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Health Outcomes Beyond Age 50 Years in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study
No full textPurpose: There are limited data on the risk for mortality and health outcomes among the increasing population of older (age \u3e50 years) survivors of childhood cancer during this later stage in life when there is an expected increase in aging-related morbidities.
Methods: We assessed cause-specific mortality, incident new cancers, chronic health conditions (CHCs), frailty, and health status among survivors from the Childhood Cancer Survivor Study, conditional on surviving to 50 years. We calculated conditional survival rates, standardized mortality ratios (SMRs), and, for incident new cancers, cumulative burden, standardized incidence ratios (SIRs), and relative rates (RRs), compared with the general US population. RRs for CHCs and prevalence ratios for frailty and health status outcomes were calculated for survivors compared with siblings. Piecewise exponential regression identified risk factors.
Results: Among 7,490 childhood cancer survivors alive at age 50 years, subsequent 5-, 10-, and 15-year mortality risks were 8%, 18%, and 32%, respectively; overall SMR was 3.2 (95% CI, 3.0 to 3.4). SMRs were highest for death due to new cancer (SMR = 4.7; 95% CI, 4.2 to 5.2). In subset analysis, survivors without radiation therapy (RT) exposure had similar new cancer rates as the general population. The population attributable fraction of new cancers to RT was 40%. Survivors had \u3e2-fold risk of severe, life-threatening, or fatal CHCs (any: RR, 2.6 [95% CI, 2.2 to 3.1]; multiple: RR, 3.3 [95% CI, 2.5 to 4.4]), specifically among survivors with history of RT exposure, compared with siblings. We identified no associations between chemotherapy and late health outcomes.
Conclusion: Older survivors of childhood cancer continue to have an elevated burden of premature mortality, new cancers, and adverse health outcomes as they age. The increased risk for cancer and CHCs among these older survivors is associated with RT, but not chemotherapy, exposure
Molecular Determinants of Sotorasib Clinical Efficacy in KRASG12C-Mutated Non-Small-Cell Lung Cancer
No full textMolecular determinants of KRAS(G12C)inhibitor efficacy in KRASG12C-mutated non-small-cell lung cancer (NSCLC) remain poorly characterized. Here we report one of the largest integrated analyses to date of sotorasib clinical efficacy biomarkers from the phase 2 CodeBreaK 100 and phase 3 CodeBreaK 200 studies. We reveal differential sotorasib activity and relative benefit compared to docetaxel across KRASG12C-mutated NSCLC co-mutational subsets and transcriptional subtypes. We also identify low expression of TTF1 and KEAP1 co-mutations/NRF2 activation as major determinants of sotorasib anti-tumor efficacy and adverse prognostic features. Exploratory analyses highlight potential tumor cell-extrinsic contributors to sotorasib anti-tumor activity and suggest that early on-treatment clearance of KRASG12C- circulating tumor DNA may refine clinical response prediction algorithms. Our findings advance precision medicine for patients with KRASG12C-mutated NSCLC and establish a framework for patient stratification and selection for treatment intensification with rationally applied therapeutic combinations
Belumosudil Reduces Oral Chronic Graft-Versus-Host Disease Tissue Inflammation and Fibrosis: A ROCKstar Companion Study
No full textBelumosudil (KD025), an oral, selective, Rho-associated, coiled-coil-containing protein kinase 2 (ROCK2) inhibitor, is approved for third-line treatment of chronic graft-versus-host disease (cGVHD). Previous studies demonstrated that ROCK2 inhibition reduces blood interleukin-17 (IL-17) activity and promotes regulatory T-cell (Treg cell) recovery. However, these studies did not evaluate immune responses within cGVHD-affected tissues. This study assessed tissue-level immune dynamics in 20 patients with oral cGVHD from the phase 2 ROCKstar trial, before and after 6 months of belumosudil treatment, focusing on key effector sites (oral mucosa [OM], minor salivary glands [MSGs], and skin) and the peripheral blood. After belumosudil treatment, reduction in collagen was observed in OM in parallel with decreased IL-17+ cell frequency in both OM (n = 14 pairs) and MSG (n = 11 pairs). IL-17 was primarily produced by non-T cells in the oral tissues. Immune cell frequencies in the OM decreased after treatment, whereas CD4 Treg cells increased in both the MSG and blood. Per overall or mouth-specific clinical response criteria, responders to belumosudil exhibited a reduction in collagen type I and IL-17 in the OM. Additionally, salivary transforming growth factor β1 (TGF-β1), a critical driver of fibrosis, decreased significantly, with a strong correlation observed between TGF-β1 and IL-17 levels. These findings illustrate the tissue-level response to belumosudil therapy and suggest that there is a reduction in tissue fibrosis and inflammation, thereby highlighting the therapeutic impact of ROCK2 inhibition in mitigating cGVHD. The ROCKstar study was registered at www.ClinicalTrials.gov as #NCT03640481
Molecular Testing for the World Health Organization Classification of Central Nervous System Tumors: A Review
No full textImportance: Molecular techniques, including next-generation sequencing, genomic copy number profiling, fusion transcript detection, and genomic DNA methylation arrays, are now indispensable tools for the workup of central nervous system (CNS) tumors. Yet there remains a great deal of heterogeneity in using such biomarker testing across institutions and hospital systems. This is in large part because there is a persistent reluctance among third-party payers to cover molecular testing. The objective of this Review is to describe why comprehensive molecular biomarker testing is now required for the accurate diagnosis and grading and prognostication of CNS tumors and, in so doing, to justify more widespread use by clinicians and coverage by third-party payers.
Observations: The 5th edition of the World Health Organization (WHO) classification system for CNS tumors incorporates specific molecular signatures into the essential diagnostic criteria for most tumor entities. Many CNS tumor types cannot be reliably diagnosed according to current WHO guidelines without molecular testing. The National Comprehensive Cancer Network also incorporates molecular testing into their guidelines for CNS tumors. Both sets of guidelines are maximally effective if they are implemented routinely for all patients with CNS tumors. Moreover, the cost of these tests is less than 5% of the overall average cost of caring for patients with CNS tumors and consistently improves management. This includes more accurate diagnosis and prognostication, clinical trial eligibility, and prediction of response to specific treatments. Each major group of CNS tumors in the WHO classification is evaluated and how molecular diagnostics enhances patient care is described.
Conclusions and relevance: Routine advanced multidimensional molecular profiling is now required to provide optimal standard of care for patients with CNS tumors
Feasibility of Manufacturing and Antitumor Activity of TIL for Advanced Endometrial Cancers
No full textLifileucel, a tumor-infiltrating lymphocyte (TIL) cell therapy approved for advanced melanoma, demonstrates promise for treating other solid tumors, including endometrial cancer (EC). The current study evaluates the feasibility of manufacturing TILs from EC tumors using Iovance’s proprietary 22-day Gen2 manufacturing process. Key parameters, including TIL yield, viability, immune phenotype, T-cell receptor clonality, and cytotoxic activity, were assessed. Of the 11 EC tumor samples processed at research scale, 10 (91%) successfully generated \u3e1 × 109 viable TIL cells, with a median yield of 1.1 × 1010 cells and a median viability of 82.8%. Of the four EC tumor samples processed at full scale, all achieved the pre-specified TVC and viability targets. Putative tumor-reactive T-cell clones were maintained throughout the manufacturing process. Functional reactivity was evidenced by the upregulation of 4-1BB in CD8+ T cells, OX40 in CD4+ T cells, and increased production of IFN-γ and TNF-α upon autologous tumor stimulation. Furthermore, antitumor activity was confirmed using an in vitro autologous tumor organoid killing assay. These findings demonstrate the feasibility of ex vivo TIL expansion from EC tumors. This study provides a rationale for the initiation of the phase II clinical trial IOV-END-201 (NCT06481592) to evaluate lifileucel in patients with advanced EC
National Immunization Awareness Month
No full textAugust marks National Immunization Awareness Month (NIAM)—a time to spotlight the vital role vaccines play in protecting people of all ages.
Explore the Power of Vaccines with Trusted Resources from the TMC Librar
Supporting Administrative Time for Advanced Practitioners: A Comprehensive Approach
No full textAdvanced practitioners (APs), including nurse practitioners (NPs), physician assistants (PAs), clinical nurse specialists, and pharmacists, are pivotal in health care. Despite their critical role, record numbers of APs are leaving the profession, primarily due to poor work-life balance, which contributes to burnout and high turnover rates. This article explores the impact of administrative time on AP job satisfaction and retention, drawing from recent surveys and case studies. Findings indicate that dedicated administrative time significantly enhances job satisfaction and reduces burnout, with data showing that APs with administrative time are less likely to leave their roles. The Advanced Practitioner Society for Hematology and Oncology (APSHO) prioritized addressing AP burnout in 2024 by advocating for structured administrative time. Following an extensive review of the literature and survey data, the APSHO Administrative Time Subcommittee recommends 8 hours of administrative time per week as reasonable for a full-time AP in clinical outpatient practice. Additionally, this committee proposes a comprehensive model for implementing administrative time. The call to action is clear: to sustain a high-quality health-care workforce, it is essential to support APs through policies that promote work-life balance, retention, and operational efficiency
Hermann Hospital One-Hundred Years
No full textIn 1925, Hermann Hospital opened its doors with a mission to provide quality healthcare to the people of Houston. One hundred years later, its legacy continues to shape the Texas Medical Center and the broader medical community.
Find out more at The McGovern Historical Center blog
Hyaluronan Network Remodeling by ZEB1 and ITIH2 Enhances the Motility and Invasiveness of Cancer Cells
Full text linkHyaluronan (HA) in the extracellular matrix promotes epithelial-mesenchymal transition (EMT) and metastasis; however, the mechanism by which the HA network constructed by cancer cells regulates cancer progression and metastasis in the tumor microenvironment (TME) remains largely unknown. In this study, inter-α-trypsin inhibitor heavy chain 2 (ITIH2), an HA-binding protein, was confirmed to be secreted from mesenchymal-like lung cancer cells when cocultured with cancer-associated fibroblasts. ITIH2 expression is transcriptionally upregulated by the EMT-inducing transcription factor ZEB1, along with HA synthase 2 (HAS2), which positively correlates with ZEB1 expression. Depletion of ITIH2 and HAS2 reduced HA matrix formation and the migration and invasion of lung cancer cells. Furthermore, ZEB1 facilitates alternative splicing and isoform expression of CD44, an HA receptor, and CD44 knockdown suppresses the motility and invasiveness of lung cancer cells. Using a deep learning-based drug-target interaction algorithm, we identified an ITIH2 inhibitor (sincalide) that inhibited HA matrix formation and migration of lung cancer cells, preventing metastatic colonization of lung cancer cells in mouse models. These findings suggest that ZEB1 remodels the HA network in the TME through the regulation of ITIH2, HAS2, and CD44, presenting a strategy for targeting this network to suppress lung cancer progression
Pan-Cancer Immune and Stromal Deconvolution Predicts Clinical Outcomes and Mutation Profiles
No full textTraditional gene expression deconvolution methods assess a limited number of cell types, therefore do not capture the full complexity of the tumor microenvironment (TME). Here, we integrate nine deconvolution tools to assess 79 TME cell types in 10,592 tumors across 33 different cancer types, creating the most comprehensive analysis of the TME. In total, we found 41 patterns of immune infiltration and stroma profiles, identifying heterogeneous yet unique TME portraits for each cancer and several new findings. Our findings indicate that leukocytes play a major role in distinguishing various tumor types, and that a shared immune-rich TME cluster predicts better survival in bladder cancer for luminal and basal squamous subtypes, as well as in melanoma for RAS-hotspot subtypes. Our detailed deconvolution and mutational correlation analyses uncover 35 therapeutic target and candidate response biomarkers hypotheses (including CASP8 and RAS pathway genes)