This study aimed to assess the efficacy and safety of three dosing regimens of JMT103 in patients with bone metastases from solid tumors. Eligible patients were randomly assigned to receive JMT103 subcutaneously, 120 mg every 4 weeks (Cohort 1), 120 mg every 8 weeks (Cohort 2), or 180 mg every 8 weeks (Cohort 3) for up to 49 weeks. The primary endpoint was change from baseline to Week 13 in creatinine-adjusted urinary N-telopeptide (uNTx/Cr). Two hundred and ninety-five patients were randomized, and 293 received at least one dose of JMT103, of whom 96 were assigned to Cohort 1, 97 were assigned to Cohort 2, and 100 were assigned to Cohort 3. The median (interquartile range) percentage reduction in uNTx/Cr at Week 13 was 80.0% (49.9%, 93.4%) in Cohort 1, 73.0% (34.5%, 94.0%) in Cohort 2, and 75.7% (40.4%, 92.0%) in Cohort 3, respectively. On-study skeletal-related events were reported by 3.1% of patients in Cohort 1, 6.2% in Cohort 2, and 7.0% in Cohort 3. Treatment-emergent adverse events occurred in 289 patients, 162 of whom were deemed treatment-related. The most common treatment-related adverse events were hypocalcemia (23.2%), hypophosphatemia (22.9%), and increased aspartate transaminase (11.9%). JMT103 demonstrated a good safety and a strong suppression of the bone turnover markers.

In mainland China, cancer registration relies on household-registered populations, overlooking migrant populations. Estimating cervical cancer incidence among permanent residents, including migrants, offers a more accurate representation of the true burden. The data from 487 cancer registries across China in 2016 were analyzed using a Bayesian spatial regression model with the integrated nested Laplace approximation-stochastic partial differential equation method. The study estimated cervical cancer incidence among household-registered populations and adjusted for migrant populations using a weighting method based on interprovincial distribution and age stratification to derive the incidence of cervical cancer in the permanent residents. Data from the China Population Census, the China Migrants Dynamic Survey, and the Urban Statistical Yearbook were incorporated. The estimated crude incidence rate of cervical cancer among permanent residents was 17.4/100,000 in mainland China, with an age-standardized incidence rate (ASIR) of 17.2/100,000. The largest disparities in cervical cancer crude incidence rate between permanent residents and household-registered populations were observed in Guizhou (2.4/100,000, 95% CI 1.9-2.9/100,000), Zhejiang (-1.2/100,000, 95% CI -1.8 to -0.6/100,000) and Tianjin (-1.1/100,000, 95% CI -1.5 to -0.7/100,000). The number of the estimated cervical cancer incident cases was 8948. Guangdong saw an increase of 887 cases, while Henan had a decrease of 1430 cases. Guizhou had the highest ASIR (28.1/100,000), and Beijing had the lowest ASIR (11.0/100,000). The significance of this study is that it improves the accuracy of cervical cancer data in China. These findings provide evidence for developing cervical cancer prevention and control strategies, and offer insights for other countries and regions facing migration challenges.

An aggressive subtype of acute myeloid leukemia (AML) is caused by enhancer hijacking resulting in MECOM overexpression. Several chromosomal rearrangements can lead to this: the most common (inv(3)/t(3;3)) results in a hijacked GATA2 enhancer, and there are several atypical MECOM rearrangements involving enhancers from other hematopoietic genes. The set of enhancers which can be hijacked by MECOM can also be hijacked by BCL11B. Enhancer deregulation is also a driver of oncogenesis in a range of other malignancies. The mechanisms of enhancer deregulation observed in other cancer types, including TAD boundary disruptions and the creation of de novo (super-) enhancers, may explain overexpression of MECOM or other oncogenes in AML without enhancer hijacking upon translocation. Gaining mechanistic insight in both enhancer deregulation and super-enhancer activity is critical to pave the way for new treatments for AML and other cancers that are the result of enhancer deregulation.

Neurologic immune-related adverse events (nirAEs) represent rare, yet severe side effects associated with immune checkpoint inhibitor (ICI) therapy. Given the absence of established diagnostic biomarkers for nirAEs, we aimed to evaluate the diagnostic utility of serum Neurofilament Light Chain (NfL) and Glial Fibrillary Acidic Protein (GFAP). Fifty-three patients were included at three comprehensive cancer centers, of these 20 patients with manifest nirAEs and 11 patients with irHypophysitis. Controls included patients without any irAE (n = 8) and other irAEs (n = 14). Using a single-molecule enzyme-linked immunosorbent assay (Simoa), serum levels were measured prior to, during and after the manifestation of (n)irAEs in 80 samples. Symptom severity of the (n)irAEs was graded according to the Common Criteria for Adverse Events (CTCAE) version 5.0. Serum NfL levels were significantly higher in the nirAE group (n = 20) compared to irHypophysitis (n = 11; p = .0025) and controls (n = 22; p = .0384). Subgroup analysis demonstrated a significant elevation of NfL in nirAEs of the peripheral nerves (PNirAE) in contrast to neuromuscular syndromes (NMirAE) (p = .0260). GFAP levels were highest in patients with nirAE affecting the central nervous system (CNSirAE) compared to PNirAE and NMirAE (p = .0064). Symptom severity of nirAEs was associated with increased levels of NfL and GFAP (p = .0069, .0092). Individuals with elevated NfL levels exhibited less favorable outcomes of the (n)irAEs (p = .0199). Measurement of NfL and GFAP may be helpful for the differentiation of the broad spectrum of nirAEs and may serve as an indicator of symptom severity. Further investigation is needed to evaluate their potential as diagnostic and prognostic biomarkers.

Cell dedifferentiation is considered an important hallmark of cancer. The atavistic reversal to a unicellular-like (UC) state is a less widely accepted concept, so far not included in the conventional hallmarks. The activated expression of ontogenetically earlier and evolutionary earlier genes in cancers supports both theories because ontogenesis partially recapitulates phylogenesis during cell differentiation (the cellular biogenetic law). We directly contested both types of gene signatures in stem vs. differentiated and cancer vs. normal cells, using meta-analysis of human single-cell transcriptomes (totally, 38 pairwise comparisons involving over 18,600 cells). Because compared cells can differ in proliferation rate, the correction for cell cycle activity was applied. Taken together as multiple variables in stem vs. differentiated cells analyses, the ontogenetic signature excluded the UC signature from predictive variables, usually even forcing it to change the sign of prediction (from plus to minus). In contrast, in cancer vs. normal cells, the UC signature excluded the ontogenetic signature. Thus, the direct contest decided in favor of the atavistic theory and placed a UC-like state as a central hallmark of cancer, which has a plausible evolutionarily formed mechanism (UC attractor) and can generate other hallmarks. These data suggest a paradigm shift in the understanding of oncogenesis and propose an integrative framework for cancer research. In a practical sense, the upregulation of UC signature over ontogenetic signature indicates potential tumorigenicity, which can be used in early diagnostics and regenerative medicine. For therapy, these results suggest the UC center of cellular networks as a universal target.

Early-onset colorectal cancer (EOCRC) is an alarming entity worldwide. Yet, stage-specific characteristics and prognosis in localized and synchronous metastatic EOCRC are not well-defined. Two cohorts of CRC patients (localized and synchronous metastatic) were evaluated, defining EOCRC as the diagnosis <50 years old. Five hundred sixty-eight patients were included (n = 432 localized, 14.4% [n = 62] EOCRC and n = 136 synchronous metastatic, 20.6% [n = 28] EOCRC). 93.5% of localized and 96.5% of synchronous metastatic EOCRC patients were symptomatic at diagnosis. Among localized patients, female gender (58.1% vs. 40%, p = .008), perineural invasion (41.9% vs. 24.9%, p = .005), folinic acid, 5-fluorouracil, and oxaliplatin chemotherapy (45.2% vs. 25.2%, p = .003), and perioperative chemotherapy cycles (9.21 [± 3.10] vs. 7.98 [± 2.92], p = .006) were higher in EOCRC compared with ≥50-year. Median recurrence-free survival (RFS) and overall survival were not reached in either group (p = .234 and p = .831). Only RAS mutant status was associated with RFS (Hazard ratio: 7.09 [95% confidence interval (CI): 1.87-26.76], p < .001) in EOCRC. Among synchronous metastatic patients, urgent surgery (32.1% vs. 11.1%, p = .014) and local treatments (39.3% vs. 20.4%, p = .037) were more frequent in EOCRC. Median progression-free survival and overall survival in the EOCRC and ≥50 years were 8.07 months (95% CI: 5.03-12.97) vs. 10.03 months (95% CI, 8.40-13.10) (p = .450) and 18.57 months (95% CI, 13.33-43.03) vs. 19.83 months (95% CI, 16.07-27.30) (p = .833), respectively. Synchronous metastatic EOCRC more frequently underwent urgent surgery (32.1% vs. 8%, p = .008) and had RAS mutation (43.5% vs. 16.7%, p = .032) than localized EOCRC. This study suggests that localized and synchronous metastatic EOCRC patients may have different characteristics than average onset, without survival differences. Implementation of stage-specific characteristics into daily practice is necessary for decision-making processes in these young patients.

Accurate staging is essential for the optimal management of patients with colorectal cancer (CRC). The role of tumor deposits (TDs) in CRC staging has been contentious due to a lack of comprehensive understanding of their clinical and biological traits. In this retrospective study, we analyzed large data from 5718 CRC patients diagnosed between 2011 and 2022, ensuring rigorous data collection and long-term follow-up. Patients with positive TDs displayed aggressive clinical features. The risk factors for TDs varied among patients with different backgrounds of lymph node (LN) involvement, and the numbers of TDs and metastatic LNs showed a significantly positive correlation. TDs significantly impacted CRC prognosis, resulting in unfavorable outcomes irrespective of LN status. To delve into the biological characteristics of TDs, we performed transcriptome sequencing, immunohistochemistry, and Kaplan-Meier analyses on tissue samples from the additional CRC cohort and The Cancer Genome Atlas datasets. TDs exhibited aggressive biological phenotypes that were distinct from primary tumors and metastatic LNs, characterized by elevated signatures of epithelial-mesenchymal transition, angiogenesis, and immune suppression. Cox proportional hazards analysis was then applied to reassess the appropriate role of TDs within the TNM staging system, revealing that the prognostic weightiness of TDs in CRC corresponded to N2a rather than N1 in patients with 0-3 LN metastases. Overall, our comprehensive analysis showed that TDs, with their aggressive clinical and biological characteristics, could optimize the staging of CRC, highlighting the need to refine their role within the TNM staging system.

Control of cell-type-specific gene activation requires the coordinated activity of distal regulatory elements, including enhancers, whose inputs must be temporally integrated. Dysregulation of this regulatory capacity, such as aberrant usage of enhancers, can result in malignant transformation of cells. In this review, we provide an overview of our current understanding of enhancer-driven gene regulation and discuss how this activity may be integrated across time, followed by epigenetic and structural alterations of enhancers in cancers.

Chromosomal rearrangements involving the Mixed Lineage Leukemia gene (MLL1, KMT2A) are defining a genetically distinct subset in about 10% of human acute leukemias. Translocations involving the KMT2A-locus at chromosome 11q23 are resulting in the formation of a chimeric oncogene, where the N-terminal part of KMT2A is fused to a variety of translocation partners. The most frequently found fusion partners of KMT2A in acute leukemia are the C-terminal parts of AFF1, MLLT3, MLLT1 and MLLT10. Unfortunately, the presence of an KMT2A-rearrangements is associated with adverse outcomes in leukemia patients. Moreover, non-rearranged KMT2A-complexes have been demonstrated to be crucial for disease development and maintenance in NPM1-mutated and NUP98-rearranged leukemia, expanding the spectrum of genetic disease subtypes that are dependent on KMT2A. Recent advances in the development of targeted therapy strategies to disrupt the function of KMT2A-complexes in leukemia have led to the establishment of Menin-KMT2A interaction inhibitors that effectively eradicate leukemia in preclinical model systems and show favorable tolerability and significant efficacy in early-phase clinical trials. Indeed, one Menin inhibitor, Revumenib, was recently approved for the treatment of patients with relapsed or refractory KMT2A-rearranged acute leukemia. However, single agent therapy can lead to resistance. In this Review article we summarize our current understanding about the biology of pathogenic KMT2A-complex function in cancer, specifically leukemia, and give a systematic overview of lessons learned from recent clinical and preclinical studies using Menin inhibitors.

In 2018, we estimated that eligibility for and response to immune checkpoint inhibitor (ICI) therapies were 44% and 12%, respectively. Since these estimates were published, there have been additional approvals. We sought to provide updated estimates of the percentage of patients with advanced and/or metastatic cancers in the US who are eligible for and respond to immune checkpoint inhibitors (ICIs). Using a cross-sectional analysis (2011-2023) of US Food and Drug Administration approvals (FDA) and deaths reported by the American Cancer Society, we estimated the percentage of patients in the US with advanced or metastatic cancers who are eligible and respond to ICI therapies and the long-term response of ICI drugs. Eleven ICI drugs have been approved for 20 tumor types in the metastatic setting. The estimated eligibility for ICIs increased from 1.54% in 2011 to 56.55% in 2023. The estimated response to ICIs increased from 0.14% in 2011 to 20.13% in 2023. The tumor types with the highest contribution to response and eligibility estimates in 2023 were non-small-cell lung cancer with PD-L1 expression ≤50% and PD-L1 expression >50%. Sixteen drug approvals had long-term progression-free survival (PFS) data available at 3 years follow-up, and 2 had PFS data at 5 years follow-up. Estimated eligibility and response have increased over time, but many people with advanced or metastatic cancers are currently ineligible for ICIs. Only about one-fifth of the patients will respond. Given the wide range of uses, the cost implications of ICIs globally are large.

Individuals with AIDS and Kaposi sarcoma (AIDS-KS) with pulmonary involvement have high-risk of poor outcomes but diagnosis of pulmonary KS in low-resource settings is difficult. We aimed to discover plasma proteins that distinguish individuals with pulmonary KS from those without pulmonary involvement. SomaScan proteomics screen measured 7288 plasma proteins in 22 cases and 17 controls selected from 181 participants with HIV-1 and cutaneous KS who underwent bronchoscopy. Cases had KS in the lower respiratory tract by bronchoscopy. Controls had no KS lesions detected by bronchoscopy. Results of the proteomics screen were confirmed by ELISA measurement of plasma alpha-1-antichymotrypsin (SERPINA3) in 18 cases and 13 controls and in an additional 162 individuals with AIDS-KS who were not included in the case-control analysis. Proteomics identified 12 plasma proteins with differential levels in controls and cases. Plasma alpha-1-antichymotrypsin (SERPINA3) complex was consistently higher in cases compared to controls in the proteomics assay. Measurement of plasma alpha-1-antichymotrypsin by ELISA confirmed higher levels in cases (median 399.4, IQR 95.77-766.4 μg/ml) versus controls (median 39.98, IQR 31.2-170.2 μg/ml; p = .001). Plasma alpha-1-antichymotrypsin correlated with the estimated burden of pulmonary KS in the respiratory tract (r = 0.439; p = .0002) and 234 μg/ml had 51% sensitivity and 94% specificity for detection of pulmonary KS by bronchoscopy. Measurement of plasma alpha-1-antichymotrypsin has potential for identifying persons with pulmonary AIDS-KS and estimating the burden of KS in the lower respiratory tract.

Prostate cancer is a common malignancy that in 5%-30% leads to treatment-resistant and highly aggressive disease. Metastasis-potential and treatment-resistance is thought to rely on increased plasticity of the cancer cells-a mechanism whereby cancer cells alter their identity to adapt to changing environments or therapeutic pressures to create cellular heterogeneity. To understand the molecular basis of this plasticity, genomic studies have uncovered genetic variants to capture clonal heterogeneity of primary tumors and metastases. As cellular plasticity is largely driven by non-genetic events, complementary studies in cancer epigenomics are now being conducted to identify chromatin variants. These variants, defined as genomic loci in cancer cells that show changes in chromatin state due to the loss or gain of epigenomic marks, inclusive of histone post-translational modifications, DNA methylation and histone variants, are considered the fundamental units of epigenomic heterogeneity. In prostate cancer chromatin variants hold the promise of guiding the new era of precision oncology. In this review, we explore the role of epigenomic heterogeneity in prostate cancer, focusing on how chromatin variants contribute to tumor evolution and therapy resistance. We therefore discuss their impact on cellular plasticity and stochastic events, highlighting the value of single-cell sequencing and liquid biopsy epigenomic assays to uncover new therapeutic targets and biomarkers. Ultimately, this review aims to support a new era of precision oncology, utilizing insights from epigenomics to improve prostate cancer patient outcomes.

Colorectal cancer (CRC) is the second overall leading cause of cancer death in the United States, with recurrence being a frequent cause of mortality. Approaches to improve disease-free survival (DFS) are urgently needed. The gut microbiome, reflected in fecal samples, is likely mechanistically linked to CRC progression and may serve as a non-invasive biomarker. Accordingly, we leveraged baseline fecal samples from N = 166 stage I-III CRC patients in the ColoCare Study, a prospective cohort of newly diagnosed CRC patients. We sequenced the V3 and V4 regions of the 16S rRNA gene to characterize fecal bacteria. We calculated estimates of alpha diversity, beta diversity, and a priori- and exploratory-selected bacterial presence/absence and relative abundance. Associations of microbial metrics with DFS were estimated using multivariable Cox proportional hazards models. We found that alpha diversity was strongly associated with improved DFS, most strongly among rectal cancer patients (Shannon HR = 0.40 95% CI = 0.19, 0.87; p = .02). Overall microbiome composition differences (beta diversity), as characterized by principal coordinate axes, were statistically significantly associated with DFS. Peptostreptococcus was statistically significantly associated with worse DFS (HR = 1.62, 95% CI = 1.13, 2.31; p = .01 per 1-SD) and Order Clostridiales was associated with improved DFS (HR = 0.62, 95% CI = 0.43-0.88; p = .01 per 1-SD). In exploratory analyses, Coprococcus and Roseburia were strongly associated with improved DFS. Overall, higher bacterial diversity and multiple bacteria were strongly associated with DFS. Metagenomic sequencing to elucidate species, gene, and functional level details among larger, diverse patient populations are critically needed to support the microbiome as a biomarker of CRC outcomes.

With the rise of anti-vascular endothelial growth factor antibody and programmed cell death-ligand 1 (PD-L1) regimens, particularly bevacizumab and atezolizumab, as first-line treatments for advanced hepatocellular carcinoma (HCC), there is a need to explore PD-L1 and programmed cell death 1 inhibitors in combination therapies for unresectable HCC (uHCC). Integrating systemic therapies with locoregional approaches is also emerging as a potent strategy. This study compares the outcomes of atezolizumab (PD-L1 inhibitor) and sintilimab (programmed cell death 1 inhibitor) with bevacizumab or its biosimilar, combined with hepatic arterial interventional therapies (HAIT) in uHCC patients. From January 2020 to September 2023, a retrospective analysis was conducted on 138 uHCC patients at Sun Yat-sen University Cancer Center. The cohort included 69 patients treated with atezolizumab with bevacizumab (Bev/Ate) and 69 with bevacizumab biosimilar with sintilimab (Bio/Sin), combined with HAIT. The propensity score matching was also employed to further explore the efficacy and safety. The median progression-free survival (mPFS) was 13.8 months for the Bev/Ate group and 10.0 months for the Bio/Sin group (p = 0.188). The Bev/Ate group showed significantly longer intrahepatic mPFS (HR 0.381; 95% confidence interval 0.176-0.824; p = .018) and higher overall response rates compared with the Bio/Sin group (60.87% vs. 31.88%, p = .001; 69.57% vs. 49.28%, p = .024) based on Response Evaluation Criteria in Solid Tumors v1.1 and modified Response Evaluation Criteria in Solid Tumors criteria. Treatment-related adverse events were similar between groups (p > .050). Combining atezolizumab or sintilimab with bevacizumab or its biosimilar alongside HAIT provided similar overall PFS in uHCC patients. However, the atezolizumab-bevacizumab combination with HAIT showed superior intrahepatic PFS and control rates, warranting further validation.

Cancer diagnosis and therapy cause stress to the body. Preclinical studies have shown that stress hormones can stimulate tumor progression and metastasis by interacting with β-adrenergic receptors, and that β-blockers can inhibit those processes. We assessed if β-blocker use was associated with survival in a nationwide cohort of women with epithelial ovarian cancer (EOC). We identified all women aged ≥40 years who underwent EOC surgery in 2004-2018 in Norway through the Cancer Registry of Norway. We estimated the association between peri-diagnostic and post-diagnostic β-blocker use and survival. We used Cox models, adjusted for sociodemographic and health factors, and reported hazard ratios (HRs) and 95% confidence intervals (CIs). The difference in overall survival time between β-blocker users and non-users was estimated as the difference in restricted mean survival time at 5 years after diagnosis using flexible parametric models. We included 3911 women with EOC; 540 (14%) used β-blockers at diagnosis, 1672 (43%) died of the disease, and 1882 (48%) died overall. We found an association between peri-diagnostic β-blocker use and longer EOC-specific survival (HR = 0.85, 95%CI 0.73-1.00; p-value = 0.048), and an indication of an association with overall survival (HR = 0.89, 95%CI 0.77-1.02; p-value = 0.101). Analysis of post-diagnostic β-blocker use, which included only women who survived 12 months or longer (n = 3344), found similar associations. At 5 years from diagnosis, peri-diagnostic β-blocker users lived on average 1.28 months longer than non-users (95%CI 0.01-2.60 months). The results support the hypothesis that β-blocker use improves EOC-specific survival in women with EOC.

Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor that typically presents in infancy or early childhood. As awareness of KHE increases, it is imperative that the management of KHE be updated to reflect the latest evidence-based guidelines. The aim of this study was to integrate the literature and Chinese expert opinions to provide updated recommendations that will guide the diagnosis, treatment, and prognosis of patients with KHE. According to this consensus statement, 28 nationally peer-recognized experts in vascular anomalies and an expert in evidence-based medicine were assembled and formed three consensus subgroups. A series of key themes and questions were developed for each group, including recommendations for diagnosis, treatment, and prognosis. A systematic search was conducted for English-language articles published in PubMed and other relevant studies identified by the expert panel. A diagnosis of KHE necessitates the integration of clinical, imaging, and histologic features. The treatment of KHE should be tailored to the specific characteristics of each patient, including the size of the lesion, the presence of symptoms, the location, and the overall condition of the patient. In addition to focusing on the disease itself, it is also important to consider the complications of KHE and their impact on prognosis. The recommendations presented herein are intended to assist in the guidance of clinical practice and decision-making in patients with KHE, with the objective of improving patient outcomes.

We aimed to investigate socio-economic inequalities in second primary cancer (SPC) incidence among breast cancer survivors. Using Data from cancer registries in England, we included all women diagnosed with a first primary breast cancer (PBC) between 2000 and 2018 and aged between 18 and 99 years and followed them up from 6 months after the PBC diagnosis until a SPC event, death, or right censoring, whichever came first. We used flexible parametric survival models adjusting for age and year of PBC diagnosis, ethnicity, PBC tumour stage, comorbidity, and PBC treatments to model the cause-specific hazards of SPC incidence and death according to income deprivation, and then estimated standardised cumulative incidences of SPC by deprivation, taking death as the competing event. Multiple imputation was performed to account for missing data. Among 649,905 included women, 47,399 SPCs and 171,223 deaths occurred during 4,269,042 person-years of follow-up. Income deprivation was consistently associated with an increased rate of SPC incidence (cause-specific hazard ratio for the most vs. least deprived quintile: 1.29; 95% CI: 1.25, 1.33) and of death (1.36; 1.34, 1.38), translating into an absolute risk difference (the most vs. least deprived quintile) of 1.3% (95% CI: 1.0, 1.5) for SPC incidence and 4.9% (95% CI: 4.6, 5.1) for death at 10 years. Women with PBC from deprived areas in England faced a substantially higher risk of SPC than their counterparts. Future research is warranted to understand mechanisms for observed inequalities to inform strategies to monitor, prevent, and identify SPC in women with PBC.