HIS) participants of the Million Veteran Program (MVP; Ntotal=544,112). mLOY was positively associated with cigarette smoking, and negatively with obesity and type 2 diabetes. Multi-ancestry genome-wide association meta-analysis of MVP and UK Biobank mLOY summary statistics, jointly comprising 167,899 cases and 581,224 controls, identified 380 independent risk loci—240 of which were novel. GWAS in MVP high cell fraction (CF&gt;10%) mLOY cases exhibited stronger effect sizes across risk loci. Local-ancestry-aware GWAS resolved ancestry-specific signals at BCL2L1 and SETBP1. Integrative eQTL analyses highlighted 51 genes that causally influence mLOY via differential expression. Finally, traits with genetic correlations and polygenic scores significantly associated with mLOY were selected for Mendelian randomization (MR), implicating thirteen traits as causal influences on mLOY, including triglycerides, high-density lipoprotein, and body mass index.

AimsPre-surgical risk classification tools for prostate cancer have shown better patient stratification with the addition of cribriform pattern 4 (CC) and intraductal prostatic carcinoma (IDC) identified in biopsies. Here, we analyse the additional prognostic impact of CC/IDC observed in prostatectomies using Cancer of Prostate Risk Assessment post-surgical (CAPRA-S) stratification.MethodsA retrospective cohort of treatment-naïve radical prostatectomy specimens from three North American academic institutions (2010–2018) was assessed for the presence of CC/IDC. Patients were classified, after calculating the CAPRA-S scores, into low-risk (0–2), intermediate-risk (3–5) and high-risk (6–12) groups. Kaplan-Meier curves were created to estimate biochemical recurrence (BCR)-free survival. Prognostic performance was examined using Harrell’s concordance index, and the effects of CC/IDC within each risk group were evaluated using the Cox proportional hazards models.ResultsOur cohort included 825 prostatectomies (grade group (GG)1, n=94; GG2, n=475; GG3, n=185; GG4, n=13; GG5, n=58). CC/IDC was present in 341 (41%) prostatectomies. With a median follow-up of 4.2 years (range 2.9–6.4), 166 (20%) patients experienced BCR. The CAPRA-S low-risk, intermediate-risk and high-risk groups comprised 357 (43%), 328 (40%) and 140 (17%) patients, and discriminated for BCR-free survival (p<0.0001). For CAPRA-S scores 3–5, the addition of CC/IDC status improved stratification for BCR (HR 2.27, 95% CI 1.41 to 3.66, p<0.001) and improved the overall c-index (0.689 vs 0.667, analysis of variance p<0.001).ConclusionThe addition of CC/IDC into the CAPRA-S classification significantly improved post-radical prostatectomy patient stratification for BCR among the intermediate-risk group (CAPRA-S scores 3–5). The reporting of CC and IDC should be included in future prostate cancer stratification tools for improved outcome prediction.

Pancreatic ductile adenocarcinoma (PDAC) has a dismal prognosis, with an overall 5-year survival of &lt;10%. At present, PDAC is treated using systemic chemotherapeutic regimens, which have shown survival benefit in clinical trials. Unfortunately, the survival benefit offered by the current standards do not greatly impact the 5-year overall survival statistics with the disease and are associated with toxicity. The large majority of PDACs are associated with a mutation in Kirsten Ras (KRAS), which results in constative activation of downstream signaling resulting in oncogenesis, tumor progression, cellular survival, and metastasis. Due to the lack of druggable sites, designing direct KRAS inhibitors have proven difficult and extensive effort has been placed in finding upstream or downstream targets as potential therapeutic avenues. The epidermal growth factor receptor (EGFR), hedgehog (HH), and mTOR signaling pathways have all gained recent attention as potential candidates for targeted PDAC therapies. Erlotinib, an EGFR small-molecule inhibitor, has shown promise in preclinical studies against PDAC. It is currently the only Food and Drug Administration (FDA) approved targeted therapy for PDAC when used in conjunction with gemcitabine. However, clinical trials comparing erlotinib plus gemcitabine to gemcitabine alone have demonstrated only modest statistical significance in overall survival. Due to the unique hypovascular microenvironment in PDAC, designated by the term desmoplasia, the HH signaling pathway has also gained recent research interest. Recent studies have shown lithium, a divalent cation originally FDA approved for bipolar disorder, to inhibit PDAC progression through its mechanism of glycogen synthase 3 inhibition in the HH pathway. Metformin, a biguanide medication used in type II diabetes mellitus, has been shown to inhibit mammalian target of rapamycin complex 1 (mTORC1) signaling indirectly through its activation of AMPK. Preclinical studies have demonstrated tumor regression, induction of apoptosis, and effects on the microenvironment in PDAC through the inhibition of mTORC1 by metformin. We present compelling scientific rationale, based on unique signal transduction pathways, tumor pathophysiology, and therapeutics potential for the combination of erlotinib, lithium, and metformin for the treatment of PDAC.