Search Results (4,881)

Background: Elevated abdominal adipose tissue at time of diagnosis is associated with breast cancer mortality. We sought to understand the association between abdominal adipose tissue (subcutaneous, SAT and visceral, VAT) assessed via dual-energy X-ray absorptiometry (DXA) and breast cancer mortality in the prevention setting. Methods: Women enrolled in the Women’s Health Initiative study with baseline whole-body DXA scans were included in the study (n = 9767). Causes of death were adjudicated up to 27 years of follow-up. Competing risk models were used to examine independent associations between baseline VAT, SAT, per 100 cm², and breast cancer-specific deaths; findings were reported as sub-hazard ratios (SHR) and confidence intervals (CI). Time-varying analyses additionally included DXA at years 3 and 6. Covariates included demographic, lifestyle, and tumor factors. Results: Baseline VAT and SAT ranged from undetectable to 616.25 cm² and 55.26–952.46 cm², respectively. There were 738 incident breast cancer cases post-enrollment, and 87 breast cancer-related deaths. Median age at diagnosis was 62 years. In adjusted models, higher baseline VAT and SAT were significantly associated with higher risk breast cancer mortality (49% and 40%, respectively); time-varying models were similar. Conclusions: Higher VAT and SAT were similarly associated with breast cancer mortality in this group of postmenopausal women. Full article

Background: Cancer-associated cachexia is a multifactorial metabolic syndrome characterized by progressive skeletal muscle and/or adipose tissue loss and affects approximately 40% of patients with non-small cell lung cancer (NSCLC). However, reliable circulating biomarkers for early detection and risk stratification remain undefined. Based on prior observations linking elevated circulating mitochondrial DNA (mtDNA) to cachexia, we hypothesized that mtDNA and inflammatory protein levels in plasma could predict cachexia onset and trajectories. Methods: We evaluated 27 patients with stage IV NSCLC enrolled in the SeroNet-CORALE cohort with plasma samples collected between 2020 and 2023. Forty biomarkers were quantified at two timepoints (T1 and T2) using a multiplexed MesoScale Discovery platform. Associations between log2-transformed biomarker levels and cachexia status were assessed using Firth’s penalized logistic regression. Results: Among 27 patients (65% female; mean age 65 ± 10 years; 89% adenocarcinoma histology), cachectic patients exhibited lower body mass index at both time points (T1: 21.0 ± 2.0 vs. 27.0 ± 7.0; T2: 21.8 ± 4.9 vs. 25.2 ± 4.9). At T1, cachexia was strongly associated with elevated GDF15 (OR 4.29; 95% CI 1.04–29.74; p = 0.044) and IL-15 (OR 43.83; 95% CI 2.39–>999; p = 0.007), whereas IL-4 had a protective association (OR 0.09; 95% CI 0.00–0.66; p = 0.013). At T2, cachexia was associated with higher mtDNA levels (OR 2.13; 95% CI 1.07–7.69; p = 0.022) and lower levels of IL-15, IL12/IL23p40, and MDC. Conclusions: Distinct inflammatory and mitochondrial biomarkers tracked cachexia evolution in advanced NSCLC, with early GDF-15/IL-15 elevations and later increases in circulating mtDNA. Larger longitudinal studies are warranted to validate these findings and define their clinical relevance. Full article

Radiotherapy is a mainstay in the management of locally advanced lung cancer; however, intrinsic and acquired radioresistance contribute to poor prognosis. S6K1, a serine/threonine kinase, regulates cell growth, protein synthesis, and survival, and is increased in tumors, which is linked to enhanced survival under therapeutic stress, including radiation. The mechanisms, however, are not fully understood. This study investigates the role of S6K1 in lung cancer radioresistance and the mechanisms involved. Intrinsic radioresistance in lung cancer cells was associated with increased S6K1 activation. Pharmacologic inhibition or genetic deletion of S6K1 enhanced radiosensitivity both in vitro and in vivo, highlighting the therapeutic potential of targeting S6K1. Transcriptomic analysis revealed that S6K1 deletion significantly downregulated STAT3 expression, a transcription factor that promotes radioresistance. S6K1 deletion reduced STAT3 phosphorylation and transcriptional activity, thereby sensitizing lung cancer to radiation. Additionally, radiation exposure or overexpression of a constitutively active S6K1 isoform restored STAT3 activation in S6K1 knockout cells, underscoring the regulatory role of S6K1 in STAT3 signaling. Together, these findings establish a novel S6K1–STAT3 axis that drives radioresistance in lung cancer and suggest that targeting this pathway may enhance radiotherapy efficacy. Full article

Breast cancer represents a paradigmatic model of precision oncology, with treatment strategies increasingly guided by molecular profiling and biomarker-driven targeted therapies. Despite these advances in biological personalization, clinical outcomes remain strongly influenced by psychological and psychiatric factors that are still insufficiently integrated into oncological decision-making. This gap underscores the need for a broader, person-centered model of personalization that extends beyond tumor biology. This narrative review synthesizes current evidence on contemporary personalized strategies in breast cancer management, with a specific focus on the integration of precision oncology and psycho-oncology. A structured literature search was conducted across major biomedical databases to identify studies addressing molecular stratification, targeted treatments, psychiatric comorbidity, psychological profiles, and psycho-oncological interventions relevant to treatment personalization. While molecular classification and biomarker-guided therapies have substantially improved breast cancer outcomes, high rates of depression, anxiety, psychological distress, and maladaptive coping styles are consistently reported across disease stages. These psychological and psychiatric dimensions significantly influence treatment adherence, tolerability, quality of life, and ultimately clinical outcomes. Growing evidence supports the systematic use of psychological screening tools and tailored psycho-oncological interventions, both psychological and pharmacological, as integral components of personalized cancer care. Integrated care models combining oncological and psycho-oncological expertise are associated with improved patient-reported outcomes and may enhance overall therapeutic effectiveness. True personalization in breast cancer treatment extends beyond biological precision and requires the structured integration of psycho-oncological assessment and intervention into routine clinical pathways. Bridging precision oncology and psycho-oncology enables a more comprehensive, patient-centered approach, optimizing adherence, quality of life, and long-term outcomes. Future strategies should prioritize multidisciplinary models of care and the development of integrated clinical frameworks to achieve genuinely personalized breast cancer management. Full article

Background: Dendritic and histiocytic cell sarcoma (DHCS) and clear cell sarcoma (CCS) are ultra-rare soft-tissue sarcomas characterized by diagnostic ambiguity, limited treatment guidelines, and poor outcomes. Their rarity has restricted the development of evidence-based management strategies, leaving clinical decisions reliant on small case series and institutional experience. DHCS typically presents without a unifying molecular driver and is often misclassified without comprehensive immunophenotyping. CCS is defined by EWSR1-ATF1/CREB1 fusions but exhibits low responsiveness to conventional chemotherapy. There remains a clear need to clarify natural history, therapeutic responses, and molecular characteristics in both. Methods: We conducted a retrospective cohort study of adult patients with histologically confirmed DHCS or CCS seen at The Ohio State University Comprehensive Cancer Center between 2010 and 2022. Demographics, treatment modalities, clinical outcomes, and molecular profiles were extracted and analyzed descriptively. Time to progression (TTP) and progression rates by treatment modality were recorded. A structured literature review was conducted to provide context for the findings. Results: Outcomes are descriptive and cohort-specific, reflecting institutional experience rather than generalizable estimates. Total of 10 patients with DHCS and 5 with CCS were evaluable. Most DHCS patients presented with metastatic disease. Among DHCS patients who received systemic therapies, five of eight (62.5%) experienced progression during or shortly after treatment. Among CCS patients who received systemic therapies, three of four (75%) progressed during or shortly after treatment. Overall mortality occurred in 4 of 10 DHCS patients (40%) and 3 of 5 CCS patients (60%). TP53 mutations were identified in four of seven next-generation sequencing (NGS)-tested DHCS cases, and PD-L1 positivity was detected in five of seven tested DHCS cases and one of five tested CCS cases. Conclusions: Despite multimodal treatment, this referral-based cohort of patients with ultra-rare DHCS and CCS showed high rates of progression and mortality. Our findings underscore the urgent need for multi-institutional collaboration and biomarker-driven clinical trials to guide management of these ultra-rare sarcoma subtypes. Full article

Triple-negative breast cancer (TNBC) is characterized by marked clinical and molecular heterogeneity, which underlies the limited success of currently available targeted therapies and results in most patients relying on cytotoxic chemotherapy. This therapeutic gap underscores the pressing need for novel therapeutic approaches, in which non-coding RNAs (ncRNAs) have emerged as promising candidates. In this systematic review, 35 pre-clinical studies published between 2020 and 2025 were analyzed to evaluate the therapeutic potential of targeting ncRNAs in TNBC, including miRNAs, lncRNAs, and circRNAs. The original articles employed in vivo tumor models to assess the therapeutic response of ncRNA expression modulation, using miRNA mimics, antagomiRs, ASOs, shRNAs, and siRNAs integrated into advanced targeted delivery systems, such as nanoparticles and exosomes. According to the selected studies, 28 specific ncRNAs were identified as actionable molecular targets. Modulation of these molecules consistently resulted in tumor growth suppression, metastasis inhibition, and restoration of sensitivity to standard chemotherapeutic agents. Collectively, the pre-clinical evidence presented in these studies positions ncRNA-based therapies as innovative, promising, and potentially effective strategies for advancing TNBC treatment. Full article

Near-infrared (NIR) imaging, including NIR-I (800–1000 nm) and NIR-II (1000–1700 nm), has been primarily evaluated using separate cameras with different detectors, limiting comparison. We investigated whether using a single-camera system capable of both NIR-I and NIR-II acquisition, NIR-II improves spatial resolution and contrast-to-noise ratio (CNR) for nanoparticle-based imaging. Dual-mode, dual-Gd ICG (DMDG-ICG) nanoparticles were characterized for absorption and fluorescence. A custom NIR imaging system using a single InGaAs camera enabled visualizing both NIR-I and -II windows. In vitro, capillary tubes containing nanoparticles in water, in tissue-mimicking Intralipid, or covered with mouse skin were imaged, and full-width-half maximum (FWHM) and CNR were measured. In vivo, the mouse femoral artery was imaged after IV nanoparticle delivery. DMDG-ICG showed strong fluorescence at both NIR-I and NIR-II. Scatter greater at NIR-I than NIR-II increased with depth and tissue layers. FWHM was lower and CNR higher at NIR-II versus NIR-I for up to 10 mm depth (p < 0.05, n = 3) in Intralipid. In vivo, femoral artery CNR was also higher at NIR-II (p < 0.05, n = 3). Using a single-camera system allowing direct comparison, NIR-II imaging provided greater penetration, spatial resolution, and CNR compared to NIR-I. The findings support the utility of NIR-II for vascular and molecular imaging applications. Full article

Triple-negative breast cancer (TNBC), particularly the androgen receptor-low (AR-low) subtype, is one of the most aggressive and hard-to-treat forms of BC, characterized by a high index of proliferation, chromosomal instability (CIN), and high prevalence of TP53 mutations. These features fuel therapy resistance, metastases, and poor clinical outcomes. An integrated framework describing the dysregulated molecular networks that support the pathobiology of AR-low TNBC is lacking. Multiple published studies in breast cancer have previously proposed mechanistic links between TP53 loss, AR-low states, and heightened FOXM1-driven G2/M transcriptional programs, potentially via deregulation of E2F activity, chromatin-associated co-regulators (e.g., ATAD2), and disruption of repressive networks involving p53–p21–DREAM and SPDEF. Additional reports suggest that FOXM1-associated circuitry may be reinforced by chromatin regulators such as WDR5 and by mitotic/spindle factors such as ASPM, including through feedback interactions and condensate-associated transcriptional organization. We previously showed that FOXM1, a master regulator transcription factor, is upregulated and is a biomarker of poor prognosis in AR-low TNBC. In this study, we filtered a set of “TNBC core genes” known to promote transcriptional chaos downstream of FoxM1. We identified a set of 15 cell cycle regulators—including mitotic kinesin motors (KIF14, KIF11, KIF4A, KIF2C, and KIF20A), centromeric proteins (CENPA, CENPO, CENPL, CENPF, and OIP5), and regulators of proteolysis (UBE2C, UBE2S, UBE2T, PSMD14, and TUBA1B). These 15 genes, which were ranked highly among genes overexpressed in TNBC featured prominently in gene signatures of chromosomal instability and were also overexpressed among AR-low TNBCs and TP53-mutant breast tumors. We show that expression of each of these 15 genes correlates positively with proliferation markers (Ki67, PCNA, and MCM2) in TNBC, and that the overexpression of this gene set is associated with shorter relapse-free survival and distinct immune/stromal infiltration patterns. In light of prior work, our findings point to a FOXM1-associated 15-gene signature enriched in AR-low TNBC and associated with the high-proliferation and high-CIN phenotypes of this clinically challenging tumor type. This 15-gene set represents an actionable vulnerability with therapeutic potential for AR-low TNBC and provides a framework for rethinking how to manage highly proliferative, genomically unstable BCs. Full article

Non-muscle-invasive bladder cancer (NMIBC) comprises approximately 75% of new bladder cancer cases and generally carries a favorable prognosis, yet high rates of recurrence and progression necessitate close surveillance with frequent cystoscopies and repeated transurethral resections. Upfront treatment for high-risk disease is typically Bacillus Calmette-Guérin (BCG), although combinations with immune checkpoint inhibitors have reported results. Patients with BCG-unresponsive, intolerant, or refractory disease represent a subset of patients with high risk of progression, with early radical cystectomy being the standard approach for this setting. Global BCG shortages and the substantial impact of cystectomy on quality of life underscore the need for therapeutic alternatives. Over the past decade, investigational trials in immunotherapy have expanded treatment options for BCG-unresponsive NMIBC with CIS, leading to FDA approval of intravesical nadofaragene firadenovec, nogapendekin alfa-inbakicept, and systemic pembrolizumab. This narrative review summarizes developments in intravesical and systemic immunotherapies for NMIBC, highlights ongoing trials, and addresses controversies in trial design, treatment sequencing, comparative efficacy, and safety. Full article

Candida esophagitis (CE) is the most common fungal infection of the esophagus and an increasingly recognized complication in patients with solid organ malignancies. Once primarily associated with advanced HIV/AIDS and hematologic malignancies, the epidemiology has shifted in the modern era of antiretroviral therapy and intensive cancer treatments. Patients with solid tumors receiving chemotherapy, corticosteroids, broad-spectrum antibiotics, and proton pump inhibitors (PPIs) are at a heightened risk for CE due to synergistic immunosuppressive and mucosal barrier-disrupting effects. Clinically, CE in cancer patients often present with odynophagia, dysphagia, or chest pain, but a considerable proportion of cases are asymptomatic or non-specific, complicating diagnosis and needing a high index of suspicion. Endoscopic evaluation with characteristic white plaques and histopathologic confirmation remains the diagnostic gold standard, as symptoms as oropharyngeal findings are unreliable indicators of esophageal infection. Disease management centers on systemic antifungal therapy. Fluconazole is the first-line treatment, achieving high cure rates, while echinocandins and posaconazole are reserved for refractory cases or non-albicans infections. Prompt therapy is crucial, as untreated CE can lead to malnutrition, interruptions in cancer therapy, and rare but serious complications (e.g., necrotizing esophagitis or perforation). We provide a comprehensive review of the epidemiology, risk factors, clinical manifestations, pathogenesis, diagnosis, and management of CE in solid organ cancer patients. Gaps in knowledge are highlighted, including the need for better non-invasive diagnostics, antifungal resistance surveillance, and tailored prophylactic strategies. A high index of suspicion and early recognition and treatment of CE in oncology patients can improve nutritional status, quality of life, and continuity of cancer care. Full article

Background/Objectives: Metaplastic breast carcinoma (MpBC) is a rare and aggressive malignancy characterized by significant histological heterogeneity and limited response to standard chemotherapy. Due to its morphological diversity, MpBC often presents diagnostic challenges and can overlap with other mesenchymal tumors. This study aimed to characterize the genomic landscape of MpBC using a nationwide Japanese database and to explore the molecular basis of its diagnostic ambiguities and therapeutic responses. Methods: We retrospectively analyzed genomic and clinical data from 123 MpBC cases registered in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database. To evaluate diagnostic boundaries, genomic profiles of histological mimickers, including 19 cases of angiosarcoma and eight cases of myoepithelial carcinoma, were also examined. Furthermore, an exploratory single-cell RNA-sequencing analysis was performed on 3274 cells from independent MpBC datasets to investigate cellular heterogeneity and potential lineage plasticity. Results: TP53 (73.2%) and PIK3CA (46.0%) were the most prevalent genomic alterations in the MpBC cohort. Exploratory analysis suggested that PIK3CA mutations may be associated with an improved disease control rate in patients receiving taxane-based therapy (p = 0.028). Comparisons with mimickers identified distinctive molecular signatures, such as MED12 and HRAS hotspot mutations, across entities. Single-cell transcriptomics identified a distinct subpopulation (7.02% of malignant cells) co-expressing epithelial and phyllodes-like signatures. Conclusions: These findings suggest that MpBC harbors hybrid malignant cell populations that may contribute to its complex morphological diversity. While the therapeutic associations are based on a limited cohort and require prospective validation, the integration of comprehensive genomic and single-cell profiling provides an exploratory framework that may potentially enhance diagnostic accuracy in the future. However, these associations remain preliminary and require prospective validation to confirm their clinical utility. Full article

Background/Objectives: Human papillomavirus (HPV) oncoproteins early (E)6 and E7 cause upregulation of the IL-6 and IL-23 cytokines in HPV16+ cancers, contributing to tumor progression through enhanced tumor cell proliferation and suppression of the tumor specific adaptive CD8 T-cell response. The IL-6 and IL-23 receptors signal through signal transducer and activator of transcription 3 (STAT3) in the tumor microenvironment. Methods: To better understand how HPV-induced STAT3 signaling contributes to tumor progression and explore its therapeutic potential, we used the platinum (IV) compound CPA-7, a specific STAT3 inhibitor. CPA-7 was tested in vitro for its ability to inhibit STAT3 signaling, alter proliferation, and cause cell death in HPV16+ C3.43 tumor cells. In vivo, CPA-7 was tested for its ability to affect the HPV specific T-cell response, tumor growth, and survival in C3.43 tumor bearing mice. Results: In vitro, CPA-7 inhibited STAT3 signaling, reduced proliferation, and caused significant cell death to HPV16+ C3.43 cells. In vivo, CPA-7 eradicated early-stage HPV16+ tumors, while therapeutic treatment of late-stage tumors led to a systemically increased presence of tumor-specific CD8 T-cells and halted tumor progression. Conclusions: These results suggest that targeting STAT3 signaling downregulates tumor cell proliferation and induces tumor cell death. In addition, targeting STAT3 increases the HPV-specific anti-tumor adaptive immune response. Combined, this results in significantly reduced late-stage HPV16+ tumor progression. Full article

Effective pain management is central to anesthesia, critical care, and perioperative medicine, and opioids remain essential agents for moderate-to-severe pain despite ongoing concerns regarding their safety and misuse. This narrative review synthesizes the current knowledge on opioid mechanisms, clinical indications, safety considerations, and evolving strategies aimed at optimizing their use. Opioids exert their analgesic effects primarily through μ-, δ-, and κ-opioid receptors, which modulate central and peripheral nociceptive pathways. They maintain a well-established role in acute postoperative and cancer-related pain, whereas their use in chronic non-cancer pain remains controversial. Contemporary evidence suggests that physiological dependence and addiction are less frequent in appropriately selected and monitored patients, although the risk increases in the presence of psychological comorbidity, prior substance use, or adverse social determinants of health. Unequal access, prescribing variability, and persistent disparities further complicate global opioid management strategies. Recent advances, including partial agonists such as buprenorphine, dual-mechanism agents such as tapentadol, individualized titration, opioid rotation, and the integration of multimodal analgesia, support safer and more tailored prescribing. Non-pharmacological interventions, including behavioral and physical therapies, increasingly complement pharmacological strategies to minimize opioid exposure and improve functional outcomes. Clinicians must balance analgesic efficacy with adverse effects, such as tolerance, opioid-induced hyperalgesia, sedation, and respiratory depression, particularly in perioperative and critically ill populations. Opioids remain indispensable for selected indications but should be incorporated into a comprehensive, patient-centered, multimodal analgesic approach that prioritizes safety, ongoing reassessment, and individualized risk mitigation. Full article

Background: Type 2 diabetes mellitus (T2DM) is a chronic condition that has been attributed to social factors; however, the cumulative effect of social determinants of health (SDOH) on T2DM incidence is not known. Objective: The aim of the present study was to examine the association between T2DM and the cumulative burden of multiple SDOH. Design: The study is a retrospective cohort study with a baseline between 2008 and 2009 and a ten-year follow-up between 2010 and 2019. Setting: The study was conducted using data from the United States Veterans Health Administration (VHA). Participants: Out of 10,537,027 patients treated in the VHA between 2010 and 2019, 6,518,102 patients were selected who had no evidence of T2DM or Elixhauser comorbidities at baseline (2008–2009). Measurements: Over 10 years following baseline, the exposure consisted of seven types of SDOH occurring in structured data: social isolation, financial stress, employment issues, food insecurity, transportation insecurity, unstably housed, and psychosocial need. Incidence of T2DM in the ten-year follow-up window was the primary outcome. Results: Veterans with ≥3 SDOH doubled their adjusted odds of T2DM (2.07; CI: 2.05–2.09). There were significant racial differences in cumulative SDOH, with 8.8% of Black individuals having the highest burden of ≥3 SDOH compared with 3.8% of White individuals. Transportation insecurity, psychosocial need, and financial stress significantly increased the odds of T2DM across all racial and ethnic groups. Black individuals had the highest T2DM odds ratio for psychosocial need (OR = 1.58; CI: 1.56, 1.60). Limitations: The Veteran population is predominantly male, limiting generalization to the wider population. Conclusions: With each additional SDOH burden, the odds of T2DM increased, and ≥3 SDOH doubled the odds. The cumulative SDOH burden and associated disparities warrant investigation to reduce T2DM incidence. Full article

Background: Circulating tumor (ct)DNA is a prognostic biomarker in gastrointestinal malignancies. In rectal cancer, its utility to inform perioperative management and predict recurrence, particularly in patients undergoing non-operative management (NOM), remains unclear. Studies are needed to clarify how post-neoadjuvant therapy (NAT) and post-surgical ctDNA status correlate with clinical outcomes in localized rectal cancer. Methods: We retrospectively analyzed ctDNA data from 220 patients with rectal cancer using a personalized tumor-informed assay (Signatera™, Natera, Inc., Austin, TX, USA). Of these, 148 (67.3%) underwent NAT followed by surgery, and 72 (32.7%) underwent NAT followed by NOM. We assessed associations between post-NAT ctDNA status and survival outcomes. In the surgical cohort, we examined associations between post-operative ctDNA status and clinical response, pathological response, survival outcomes, and NAR scores. Results: In the surgical cohort, ctDNA positivity at the post-operative MRD timepoint was a strong predictor of recurrence, with an 88.3% relapse rate compared to 11.5% in ctDNA-negative patients (p < 0.001). Among the 64 NOM patients with post-NAT ctDNA, 21.9% (14/64) were ctDNA-positive, of whom 100% (14/14) relapsed (92.9% local-only), 13 relapsed by the time of data cut-off, and one relapsed 8 months after the cut-off. Only 10% (5/50) of the ctDNA-negative NOM patients experienced local recurrence (p < 0.0001). ctDNA positivity post-NAT was associated with inferior DFS (p = 0.003). Conclusion: ctDNA was a strong predictor of recurrence in rectal cancer, including in NOM settings. In NOM patients, ctDNA detected local recurrences, highlighting its potential to guide post-NAT surveillance and treatment. Full article