Citations

Abstract Clonal hematopoiesis (CH) of indeterminate potential (CHIP), driven by somatic mutations in leukemia-associated genes, confers increased risk of hematologic malignancies, cardiovascular disease, and all-cause mortality. In blood of healthy individuals, small CH clones can expand over time to reach 2% variant allele frequency (VAF), the current threshold for CHIP. Nevertheless, reliable detection of low-VAF CHIP mutations is challenging, often relying on deep targeted sequencing. Here, we present UNISOM, a streamlined workflow for enhancing CHIP detection from whole-genome and whole-exome sequencing data that are underpowered, especially for low VAFs. UNISOM utilizes a meta-caller for variant detection, in couple with machine learning models which classify variants into CHIP, germline, and artifact. In whole-exome sequencing data, UNISOM recovered nearly 80% of the CHIP mutations identified via deep targeted sequencing in the same cohort. Applied to whole-genome sequencing data from Mayo Clinic Biobank, it recapitulated the patterns previously established in much larger cohorts, including the most frequently mutated CHIP genes and predominant mutation types and signatures, as well as strong associations of CHIP with age and smoking status. Notably, 30% of the identified CHIP mutations had < 5% VAFs, demonstrating its high sensitivity toward small mutant clones. This workflow is applicable to CHIP screening in population genomic studies. The UNISOM pipeline is freely available at https://github.com/shulanmayo/UNISOM and https://ngdc.cncb.ac.cn/biocode/tool/7816.

Abstract There are limited prospective data on whether established risk factors modify breast cancer risk in women with pathogenic variants (PV) in BRCA1/2 and virtually no risk modification data for ATM, CHEK2, or PALB2. We conducted a nested case–control study in the Women’s Health Initiative (WHI), randomly selecting women with and without breast cancer for DNA sequencing. We evaluated breast cancer odds associated with obesity, family cancer history, smoking, alcohol, parity, breastfeeding, oophorectomy, tubal ligation, neighborhood socioeconomic status, and menopausal hormone therapy (MHT) with estrogen and progestin or estrogen only in PV carriers and noncarriers. In exploratory analyses, we grouped genes by established predisposition for estrogen receptor (ER)-positive (ATM and CHEK2) or ER-negative (BRCA1 and PALB2) disease. Multivariable models with interaction terms were used to assess differential risk modification by PVs. Among 12,957 WHI participants, 287 carried PVs. Breastfeeding was modestly associated with reduced risk for PALB2 [OR = 0.08; 95% confidence interval (CI), 0.00–0.92; P value = 0.042]. With one-sided 95% CI, power was sufficient to exclude OR ≥2.0 with obesity for ATM and BRCA2; smoking and alcohol for CHEK2; no breastfeeding for ATM; no oophorectomy for BRCA2 and CHEK2; no tubal ligation for CHEK2; and neighborhood socioeconomic status for all genes. Estrogen + progestin MHT was modestly associated with increased risk for ER-positive PVs (OR = 7.31; 95% CI, 1.14–64.20; P = 0.036). PVs did not modify risk (interaction P ≥ 0.05). BRCA1/2, ATM, CHEK2, and PALB2 PV carriers do not have breast cancer OR ≥2.0 with many established risk factors. However, MHT warrants additional study in PV carriers. Significance: There is limited information on whether established risk factors increase breast cancer risk from PVs. In the WHI, PV carriers had no substantial (≥2-fold) increase with most risk factors, except potentially MHT in ATM or CHEK2 carriers. The results may inform counseling and research on MHT.

Précis: Micropulse transscleral laser treatment (MP-TLT) and continuous wave transscleral cyclophotocoagulation demonstrated comparable intraocular pressure across all follow-ups. MP-TLT was associated with significantly lower risks of ocular complications, such as hypotony, prolonged inflammation, and phthisis bulbi. Purpose: To compare the efficacy and safety of micropulse transscleral laser treatment (MP-TLT) and continuous wave transscleral cyclophotocoagulation (CW-TSCPC) for the treatment of glaucoma or ocular hypertension. Methods: A systematic search was conducted in PubMed, Cochrane Library, Embase, and ClinicalTrials.gov. Randomized controlled trials (RCTs) or cohort studies comparing MP-TLT and CW-TSCPC were included. Weighted mean differences (MDs) were computed for continuous endpoints and risk ratios (RRs) for binary endpoints, with 95% CIs. Heterogeneity was assessed with I 2 statistics. Software R, version 4.4.0, was used for statistical analyses. Subgroup analyses were conducted on glaucoma types. Results: Eleven studies encompassing 1054 eyes from 986 patients were included, with 47.4% receiving MP-TLT. There were no significant differences in IOP between CW-TSCPC and MP-TLT at 1 week, 1 month, 3 months, 6 months, 12 months, and 18 months of follow-up. The MP-TLT group required a significantly higher number of hypotensive medications but displayed significantly reduced risks of overall complications, ocular hypotony, prolonged inflammation, and phthisis bulbi compared with CW-TSCPC. Conclusion: MP-TLT and CW-TSCPC showed similar efficacy in IOP control. However, MP-TLT demonstrated a greater safety profile, suggesting its potential suitability for patients requiring repeat interventions or those with lower tolerance for ocular complications.

ABSTRACTIntroduction/AimsNeuromuscular ultrasound (NMUS), initially performed by physicians, is increasingly performed by technicians in many electrodiagnostic (EDX) laboratories for certain studies under physician supervision. The aims of this study were to determine: (1) the reproducibility of nonphysician sonographers' assessments of the median nerve and (2) the need for ongoing training to maintain the reproducibility and reliability of median nerve ultrasound assessments.MethodsThe median nerve was examined sonographically in a healthy volunteer by 12 nonphysicians on 3 separate occasions: Day 1 and then 2 weeks (Day 2) and 4 months (Day 3) later. Cross‐sectional area (CSA) and wrist‐to‐forearm ratios (WFRs) were calculated each time. Sonographers were retrained prior to Day 2. Reproducibility and reliability were determined using coefficients of variation calculated for each characteristic for each day and each nonphysician sonographer, comparing performance across the 3 time points.ResultsThere was overall less variation for each characteristic (wrist CSA, forearm CSA, and WFR) on Day 2 compared to Day 1 (coefficients of variation 3.0%, 5.4%, and 5.7% vs. 8.8%, 15.5%, and 11.3%, respectively), both when viewed at the group and individual levels, indicating an improvement in reproducibility and reliability after the retraining session. The improvement was similar for Day 3.DiscussionThis study demonstrates the need for training and subsequent retraining sessions to ensure the reproducibility and reliability of NMUS measurements in the median nerve.

Abstract Background Early tumor shrinkage and depth of response have emerged as potential prognostic indicators in metastatic colorectal cancer (CRC). However, their associations with overall survival, progression-free survival (PFS), and postprogression survival in patients receiving anti–epidermal growth factor receptor (EGFR) antibodies or bevacizumab remain unclear. Methods We analyzed 3219 treatment-naive patients with RAS wild-type metastatic CRC from 8 randomized studies (CRYSTAL, OPUS, PRIME, CAIRO2, CALGB80405, WJOG4407G, ATOM, PARADIGM) in the Aid and Research in Digestive Cancerology database. Early tumor shrinkage was defined as a 20% or more reduction in tumor size at 8 ± 2 weeks, whereas depth of response was assessed by maximum tumor shrinkage at nadir. Cox regression models evaluated the associations of early tumor shrinkage and depth of response with overall survival, PFS, and postprogression survival, adjusting for confounders. A 2-sided test was conducted with a significance level of .05. Results Early tumor shrinkage and depth of response substantially stratified overall survival, PFS, and postprogression survival outcomes across all treatment groups. Early tumor shrinkage positivity was associated with improved overall survival, PFS, and postprogression survival in anti-EGFR and bevacizumab-based therapies, with a trend toward better outcomes in the anti-EGFR group. The depth of response analysis revealed optimal cutoff values of 0.55 for anti-EGFR–based therapy and 0.47 for bevacizumab-based therapy to achieve a median overall survival of approximately 32 months. Conclusions Early tumor shrinkage and depth of response serve as valuable prognostic markers in RAS wild-type metastatic CRC, particularly for patients treated with anti-EGFR antibodies. These findings highlight the potential role of early tumor shrinkage and depth of response in guiding treatment strategies and improving outcomes for patients with CRC.

Abstract Background: Given the dramatic rise in incidence of colorectal cancer in young adults, there remain limited treatment options effective in metastatic disease. Although T cell-based therapies have been successful in treating highly antigenic cancers, like melanoma and lung, they have not yet been shown to induce consistent and durable tumor regression in common epithelial malignancies, including metastatic colorectal cancer (mCRC). CISH (Cytokine inducible SH2 containing protein) is a novel intracellular checkpoint target demonstrating PD-L1 ligand independent mechanisms of enhanced anti-cancer activity. Given that CISH is not currently tractable via antibody or small molecule drug modalities, we employed CRISPR for precise inhibition of CISH in tumor infiltrating lymphocytes (TILs). Here, we provide the first clinical report of safety and anti-tumor activity of CISH edited TILs in 12 patients with metastatic gastrointestinal cancers (NCT04426669), including a clinical complete response (CR) in a young-adult patient with immunotherapy-refractory mCRC. Methods: Tumors were surgically resected for TIL harvest, followed by a rapid expansion protocol and CRISPR/Cas9 knockout (KO) CISH. CISH KO, neoantigen-reactive TILs were expanded, then infused following non-myeloablative lymphocyte depleting (LD) chemotherapy (cyclophosphamide & fludarabine) followed by high-dose IL-2. To establish mechanistic attribution of the CR, we used iR-RepSeq+ for serial analysis of the TCR immune repertoire. Results: Our CRISPR engineering led to KO of CISH in T cells with high-efficiency (>90%) without detectable off-target editing. We safely dosed patients at all five dose levels (range: 1.91e8 to 9.93e10 cells). No dose-limiting toxicities attributable to the CISH-KO TIL product were observed. Adverse events were consistent with established risks of LD chemotherapy, IL-2, or disease progression. A durable ongoing complete response (>21 months) was achieved in a patient with microsatellite instability-high (MSI-H) mCRC refractory to anti-PD1/CTLA-4 combination therapy. Conclusions: We provide the first clinical report of CISH checkpoint targeting via genetically modified T cell therapy, with complete response in a patient with mCRC. Persistence and expansion of unique TCR clonotypes detected in neoantigen responsive TIL was temporally consistent with spikes in CISH edited alleles detected by NGS assay; in the patient with CR, four of the clonotypes exhibiting prolonged persistence greater than one-year post-infusion exhibited significantly reduced or undetectable expression of CISH compared to the total infused TIL population. Given these findings, further investigation of CISH checkpoint inhibition, via gene and cell therapy, and next-generation small molecule drugging modalities, is underway. Citation Format: Emil Lou, Modassir S. Choudhry, Timothy K. Starr, Timothy Folsom, Jason Bell, Blaine Rathmann, Anthony P. DeFeo, Ji Hyun Kim, Nicholas Slipek, Zhaohui Jin, Darin Sumstad, Christopher A. Klebanoff, Katherine Ladner, Akshat Sarkari, R Scott McIvor, Thomas A. Murray, Jeffrey Miller, Madhuri Rao, Eric Jensen, Jacob Ankeny, Mahmoud A. Khalifa, Anil Chauhan, Benjamin Spilseth, Ajay Dixit, Paolo P. Provenzano, Wenjing Pan, Daniel Weber, Miranda Byrne-Steele, Tom Henley, David H. McKenna, Matthew J. Johnson, Beau R. Webber, Branden S. Moriarity. First-in-human trial in patients with metastatic colorectal cancer using CRISPR-engineered tumor infiltrating lymphocytes in which the intracellular immune checkpoint CISH is inhibited [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT269.

Refractory ascites often requires therapeutic paracentesis, which is associated with potential risks and diminished quality of life. Terlipressin is a vasopressin analog that is indicated for i.v. bolus injection for hepatorenal syndrome, with the potential to reduce large-volume ascites and its complications. Continuous infusion of terlipressin is associated with fewer adverse effects than bolus dosing. The efficacy and safety of continuous infusion of a novel liquid formulation of terlipressin acetate (BIV201) were evaluated in this open-label phase 2 study. Patients with cirrhosis and refractory ascites were randomly assigned (2:1) to receive two 28-day cycles of continuous infusion BIV201 plus standard of care (SOC) separated by a ≤56-day washout (n=10), or SOC alone (n=5). Data analysis was limited by the small sample size and confounded by a potential interaction with gabapentinoids in the BIV201+SOC group. Nonetheless, there were differences in favor of BIV201+SOC versus SOC in the coprimary efficacy endpoints and several quality of life assessments. The beneficial effects of BIV201 on liver complications (mean: 90% CI; BIV201-completers=2.87: 1.51; 5.46 vs. SOC=2.38: 1.20; 4.73) and the change in cumulative ascites (mean: 90% CI; BIV201-completers=−10.76: −26.51; 5.00 vs. SOC=−4.99: −21.95; 11.97) were more pronounced versus SOC in the 5 BIV201+SOC patients who completed both treatment cycles. There were also greater improvements in exploratory quality of life assessments and the percent change in therapeutic paracenteses with BIV201+SOC (−27.94±41.80) versus SOC (−16.67±45.64). Despite the high rate of hyponatremia in the BIV201+SOC group (4/10 patients), the safety profile suggested that continuous BIV201 infusion was well tolerated. These findings support further development of BIV201 in confirmatory trials.