Purpose: We explored the association between metastatic cancer, chemotherapy, and the risk for suicide attempts (suicide injuries) in adult trauma patients.Methods: We conducted a retrospective analysis of the Trauma Quality Program Participant Use File (2017-2019), comprising 27,474 patients from 700 U.S. Trauma Centers. Self-harm/suicide injury (compared to controls) was the dependent variable; presence of metastatic cancer and current chemotherapy were the key independent variables. We adjusted for age, sex, race/ethnicity, method of payment, facility levels, and discharge year (Model 1), and Model 1 plus trauma type, injury location, stay length, comorbidities, Injury Severity Score, and Glasgow Coma Scale (Model 2). We employed chi-square analysis, Fisher's exact test, and unadjusted and adjusted logistic regression using Stata v18, setting statistical significance at P≤0.05.Results: Of 27,474 patients, 249 (0.91%) reported suicide injuries. Significantly higher attempts were noted among patients with metastatic cancer (201 out of 249; 80.72%) and those not receiving chemotherapy (184 out of 249; 73.90%), P<0.001. Metastatic cancer was associated with higher odds of suicide injuries (unadjusted OR:2.252, 95%CI: 1.642-3.089; adjusted OR in Model 1:1.925, 95%CI:1.302-2.848). Chemotherapy was associated with lower odds of suicide injuries (unadjusted OR:0.408, 95%CI:0.307-0.541; adjusted OR in Model 1:0.444, 95%CI:0.311-0.636). However, neither metastatic cancer nor chemotherapy was significantly associated with suicide injuries in adjusted Model 2, suggesting the crucial role of other factors in influencing this risk.Conclusion: Patients with metastatic cancer exhibited notable prevalence of suicide injuries. Findings suggested metastatic cancer was associated with higher odds, and chemotherapy with lower odds, of suicide injuries. Multifaceted factors were associated with suicide risk beyond the presence of metastatic cancer or chemotherapy status, underscoring the importance of mental health assessments and interventions in oncology care, particularly for those with advanced cancer.

Primary cutaneous T-cell and B-cell lymphomas may occur at any age and are defined by specific clinical, histopathologic, and immunophenotypic features. Clinical correlation is critical to differentiate indolent and aggressive entities, such as the lymphomatoid papulosis subtypes, which may have histopathologic and immunophenotypic features that are indistinguishable from aggressive cutaneous T cell lymphomas. Awareness of mycosis fungoides variants that overlap with benign conditions may help prevent misdiagnosis. Lymphoproliferative disorders do not require aggressive treatment or extensive staging. Watchful waiting is often appropriate.

Onychopathology (nail unit pathology) is a niche area in dermatopathology. There is a lack of familiarity with nail unit pathology and basic anatomy in general among pathologists and dermatopathologists, because of the relative rarity of such specimens in practice, and the lack of exposure and teaching regarding these lesions in training. It is however a vibrant area of dermatopathology, with knowledge evolving rapidly. In this article, we explore new information in the analysis of melanocytic and epithelial lesions of the nail unit, as well as nail inflammatory disease.

This article highlights selected cutaneous mesenchymal tumors, emphasizing histopathology, immunophenotype, and molecular alterations. It outlines diagnostic pitfalls, distinguishing features, and clinical behavior of indolent and malignant lesions. Awareness ensures accurate and appropriate treatment, and prevents overtreating benign mimics.

Refinements in histologic criteria, staging systems (American Joint Committee on Cancer 8th edition, Brigham and Women's Hospital), clinical guidelines (National Comprehensive Cancer Network [NCCN]), and molecular tools like gene expression profiling have enhanced the precision of cutaneous squamous cell carcinoma diagnosis and treatment. In Merkel cell carcinoma, recent updates in viral pathogenesis, immunohistochemistry, and emerging biomarkers have aided in better diagnostics. As immunotherapies and precision oncology evolve, dermatopathologists remain essential in guiding patient-specific management strategies for both cutaneous squamous cell carcinoma and Merkel cell carcinoma.

Cutaneous adnexal tumors recapitulate hair follicles, sweat glands, and/or sebaceous glands. These tumors range from benign to malignant and might herald an underlying inherited tumor syndrome. Accurate classification of adnexal tumors is thus critical but can be challenging due to many knowledge gaps in this area. Recent advances have dramatically improved our understanding and diagnosis of adnexal tumors. Here, we review several recently described adnexal carcinomas and summarize new molecular drivers reported in previously established tumor entities. We highlight morphologic, immunohistochemical, and molecular clues helpful for diagnosis of these adnexal tumors.

Vulvar squamous cell carcinoma and its precursors are heterogeneous and classified into 3 biologically distinct subgroups: human papillomavirus (HPV)-associated, HPV-independent TP53-mutated, and HPV-independent TP53-wild type. Although nomenclature is established for HPV-associated high-grade squamous intraepithelial lesion and TP53-mutated differentiated vulvar intraepithelial neoplasia lesions, terminology for precursors in the TP53-wild-type subgroup is evolving. Accurate classification is essential, as prognosis, progression risk, and recurrence rates differ among subgroups. Diagnosis relies on integrated assessment of clinical presentation, histopathology, and immunophenotype, particularly p16 and p53 expression.

This article highlights current advances in melanocytic lesions and their impact on histopathologic diagnosis and patient management. Special emphasis is given to the concept of melanocytoma and the study of dysplastic nevi. Finally, the article describes the current status and possible future applications of immunohistochemistry, digital analysis, and artificial/augmented intelligence.

In the past 2 decades, several molecular methods have been developed as an adjunct for the assessment of melanocytic neoplasms. Some tests can assist in the diagnostic workup of neoplasms with ambiguous histopathologic findings. Others can optimize the selection of patients for targeted therapy. Some tests also aim to provide prognostic information. Scenarios when ordering these tests may be appropriate and helpful are discussed in this article as well as pitfalls in the interpretation of test results. Due to the inherent limitations in sensitivity and specificity of various tests, correlation with the histopathologic findings is paramount.

This study aimed to systematically review the literature regarding topical therapies for reducing the risk of cervical intra-epithelial neoplasia (CIN) grade 2 or higher (CIN II+) lesions among women with high-risk human papillomavirus (HPV) infection and histologically confirmed CIN I or either no cervical lesions.

Carcinoembryonic antigen (CEA) is commonly raised in patients with colorectal carcinoma (CRC) and has an established role in postoperative monitoring to detect early recurrence. CEA is not recommended as a screening tool for CRC; however, a de novo raised level mandates further investigation with a colonoscopy. This report describes a patient referred from primary care with a raised CEA and functional bowel symptomatology who went on to have a normal colonoscopy. The persistently rising CEA prompted a repeat colonoscopy, upper gastrointestinal and small bowel investigation and a CT of the abdomen and pelvis, without any cause being found. Finally, a CT-positron emission tomography scan revealed localised uptake in the thyroid gland, with a fine-needle aspiration confirming a diagnosis of medullary cell thyroid carcinoma with regional lymph node involvement.

Breast cancer is the most common invasive malignancy among women and represents the second leading cause of cancer-related mortality in this population, following lung cancer. While metastases typically involve the bones, liver and lungs, less common metastatic sites have also been documented. Metastatic involvement of the pancreas or duodenum from an extrapancreatic primary tumour is rare, accounting for less than 3% of all pancreatic and periampullary malignancies. We report a case of isolated ampullary metastasis originating from invasive lobular breast carcinoma in a female patient in her late 50s, more than a decade after the initial diagnosis, accompanied by a review of the relevant literature.Given the limited number of published cases, this report underscores the importance of considering metastatic breast cancer in the differential diagnosis of women presenting with obstructive jaundice, particularly in the presence of a relevant clinical history.

As a key guanine nucleotide exchange factor, SOS1 is an attractive therapeutic target for KRAS-driven colorectal cancer. In this study, based on the co-crystal structure of SOS1 in complex with BI-68BS, we developed a high-affinity fluorescent tracer TRR2 (KD = 0.134 μM), and established a robust fluorescence polarization assay for the profiling of SOS1 inhibitors. Subsequent structure-based optimization yielded a series of SOS1 inhibitors, among which SL43 emerged as the most promising candidate. SL43 demonstrated superior binding affinity to SOS1 (KD = 0.16 μM), potently disrupted the SOS1-KRASG12C interaction (IC50 = 13.0 nM) and broadly inhibited SOS1-mediated nucleotide exchange on multiple KRAS mutants (G12C, G12V and G12D; IC50 = 13.4-29.1 nM). Biologically, SL43 exhibited potent and selective antiproliferative activity against KRAS-mutant colorectal cancer cells (IC50 = 0.028-0.238 μM), achieving over 100-fold selectivity over KRAS wild-type cells. in Balb/c mice, SL43 displayed a favorable profile with a moderate half-life (T1/2 = 4.6 h) and high oral bioavailability (F = 56.8%). In an HCT116 xenograft model, oral administration of SL43 (20 and 40 mg/kg) also significantly suppressed tumor growth (TGI = 57.2% and 74.9%, respectively), outperforming MRTX0902 (60 mg/kg, TGI = 47.1%) with no observable systemic toxicity. In conclusion, SL43 represents a potent and orally bioavailable SOS1 inhibitor that effectively suppresses KRAS signaling and exerts strong antitumor efficacy, highlighting its potential as a promising candidate for KRAS-mutant colorectal cancer.

Although immune checkpoint inhibitors (ICIs) and targeted therapies (TTs) have transformed the treatment of non-small cell lung cancer (NSCLC) across disease stages, real-world access remains highly unequal worldwide. Persistent cost barriers, fragmented reimbursement frameworks, and heterogeneous regulatory pathways limit equitable availability. The rapid proliferation of me-too agents has been proposed to counter monopolies; yet, this expansion has not consistently improved affordability. Heterogeneous evidentiary requirements-along with differences in clinical end points, comparator selection, crossover policies, and treatment duration-fragment therapeutic markets and complicate assessment of incremental clinical benefit. Divergent regulatory decisions, particularly between the US Food and Drug Administration and European Medicines Agency, underscore how trial design and geographic representation influence drug availability, especially when approvals rely on single-country data sets. These challenges are amplified in perioperative treatment strategies and rare oncogene-defined subgroups, where feasibility constraints and limited clinical equipoise hinder large randomized trials. As a result, an increasingly crowded therapeutic landscape makes cross-trial comparisons difficult and allows disparities in patient access to persist despite multiple approved therapies. Dose selection has historically followed maximum tolerated dose principles, even when preclinical and pharmacologic data suggest activity plateaus at lower exposure of ICI and TT. Dose and schedule optimization-through reduced dosing, extended intervals, or other deintensified strategies-therefore represents a rational and ethically grounded approach with a meaningful clinical impact. Such strategies may preserve efficacy while improving tolerability, reducing treatment burden, and mitigating financial toxicity, particularly in resource-limited settings. Aligning regulatory frameworks with dose optimization could promote more scalable, equitable, and sustainable NSCLC innovation.

Reviewing pathology reports requires physicians to integrate complex histopathologic, immunohistochemical, and molecular findings from multiple reports and institutions, often under time constraints that increase the risk of error and fatigue. Large language models (LLMs) offer a potential solution by generating concise, coherent summaries from complex pathology data.

Immune checkpoint inhibitors (ICIs) can essentially treat cancer but only in a small subset of patients. Treatment strategies capable of effectively and robustly sensitizing refractory patients to ICIs represent a highly coveted yet unmet clinical need. In this study, we identified DJ-1 as a negative T cell regulator. DJ-1 knockout boosts antitumor immunity and significantly potentiates PD-1 and TIM-3 blockades in murine cancer models. Single-cell sequencing of tumor-infiltrating CD45+ cells revealed that DJ-1 deficiency indirectly activates T cells by reprogramming macrophages. Mechanistically, loss of DJ-1 increases reactive oxygen species (ROS) in macrophages, activating NF-κB/STAT3 signaling to promote differentiation into Cxcl9+ immune-stimulatory phenotypes while reducing immune-suppressive Spp1+ macrophages. Notably, this reprogramming may be stable across tumor microenvironments because the transplanted DJ-1-deficient macrophages maintain T cell-activating capacity. Pharmacological inhibition of DJ-1 by disulfiram markedly potentiated antitumor efficacy of PD-1 blockade. This designates DJ-1 as a promising target for overcoming immune checkpoint resistance and optimize combination therapies.

Metabolic reprogramming is a hallmark of cancer, while tricarboxylic acid cycle is increasingly recognized as a multifaceted hub driving tumor metabolism and progression. Integrated analysis of solute carrier (SLC) transporters revealed consistent down-regulation of SLC13A2 in hepatocellular carcinoma (HCC) cells and liver tissues from human patients and mouse models. Adeno-associated virus-mediated liver-specific knockout or overexpression of SLC13A2 (SLC13A2-OE) promoted or ameliorated HCC progression, indicating its protective role. SLC13A2 inhibited HCC proliferation by decreasing mitochondrial function via suppressed glycolysis, respiration, and adenosine 5'-triphosphate production. Flux analysis showed that SLC13A2 imported citrate to generate acetyl-coenzyme A for pyruvate kinase isozyme type M2 acetylation, triggering its degradation. Reduced pyruvate kinase activity limited pyruvate supply, impairing amino acid synthesis and nucleotide metabolism. Moreover, SLC13A2-imported citrate induced intracellular protein acetylation, particularly histone proteins, which provided an epigenetic basis for transcriptional regulation and contributed to tumor suppression. Thus, SLC13A2 perturbs metabolic and transcriptional programs to suppress tumor growth, highlighting potential drug targets for HCC therapy.

Both primary and metastatic brain malignancies are fatal and highly infiltrated with tumor-associated macrophages (TAMs). Enhancing the phagocytosis of neoplastic cells by TAMs is pivotal for slowing tumor growth. Great endeavors have been made to develop tyrosine kinase inhibitors (TKIs) for brain malignancies, yet whether tumor-targeting TKIs affect the phagocytic capacity of TAMs remains largely unknown. In this preclinical study, we report that repurposing ibrutinib, a blood-brain barrier-penetrable TKI, effectively suppresses the growth of several primary and metastatic brain tumors highly expressing Bruton's tyrosine kinase (BTK) or bone marrow X-linked nonreceptor tyrosine kinase (BMX) but concurrently dampens the TAM phagocytic function. Mechanistically, BTK, which is activated in TAMs, interacts with and phosphorylates Wiskott-Aldrich syndrome protein (WASp) to organize the actin cytoskeleton, which is imperative for phagocytosis. Ibrutinib treatment disrupts BTK-mediated WASp activation, thereby compromising TAM phagocytic efficacy. Pharmacological activation of WASp by its selective small-molecular activator EG-011 restores the ibrutinib-impaired TAM engulfment of tumor cells and effectively improves ibrutinib efficacy in mice bearing glioblastomas, primary central nervous system lymphomas, and lung carcinoma brain metastases. Furthermore, elevated expression of phosphorylated BTK or phosphorylated WASp in TAMs correlates with an increased phagocytic TAM subset identified by single-cell RNA sequencing and correlates with prolonged patient survival in a cohort with glioblastoma. Our preclinical study highlights the necessity of evaluating the on-target, off-tumor attack of TAMs during TKI administration and provides a proof of concept for reinvigorating the TAM phagocytic function to achieve additional clinical benefit.

In this article, we propose a deep reinforcement learning based chemotherapy regulation framework to realize personalized and dynamic optimization of cancer treatment. We use a nonlinear dynamic system to model the dynamic evolution of the tumor microenvironment including tumor cell, normal cell and immune cell interactions, with drug concentration serving as the control input variable. The Deep Deterministic Policy Gradient (DDPG) algorithm makes agents can study optimal dosing strategy in a continuous space of movement to inhibit tumor growth effectively and minimize damage to normal tissues. To make the strategy more stable, Gauss noise is added to the model to simulate physiological oscillations and uncertainties in the treatment reaction. Experimental results show that it can control the growth of tumor in various initial scenarios and the accumulation of the drug concentration with high flexibility and safety. Our technique provides a feasible technical way for precision, low toxicity adaptive chemotherapy.

Tumor-derived exosomes play critical roles in pancreatic ductal adenocarcinoma (PDAC) progression by mediating intercellular communication within the tumor microenvironment. This study identifies the long non-coding RNA PLBD1-AS1 as a functional oncogenic lncRNA enriched in PDAC exosomes. We demonstrate that PLBD1-AS1 promotes tumor cell proliferation, migration, and invasion by interacting with the glycolytic enzyme ALDOA and enhancing glycolytic flux. Furthermore, tumor exosomes deliver PLBD1-AS1 to pancreatic stellate cells (PSC), augmenting their glycolysis and facilitating their activation into cancer-associated fibroblasts, thereby shaping a pro-tumorigenic microenvironment. To target it, we developed an engineered exosome system modified with the tumor-penetrating peptide iRGD for specific delivery of siPLBD1-AS1 to both tumor and stromal cells. The resulting iRGD-exo-siPLBD1-AS1 construct demonstrated enhanced cellular uptake and effectively suppressed PLBD1-AS1 expression, inhibited glycolysis, impaired PSC activation, and significantly attenuated tumor growth. Our findings reveal a novel mechanism of exosome-mediated metabolic crosstalk in PDAC and establish a promising RNAi-based therapeutic strategy targeting this lethal malignancy.