Abstract The Social Vulnerability Index (SVI) identifies communities that may be vulnerable to health issues and need additional support. Studies have explored the incidence and mortality of many common cancers using the SVI but not chronic lymphocytic leukemia (CLL). This study aimed to assess the relationship between CLL survival rates and social vulnerability factors in the Detroit Tri-County Area using the SVI. This was a retrospective study among people diagnosed with CLL from 2016 to 2020 as recorded in the Metropolitan Detroit Cancer Surveillance System. Participants’ SVI scores, based on address at diagnosis, were categorized into quartiles. The lowest quartile (Q1) represented the lowest social vulnerability and thus a greater capacity to withstand the effects of a public health crisis. The highest quartile (Q4) represented the highest social vulnerability. Proportional hazard regression was used to estimate the hazard of death for each quartile. The final sample was 1406 people with CLL living in the Detroit Tri-County Area. Within Q4, notable variables were racial and ethnic minority status (65.1% of people), a sub-150% poverty level (43.4%), and living in cost-burdened occupied housing units with an annual income of less than $75,000 USD (39.9%). With respect to survival outcomes, those in Q1 had the highest 5-year survival rate (76.7%). In comparison, those in Q4 were 2.02 times more likely to die from CLL compared to those in Q1. This study’s findings provide a foundation for the implementation of programs and policy changes to address socioeconomic and survival rate disparities among CLL patients.
Abstract Primary mediastinal large B-cell lymphoma (PMBL) is a subtype of non-Hodgkin B-cell lymphoma that most frequently occurs in young adults and is thought to reflect neoplastic transformation of thymic medullary B-cells. We characterized 59 PMBL cases from the Atlas of Blood Cancer Genomes Project. The cohort was predominantly young (median age 35), female (62%), and included individuals from diverse racial backgrounds. Most individuals presented with low-stage disease, favorable ECOG performance status, and high overall survival rate at last follow-up (89%). Whole transcriptome sequencing of 49 PMBL cases revealed gene expression profiles distinct from diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), both activated B cell-like (ABC) and germinal center B cell-like (GCB) cell-of-origin subtypes. PMBLs showed significantly higher expression of thymic B cell-associated genes (p=0.032), supporting their presumed thymic origin. Whole exome and targeted sequencing confirmed recurrent mutations in JAK/STAT, NF-κB signaling, and DNA damage response pathways, with frequent aberrant somatic hypermutation (aSHM) affecting multiple genes. Recurrent copy number alterations included gains at 9p and 12, and losses at 13q. As in prior studies, CIITA rearrangements with diverse partners were recurrent. Although PMBL generally demonstrates excellent outcomes, aSHM-positive cases exhibited inferior progression-free survival (p=0.031), suggesting aSHM as a potential adverse prognostic marker. Our findings further refine the genomic landscape of PMBL and provide new insights into the biology of this neoplasm, with implications for prognostic stratification.
Abstract Recent data indicate that radiation-induced papillary thyroid carcinomas (PTC) after the 1986 Chornobyl accident can be distinguished from sporadic PTC by examining patterns of DNA damage related to the generation of oncogenic drivers. PTC with fusion/structural variant (SV) drivers generated from two breakpoints with <20 basepairs (bp) breakpoint loss/gain (fusion2B<20bp) were consistent with radiation causation based on a series of analyses, including higher frequency with increasing radiation dose and an even distribution by sex. In contrast, fusion≥3B≥1000bp-, RAS-, and BRAFV600E-driven PTC exhibited no dose association and female predominance, as observed in sporadic PTC. We conducted DNA and RNA sequencing and reconstructed thyroid radiation dose for 229 PTCs to replicate and extend previous reports. Combined analyses with 331 published PTCs enabled investigation of dose and sex distributions for additional, less common fusion/SV driver categories. Among newly characterized PTCs, only fusion2B<20bp had statistically significantly lower female predominance and higher dose compared with BRAFV600E (67.1% vs. 82.4% female, P=0.034; median dose=186 vs. 52 mGy, P=6.410-5; 0% vs. 11.0% in unexposed), replicating the previous report (pooled Psex=7.910-4; pooled Pdose=3.010-10). Analyses of additional fusion/SV driver categories revealed similarly elevated doses for fusion≥3B<20bp (N=4, median=203 mGy, P=9.210-3). Doses were also significantly higher but to a lesser extent for fusion2B<1000bp (N=34, median=131 mGy, P=6.210-4) and fusion≥3B<1000bp (N=13, median=127 mGy, P=5.010-5). Our results suggest that the amount of loss/gain at the fusion/SV driver breakpoint appears to be a more informative feature than the number of DNA DSBs for distinguishing radiation-induced from sporadic tumor groups in this dose range.
Abstract Radiotherapy is clinically established in rectal cancer and is also used in selected colon cancer settings. However, treatment resistance and post-irradiation tumor regrowth remain major clinical challenges, and the residual cellular states that survive irradiation and later drive tumor regrowth remain poorly defined. We investigated irradiation-surviving persister populations in colorectal cancer (CRC), with a particular focus on cancer stem cell-associated changes, using CRC cell lines and patient-derived CRC organoids, including radiation-resistant models. Cells were analyzed before and after irradiation by flow cytometry, cell-tracing experiments, proliferation and drug sensitivity assays, xenograft studies, RNA sequencing, and DNA methylation profiling. In conventional CRC cell lines, CD44 and CD133 distributions remained largely unchanged after irradiation, even in radiation-resistant models. In contrast, patient-derived CRC organoids revealed the emergence of a CD44low persister population after irradiation. Cell-tracing experiments demonstrated that this population arose predominantly from parental CD44high cells rather than from expansion of pre-existing CD44low cells. Surviving CD44low cells regenerated CD44high cells, reconstituted parental-like heterogeneity, and exhibited enhanced proliferative capacity, chemoresistance, and tumor-forming ability with more prominent mucinous features compared with the surviving CD44high fraction. In radiation-resistant organoids, the CD44low/SSEA-4high persister population was associated with global hypomethylation and activation of pluripotency-related programs, including upregulation of NANOG, POU5F1, and SOX2 with reduced promoter-region methylation. These findings support the presence of an irradiation-associated, reversible CD44low/SSEA-4high persister state with epigenetic alterations linked to tumor regrowth and therapeutic resistance. Treatment-induced plasticity and associated epigenetic alterations may represent potential avenues for therapeutic intervention to achieve more durable radiotherapy responses in CRC.
PURPOSE Preclinical data suggest that the anti-cancer efficacy of ATR inhibitors can be synergistically enhanced by low-dose gemcitabine. To test the clinical feasibility of this regimen, we conducted a phase 1 trial of low-dose gemcitabine combined with the ATR inhibitor elimusertib (BAY1895344). PATIENTS AND METHODS This phase 1 study evaluated the combination of gemcitabine and elimusertib in patients with previously treated, incurable solid tumors. The primary objective was to assess the safety and tolerability of this regimen and to determine the maximum tolerated dose (MTD). Secondary objectives included assessment of objective response rate (ORR) per RECIST v.1.1 and characterization of the pharmacokinetic (PK) profile. RESULTS Fourteen patients were enrolled; most patients had pancreatic cancer (n=6) or ovarian cancer (n=6). The median age was 63.5 years of age, and the median number of prior therapies was 2. The regimen caused significant toxicity, and four patients (28%) discontinued the trial due to treatment-related adverse events. The trial was stopped prior to establishing an MTD due to the pharmaceutical company's decision to halt development of the agent. A confirmed partial response was observed in one patient with platinum-refractory ovarian cancer harboring a gain in CCNE1. Another patient with pancreatic adenocarcinoma harboring biallelic ATM loss remained on trial for 9.5 months with stable disease, with an 85% decrease in CA19-9. CONCLUSIONS The combination of low-dose gemcitabine combined with elimusertib was not tolerable. Although evidence of anti-tumor activity was observed, significant improvements in tolerability are required for future ATR inhibitor combinations to be clinically feasible.
