INTRODUCTION: Approximately 5% of patients with peritoneal carcinomatosis are excluded from pressurized intraperitoneal aerosol chemotherapy (PIPAC) due to a "non-accessible abdomen" caused by extensive adhesions. Preoperative progressive pneumoperitoneum (PPP) is traditionally used in complex hernia repair but has not been applied to facilitate PIPAC. This study evaluates the feasibility and safety of ultrasound-guided PPP to overcome this technical barrier. MATERIALS AND METHODS: A prospective study was conducted in five patients with histologically confirmed inoperable peritoneal carcinomatosis and a pre-established non-accessible abdomen. PPP was performed using controlled, intermittent air insufflation via a percutaneous catheter placed under ultrasound guidance with hydrodissection. Pre-PIPAC computed tomography confirmed adequate intra-abdominal volume for safe laparoscopic access. Primary outcomes were technical success (successful laparoscopic access and PIPAC delivery) and safety (complications and 30-day mortality). RESULTS: The combined PPP-PIPAC approach achieved 100% technical and clinical success. All five patients underwent successful transformation of non-accessible abdomens to accessible ones, enabling safe laparoscopic PIPAC or electrostatic PIPAC (ePIPAC) delivery. No procedure-related complications or adverse events occurred during the 30-day post-procedure period. High clinical tolerability was observed across repeated treatment cycles. CONCLUSION: Ultrasound-guided PPP with hydrodissection successfully transforms non-accessible abdomens into accessible ones, enabling safe PIPAC delivery in previously excluded patients. This novel, reproducible approach provides a practical solution to a common technical limitation in surgical oncology, potentially expanding treatment eligibility by approximately 5% for patients with peritoneal carcinomatosis.

OBJECTIVE: Dysregulation of Cholesterol homeostasis(CH) and NK cells proportion can increase risk of ST-Elevated Myocardial Infarction(STEMI) for Coronary atherosclerotic heart disease(CAD) patients. Hence, it is necessary for the investigation of CH and MC in pathogenesis of STEMI for CAD patients, providing additional choice for the prevention of STEMI for CAD patients. METHODS: By combining 5 peripheral blood bulk profiles of CAD patients with STEMI and integrative bioinformatic pipelines, such as ssGSEA, CIBERSORT, WGCNA, machine learning, consensus clustering, we first identified novel CH and NK cell(NCH)-associated molecular subgroup and hub genes for CAD patients with STEMI, and then estimated hub genes predictive performance for STEMI onset among CAD patients. Besides, the biological features of hub gene were estimated both in bulk and single-cell profiles of CAD patients with STEMI, especially in artificial intelligence(AI)-driven virtual cells. Indeed, AI-empowered therapeutic enrichment framework(DrugRefLector) and molecular docking were cross-performed for identification of optimal preventative agents targeting hub genes for CAD patients. Finally, in vitro study confirmed the differentially expressed level of hub genes. RESULTS: Integrated NCH can lead to the molecular stratification for CAD patients with AMI, which provides insights into the patient precision medicine. Besides, NAMPT and CLEC4D can be considered as up-regulated NCH-associated hub gene involved in STEMI pathogenesis of CAD patients with satisfied predictive efficacy, which was mainly distributed at NK cells. Novelty, BRD-K92455082 can be considered as optimal STEMI-preventative agent for the CAD patients by targeting NAMPT and CLEC4D. CONCLUSION: Our study provides integrative evidence suggesting a potential combined role of cholesterol homeostasis and NK cell-associated transcriptional programs of AMI for CAD patients, which offers novel insights into patient precision and personalized medicine.

PROBLEM: Early career researchers in low- and middle-income countries (LMICs) face substantial barriers when writing research grants and have limited writing support. A designathon approach was applied to organize a grant writing workshop (grant-o-thon) tailored for early-career LMIC researchers. This study describes the planning, implementation, and participant-reported outcomes of the grant-o-thon as a participatory training approach. APPROACH: Grant-o-thons were organized in 2023, 2024, and 2025. Consistent with the designathon model, the grant-o-thon was structured in three stages: preparation using co-creation with end-users, intensive collaborative teamwork supported by mentor feedback and weekly writing deliverables, and structured follow-up. Each grant-o-thon consisted of six weekly 90-minute online sessions focused on US NIH grant writing. Each session included a 30-minute didactic lecture open to all and a 60-minute small-group activity for participants who submitted specific aims. Small group participants were matched with coaches and assigned to groups based on research interests. Follow-up surveys assessed self-reported skills, mentorship experiences, and later grant-related activities. Survey data were analyzed descriptively, and open-ended responses were analyzed thematically. OUTCOMES: A total of 221 participants attended the didactic lectures, and 32 joined the small group activities. Among 60 survey respondents, 51 (85%) were from LMICs. Participants in both formats reported higher self-assessed grant-writing competencies after the program. Many described peer mentorship as a valuable component of the experience. In 2025 follow-up data, small-group participants reported higher NIH grant submission rates than lecture-only participants (P = .0097). NEXT STEPS: These findings suggest that this designathon-informed grant-writing program was feasible and acceptable for early-career LMIC researchers. Future iterations will focus on strengthening post-grant-o-thon mentorship and deepening partnerships with existing global health training programs. In light of limited grant-writing support, adaptation of this participatory model may be warranted.

HIF-2α signaling is a central driver of clear cell renal cell carcinoma (ccRCC) biology. With regulatory approval of the HIF-2α inhibitor, belzutifan, in the third- and fourth-line refractory setting, therapeutic targeting of this pathway has entered clinical practice. At the 2026 ASCO GU Cancer Symposium, two randomized phase III trials evaluated earlier integration of belzutifan: LITESPARK-022 (belzutifan plus pembrolizumab vs. pembrolizumab alone in the adjuvant setting) and LITESPARK-011 (belzutifan plus lenvatinib vs. cabozantinib in the post-PD-(L)1 setting). LITESPARK-022 demonstrated a disease-free survival (DFS) benefit (HR 0.72; 95% CI 0.59-0.87; p = 0.0003), with early and sustained curve separation, though grade ≥3 adverse events doubled and overall survival (OS) data remain immature. LITESPARK-011 enrolled patients after progression on prior PD-(L)1 therapy in the metastatic setting. The combination improved median progression-free survival (PFS; 14.8 vs. 10.7 months; HR 0.70), objective response rate (ORR; 52.6% vs. 40%), and duration of response (23 vs. 12 months), with a manageable toxicity profile. Together, these studies suggest that earlier targeting of HIF-2α biology may improve disease control and durability. However, patient selection, toxicity considerations, and the absence of mature OS data remain critical factors in determining the optimal role of belzutifan-based strategies across disease states.

Precise induction of pyroptosis remains a formidable challenge in cancer therapy due to the stringent requirements for spatiotemporal and subcellular control. Herein, we report a zwitterionic nanogels platform (poly(N-oxide dimethylaminoethyl methacrylate), PODMMA) that enables precise induction of photopyroptosis via intrinsic mitochondrial targeting. Owing to its unique N-oxide zwitterionic structure, the PODMMA nanogels exhibit prolonged blood circulation, selective mitochondrial localization without the need for additional targeting ligands, and enhanced tumor accumulation. In vitro studies demonstrate that the drug-loaded nanogels efficiently accumulate in mitochondria. Upon irradiation with a 640 nm laser (5 min, 30 mW/cm), reactive oxygen species (ROS) amplification is triggered leading to the activation of the caspase-3/gasdermin E (GSDME) pyroptosis pathway. In vivo evaluations demonstrate exceptional therapeutic efficacy with 99.3% tumor inhibition and negligible systemic toxicity. This study establishes a versatile strategy for subcellular-targeted photopyroptosis and precision cancer therapy.

Stimuli-responsive "off-on" theranostic nanoprobes enable precise cancer diagnosis and treatment by activating functions within the tumor microenvironment. Current challenges include selectivity, multi-functionality, and structural definition. Here, we report a tandem-responsive multiple-functional (TRIPLE) dendritic dot (DD) synthesized via a single-molecule all-in-one (SMALL) strategy. This TRIPLE DD integrates tumor-responsive drug release, fluorescence activation for imaging, and transcytosis for deep tumor penetration. Utilizing a polylysine dendrimer with a Cy5 core and covalently conjugated camptothecin (CPT), Cy5 fluorescence is initially quenched by CPT via photoinduced electron transfer (PET) ("off" state). A surface β-carboxylic amide-linked γ-glutamylglycine motif enables sequential cleavage by acidic pH and γ-glutamyl transpeptidase (GGT), exposing amines. These amines catalyze CPT release and activate Cy5 fluorescence. The resulting cationic DD induces cellular transcytosis, enhancing drug infiltration. We demonstrate pH/GGT tandem-responsive drug release, fluorescence activation, and potent antitumor activity in vitro and in vivo, notably against hepatocellular carcinoma. This work represents a rational design of multifunctional stimuli-responsive off-on nanoprobes, paving the way for advanced precision theranostics.

Testicular sex cord stromal tumors are rare neoplasms arising from the sex cord and stromal elements of the testis, exhibiting highly heterogeneous behavior. Although 90% of cases represent biologically benign lesions, the remainder show aggressive, therapy-resistant clinical courses that can rapidly become fatal. In addition, it is challenging to distinguish them from germ cell tumors. The authors present the clinicopathological features of the following entities: Leydig cell tumor, Sertoli cell tumor not otherwise specified, large cell calcifying Sertoli cell tumor, adult-type granulosa cell tumor, juvenile-type granulosa cell tumor, the fibroma/thecoma group, mixed sex cord-stromal tumor, signet-ring stromal tumor, myoid gonadal stromal tumor, and sex cord-stromal tumor not otherwise specified. The aim of the publication is to introduce these lesions to Hungarian medical practitioners, thereby increasing their awareness, appropriate management, and the collection of cases for various targeted tests. Orv Hetil. 2026; 167(20): 784-797.

Mesenteric cystic lymphangiomas are benign tumors, considered surgical rarities. They can develop from the duodenum to the rectum, on the entire mesentery surface. The preoperative diagnosis is difficult because they can mimic a wide range of tumors. The treatment of choice is surgery and diagnosis is confirmed by histopathological examination. A 57-year-old male patient was admitted to the 2nd Surgery Clinic from Târgu Mureş, after a control ultrasonography examination incidentally highlighted a tumor mass at the mesenteric level and the growth of the tumor volume was observed. The preoperative CT scan presented a cystic mass adjacent to the jejunal loops, at a distance of 65 mm from the Treitz angle, measuring 75 × 100 × 92 mm with a volume of 430.24 cm3. During surgery total enucleation of the mesenteric cyst was performed. The cystic wall presented yellowish color and the fluid content had a milky white appearance. Histopathological examination confirmed the diagnosis of cystic lymphangioma. The immunohistochemical profile presented positive reaction of endothelial cells with CD34, CD31, podoplanin, and negative reaction with CK AE1/AE3 and CK7. The patient was discharged after 7 days following the surgical intervention. No recurrence was highlighted during the 12 months of follow-up. In most cases, the diagnosis of mesenteric cystic lymphangioma is made incidentally. During imaging investigations, they can mimic multiple malignant lesions. The gold standard of treatment is radical resection which ensures also recurrence prevention and a good prognosis. Orv Hetil. 2026; 167(20): 798-804.

Endometriosis, particularly ovarian endometrioma, is associated with a 2-fold increased risk of ovarian cancer (OC), especially the clear cell and endometrioid subtypes. However, the absolute lifetime risk of OC in women with endometriosis remains relatively low, estimated at 1.9%. This review provides a focused overview of the relationship between these two conditions, addressing epidemiologic data, molecular links, advances in diagnosis, and clinical management. Somatic mutations in ARID1A, PIK3CA, and KRAS are shared between endometriosis and certain OC subtypes, and the nature of the environment typical of ovarian endometriomas suggests a context-specific oncogenic journey. Although advances in imaging, like transvaginal ultrasound and MRI, have improved endometriosis diagnosis, these modalities remain unreliable for identifying malignant transformation. Biomarkers, including CA-125 and HE4, provide additional diagnostic information, although their low specificity limits their role in clinical practice. Hormonal therapies, particularly the long-term use of combined oral contraceptives (COCs), have proven to be highly effective in reducing OC risk in women with endometriosis. This protective effect persists for more than a decade after discontinuation and has been associated with a risk lower than that of the general population. In addition, COC use has been linked to further protective effects against endometrial and colorectal cancers, highlighting its potential value as a cancer prevention strategy, especially for high-risk groups. Surgical management, particularly the excision of ovarian endometriomas, may also confer protection against OC, although this must be balanced against the risks of recurrence and ovarian reserve loss, especially in younger women. Prophylactic salpingo-oophorectomy is recommended for women with known genetic predispositions, but is not routinely indicated for those with endometriosis alone. Emerging evidence highlights the need for personalized risk prediction models that incorporate genetic, clinical, and environmental factors to guide care. Long-term studies are required to assess the impact of conservative versus surgical management on OC risk and overall survival. This review emphasizes the importance of a multidisciplinary approach to the management of endometriosis in relation to OC risk. While the link between endometriosis and OC is well-established, treatment strategies must be tailored to balance cancer prevention, fertility preservation, and quality of life.

BACKGROUND: Current treatment guidelines for stage IV colorectal cancer (CRC) with isolated synchronous lung metastases are limited. This study aimed to assess the association between management strategies and cancer-specific survival (CSS). METHODS: This study was a retrospective cohort analysis of patients with stage IV colorectal adenocarcinoma and isolated synchronous lung metastases from the SEER registry (2010-2022). Patients were grouped by treatment strategy: surgery-only, chemotherapy-only, or combined surgery and chemotherapy. The main outcome measure was 3-year CSS, assessed by Kaplan-Meier statistics and multivariable Cox regression to adjust for survival confounders. RESULTS: 5666 (6.9%) of 82,502 patients with stage IV CRC had isolated lung metastases. 736 (13%) were treated with surgery-only, 1870 (33%) chemotherapy-only, and 1908 (33.6%) surgery and chemotherapy; no treatment was recorded in 20.3% of patients. Chemotherapy alone was increasingly used over time (from 33.8% to 51.1%), whereas combined treatment decreased. Combined surgery and chemotherapys was associated with the highest 3-year CSS (55.1%) compared with chemotherapy-only (26.1%) and surgery-only (21.7%) (p < 0.001). Resection of both primary CRC and lung metastases combined with chemotherapy conferred the best 3-year CSS (66.2%). Combined surgery for primary and metastatic tumors and chemotherapy was associated with significant mortality risk reduction (HR 0.31, p < 0.001) compared with chemotherapy-only. Older age, signet-ring cell histology, poor differentiation, N2 primary disease, elevated CEA, and perineural invasion were associated with reduced CSS. CONCLUSIONS: Combined resection of primary CRC and synchronous lung metastases with chemotherapy was associated with the best survival outcomes. However, use of this combined strategy is employed in select patients and has decreased over time.

Large language models (LLMs) represent a rapidly advancing subset of artificial intelligence with significant potential to augment clinical practice. These tools can assist in literature synthesis, documentation, clinical reasoning, and patient communication. Despite demonstrated capabilities, adoption in healthcare remains limited due to barriers such as limited AI literacy, trust concerns, integration challenges, and generational disparities in digital proficiency. This review critically examines the role of LLMs as cognitive adjuncts in medicine, emphasizing the need for calibrated trust, human oversight, structured implementation strategies, and robust regulatory governance. Evidence suggests that stepwise integration of LLMs, beginning with low-risk tasks, may enhance physician efficiency, reduce cognitive burden, and may support high-quality care. Key limitations, including hallucinations, data currency, environmental impact, and data security, have to be addressed, alongside the need for continuous model refinement. Rigorous clinical trials are needed to establish the efficacy of LLMs. This includes the recognition that LLMs trained on vast web data may contain personal health information, creating a significant privacy risk. Responsible adoption of LLMs is essential to meet the demands of modern medicine while preserving clinical accountability and patient-centered care.

PURPOSE: To report the efficacy and safety of enfortumab vedotin combined with toripalimab as neoadjuvant therapy in an elderly patient with muscle-invasive bladder cancer (MIBC) who sought bladder preservation. METHODS: An 83-year-old male presented with painless gross hematuria. Imaging revealed a 44 mm × 39 mm × 60 mm bladder mass, and biopsy confirmed high-grade invasive papillary urothelial carcinoma (cT2NxM0). After informed consent, the patient received three cycles of neoadjuvant therapy combining enfortumab vedotin (60 mg on days 1 and 8) with toripalimab (240 mg on days 1 and 8) in 21-day cycles. RESULTS: Treatment-related adverse events included hyperglycemia and rash, both managed conservatively without treatment interruption. Post-treatment MRI demonstrated marked tumor reduction, showing only bladder wall thickening. Subsequent transurethral resection of bladder tumor (TURBT) revealed chronic mucosal inflammation with histiocyte aggregation and focal cystic cystitis, with no residual carcinoma identified in the resected specimen, indicating a favorable pathological response. CONCLUSION: In this carefully selected elderly MIBC patient, neoadjuvant enfortumab vedotin combined with toripalimab was well tolerated and associated with marked tumor regression and a favorable pathological response on post-treatment TURBT. Bladder preservation was attempted, illustrating the feasibility of this regimen and generating a hypothesis for future investigation.

BACKGROUND: Muscle-invasive and metastatic urothelial carcinoma of urinary bladder (UCUB) is associated with poor overall survival. However, individual years of life lost (YLL) according to detailed patient and disease characteristics have never been quantified. PATIENTS AND METHODS: Within the Surveillance, Epidemiology, and End Results (SEER) database (2004-2021), muscle-invasive organ-confined (OC, T2N0M0), non-organ-confined (NOC, T3-4 and/or N1-3 M0), and metastatic (anyT, anyN, M1) UCUB patients aged 40-75 years were included. Relying on Social Security Administration (SSA) life tables, a 1:1 age, sex, and year of diagnosis matched control (Monte Carlo simulation) was simulated for each patient. Kaplan-Meier method was used to calculate average YLL truncated at the age of 75 years between SEER cases and SSA simulated controls. RESULTS: A total of 30,519 patients were included: 14,754 (48.3%) OC, 10,330 (33.8%) NOC, and 5435 (17.8%) metastatic. Compared with simulated population controls, average YLL was 3.7, 6.0, and 9.1 years for OC, NOC, and metastatic disease, respectively. YLL was most pronounced among patients diagnosed at younger ages (40-55 years: 9.2, 14.1, and 18.0 years for OC, NOC, and metastatic, respectively), decreasing with advancing age at diagnosis. Less pronounced YLL observations were recorded in most contemporary years (2017-2021: 2.7, 4.4, and 7.9 years for OC, NOC, and metastatic, respectively) across all stages compared with earlier periods. No clinically meaningful differences in YLL were observed between sexes. (male OC: 3.6, NOC: 5.9, metastatic: 9.0; female OC: 4.1, NOC: 6.6, metastatic: 9.5). CONCLUSIONS: UCUB is associated with substantial YLL, particularly in metastatic and younger patients. However, an YLL decrease over time was observed.

INTRODUCTION: Recurrent endometrial carcinoma involving major pelvic vasculature poses significant surgical challenges, particularly when residual disease persists after systemic therapy and radiation is contraindicated. Robotic-assisted surgery offers a minimally invasive solution for precise tumor dissection near critical vessels. CASE REPORT: A 67-year-old woman with recurrent endometrial carcinoma presented with deep vein thrombosis and pulmonary embolism 3 years after primary treatment with hysterectomy, chemotherapy, and brachytherapy. Imaging revealed a 5-cm pelvic mass encasing the right external iliac vessels and two lung nodules. After six cycles of carboplatin and liposomal doxorubicin, lung lesions resolved, but the pelvic mass persisted. OPERATIVE TECHNIQUE: A multidisciplinary team, including gynecologic oncologists and vascular surgeons, performed a robotic-assisted secondary cytoreductive surgery. A prophylactic iliac vein balloon was placed by the vascular team but remained uninflated. The procedure involved adhesiolysis, retroperitoneal dissection, and careful tumor separation from the external and internal iliac vessels with vascular preservation. Metal clips were applied to guide postoperative radiation planning. The tumor was completely resected without vascular injury. The patient recovered uneventfully and was discharged on postoperative Day 1. CONCLUSIONS: This case underscores the feasibility and safety of a multidisciplinary robotic-assisted approach for pelvic tumor resection involving major vasculature. Preoperative vascular planning and endovascular readiness enhance surgical safety, while minimally invasive techniques offer improved recovery and precision in managing recurrent endometrial carcinoma.

BACKGROUND: Meningiomas exhibit clinical heterogeneity. Radiotherapy (RT) remains the only adjuvant therapy, but tumor-control is variable, and biomarkers are limited. NRG/RTOG-0539 is the first prospective phase 2 trial to stratify meningioma patients for adjuvant RT based on clinical risk. Here, we apply modern molecular tools to this cohort and identify correlates of RT response. METHODS: Tumor tissue from 100 RTOG-0539 patients was profiled using DNA methylation arrays, RNA sequencing, and whole-exome sequencing. Recurrence scores, Molecular Groups, gene expression, and copy number alterations were compared across clinical groups and between RT responders and non-responders; non-response was defined as progression or death within 3 years. RESULTS: Modern grading criteria, including brain invasion, TERT mutation, CDKN2A/B deletion, and 1p/1q status, would reclassify 10% of tumors and alter treatment group assignment in 7%. Non-responders to RT exhibited more frequent 1p and 14q loss, and more copy number alterations. Transcriptomic and epigenetic profiling revealed immune-related signatures in responders and cell cycle-related pathways in non-responders, several of which overlapped with targets of vorinostat, a histone deacetylase inhibitor previously validated in aggressive meningioma models. The Proliferative Molecular Group was an independent predictor of post-RT recurrence in multivariable analysis, outperforming WHO grade. CONCLUSION: Multi-omic analysis of the NRG/RTOG-0539 cohort shows that updated WHO grading criteria, incorporating molecular and cytogenetic features, improve risk stratification. However, molecular classification, particularly the Proliferative group, remains an independent and stronger predictor of RT response. These findings support integrating molecular biomarkers alongside modern grading frameworks to guide treatment and trial design in meningioma.

Enhancer RNAs (eRNAs) play crucial roles in regulating cancer progression and serve as clinical biomarkers or therapeutic targets. However, systematic identification of oncogenic eRNAs and strategies to target them for precision oncology remain largely unexplored. In this study, we comprehensively identified tens of thousands of eRNAs significantly associated with cancer hallmark signatures across diverse tumor types, which we defined as hallmark eRNAs. These eRNAs exhibit a strong capacity to promote specific cancer hallmarks by mediating distinct oncogenic pathways in a cancer type-dependent manner. We also found that RNA-binding proteins can directly bind to eRNAs to regulate tumorigenesis. By integrating regulator-eRNA networks with drug response data, we identified drugs that target different cancer processes with specific associations to hallmark eRNAs. Specifically, in liver hepatocellular carcinoma, we characterized a hallmark eRNA, ADAMTS5e, which can activate the expression of oncogene ADAMTS5 to promote metastasis in vivo and in vitro. Cancer cells with high ADAMTS5e expression are resistant to sorafenib but are sensitive to the combination treatment of sorafenib and docetaxel, or sorafenib and navitoclax. Our study developed a platform to identify cancer-hallmark eRNAs and provided promising drug screening strategies. This approach was exemplified by the functional characterization of ADAMTS5e in cancer metastasis and the discovery of an effective combinational treatment. Together, these findings highlight the potential of hallmark eRNAs in precision oncology.

OBJECTIVES: This multicentre real-world evaluation, commissioned by NHS England, evaluated the impact of AI-assisted contouring of organs at risk on contour acceptability, workflows and staffing. METHODS: Data from 626 patients were collected from eight NHS radiotherapy departments. Time metrics from date of planning CT scan to start of first treatment were compared between manual and AI-enabled pathways. Acceptability scores for AI-generated contours were also collected. RESULTS: AI-assisted contouring increased potential efficiency in treatment planning compared to manual methods, reducing time for contouring and redistributing workload across different staff types. 100% manual contour reviews involved clinical oncologists compared to 38% reviewing AI-generated contours. However, workflow design meant that time saving was not observed across the whole pathway to start of treatment.AI contours were generally well accepted, with 15.9% requiring no edits and 64.4% only minor edits. This varied by anatomy, with breast having the best acceptability and prostate and head and neck contours requiring more editing. CONCLUSIONS: AI contouring tools have the potential to enhance efficiency in radiotherapy treatment planning, creating operational flexibility. Pathway review and revision could unlock further benefits, for example, involving different staff types to address local bottlenecks. Workflow, capacity and staffing review pre- and post-implementation could increase efficiency gains with AI-assisted contouring. ADVANCES IN KNOWLEDGE: This study evaluated AI contouring tools in complex, real-world systems which differ between departments for generalisable conclusions. It describes the changes in time across the whole treatment planning pathway and system-level impact of using AI tools to help inform holistic planning.

BACKGROUND: Low testosterone (T) is associated with several sequelae, including a high prevalence of bone density loss (BDL). AIM: We aimed to identify predictors of BDL in men with low T. METHODS: The sample included (1) men ≥50 years old, (2) with low total T levels (<300 ng/dL using LCMS on 2 early morning blood draws), (3) who had dual-energy X-ray absorptiometry (DEXA) within 6 months of T measurement. Men with prior T therapy were excluded. On DEXA, osteopenia was defined as a T score between -1.0 and -2.5, and osteoporosis as a T score below -2.5. Additionally, demographics and comorbidity data were collected. We report BDL rates and identify predictors of any BDL using logistic regression. OUTCOMES: Bone density loss, which was defined as the presence of osteopenia or osteoporosis. RESULTS: Nine hundred ninety-seven men were analyzed, with a median age of 64 (IQR 59, 70) years. Median total T was 202 (IQR: 107, 256) ng/dL, median free T 5.8 (IQR: 4.3, 7.5) ng/dL. 24% had a total T ≤ 100 ng/dL. Thirty-three percent had ≥3 comorbidities. Seventy-four percent of our cohort had an oncological history; most of them had a history of prostate cancer. Bone density loss was present in 36% of the patients (89% osteopenia, 11% osteoporosis). On multivariable analysis, significant predictors of BDL were lower total T levels (OR = 1.09), older age (OR = 1.59), and the presence of ≥3 comorbidities (OR = 1.60). CLINICAL IMPLICATIONS: It is critical to be aware of the significant prevalence of BDL in men with low T. Early identification may enable targeted counseling, the initiation of preventive or therapeutic strategies to improve bone density outcomes, and the reduction of the risk of fractures and other serious skeletal complications. STRENGTHS & LIMITATIONS: Limitations related to retrospective design, including selection bias and unmeasured confounding factors. Another limitation is that most cases had an oncological history. However, several strengths include the use of a large, systematically audited database; T labs were assessed using gold-standard methodology; and bone mineral density was assessed using a standardized scanning protocol. CONCLUSION: In our cohort of older men, most with oncological history and low T, around one-third had BDL, and around 10% of those with BDL had osteoporosis. Lower T levels, older age, and a greater number of comorbidities were significant predictors of BDL.

BACKGROUND: In the era of immuno-oncology (IO) combination therapy, prognostic tools for elderly patients with metastatic clear cell renal cell carcinoma (ccRCC) are lacking. This study aimed to identify prognostic factors in elderly patients and evaluate a novel risk model using the restricted mean survival time (RMST) and a decision curve analysis (DCA). METHODS: We retrospectively analyzed 203 patients aged ≥70 years with metastatic ccRCC treated with first-line IO combination therapy. Independent prognostic factors for overall survival (OS) were identified. Beyond the hazard ratio, a RMST analysis with a 24-month truncation time quantified absolute survival differences between risk groups. Clinical utility was evaluated using DCA. RESULTS: A multivariable analysis identified low body mass index, low Karnofsky performance status, elevated lactate dehydrogenase, low serum albumin, and liver metastases as independent prognostic factors. In the RMST analysis at 24 months, significant survival disparities were quantified. The intermediate- and poor-risk groups showed mean survival reductions of 1.92 and 6.27 months, respectively, from OS in the favorable-risk group. The model demonstrated a higher net benefit through DCA than the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) classification across a wide range of threshold probabilities for 24-month OS. The model's C-index (0.728) was higher than that of the IMDC classification (0.603). CONCLUSIONS: Our prognostic model for elderly patients provides a practical tool for clinical decision-making by visualizing time-based survival differences via RMST and demonstrating potential clinical utility in DCA.

The quantification of key protein variants can guide precision oncology to enable better identification of driver mutations. Bottom-up assays infer parent protein levels through the quantification of surrogate peptides. Assay methods designed for absolute quantification of protein variants, such as multiple reaction monitoring mass spectrometry (MRM-MS), can achieve quantitation with high precision and specificity. Bottom-up approaches rely on proper selection of suitable surrogate proteogenotypic peptide targets to quantify protein variants of interest. To this end, we developed an R-based bioinformatics pipeline to predict and evaluate variant-specific peptides. The workflow generates variant protein sequences from wild-type sequences and mutations encoded in the Human Genome Variation Society (HGVS) recommended nomenclature, performs in-silico tryptic digestion, and identifies both variant and corresponding wild-type peptides. Each peptide is evaluated by 37 selection criteria to determine suitability as MRM targets. To assess the strictness of these criteria, we applied all protein-altering mutations from the NCI-Genomic Data Commons (GDC) and COSMIC to our pipeline. Of the peptides outputted, 5% satisfied all defined criteria, representing the highest confidence candidates for assay development. We developed a database and web application from NCI-GDC generated peptides for searching, filtering, and downloading. Another web application was developed to provide access to our pipeline.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but are associated with immune-related adverse events (irAEs), including musculoskeletal symptoms. We report a case of rapid exacerbation of bilateral hip osteoarthritis (OA) induced by nivolumab. A 56-year-old woman with a history of developmental hip dysplasia and malignant melanoma was treated with nivolumab. Following nivolumab administration, she developed severe bilateral hip pain and polyarthralgia, with necessitating drug discontinuation. Despite cessation of the ICI, her symptoms persisted, accompanied by elevated C-reactive protein levels. Imaging showed end-stage OA with joint space narrowing and increased 18F-FDG uptake in both hip joints. She underwent staged bilateral total hip arthroplasty. Intraoperative pathology showed marked synovial hyperplasia. Immunohistochemical analysis showed diffuse positivity for CD68, TNF-α, IL-6, PD-1, and PD-L1, findings consistent with an immune-mediated inflammatory process superimposed on degenerative changes. Postoperatively, her hip pain and associated symptoms gradually improved, accompanied by normalization of inflammatory markers during follow-up. Histological evidence suggests that PD-1/PD-L1 blockade may locally amplify inflammation within the osteoarthritic joint. Clinicians must be vigilant regarding the potential for ICIs to rapidly worsen underlying joint disease, warranting timely surgical intervention when conservative management fails.

BACKGROUND: Breast cancer (BC) is one of the most common malignancies in women. Lipase E, hormone-sensitive type (LIPE), is a key lipase with potential regulatory roles in tumor lipid metabolism and the immune microenvironment. However, the molecular mechanisms by which LIPE regulates BC progression remain unclear. METHODS: The Gene Expression Omnibus (GEO) database was used to download BC-related transcriptomic data. The Weishengxin platform was used for gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses. TNMplot and gene expression profiling interactive analysis (GEPIA) platforms were used to obtain LIPE expression in BC tissues and at different clinical stages. Real-time quantitative polymerase chain reaction (RT-qPCR) and western blot were used to detect messenger RNA (mRNA) and protein expression. Cell transfection, 5-ethynyl-2'-deoxyuridine (EdU), transwell, and wound healing assays were used to evaluate gene overexpression, cell proliferation, invasion, and migration. Commercial kits were used to measure free fatty acid (FFA) and lipoprotein lipase (LPL). Flow cytometry was used to analyze the proportion of cluster of differentiation 206 (CD206)-positive cells. In vivo experiments were conducted to validate the effects of LIPE on BC lipid metabolism and macrophage polarization. Immunohistochemistry (IHC) was used to detect CD206 and Ki-67 levels. RESULTS: BC transcriptomic analysis identified c-x-c motif chemokine receptor 4 (CXCR4), LIPE, and cyclin-dependent kinase inhibitor 1c (CDKN1C) as potential key regulators of BC progression. GO and KEGG enrichment analyses showed that lipid droplet, acylglycerol lipase activity, regulation of lipolysis in adipocytes, and leukocyte transendothelial migration were significantly enriched. LIPE was significantly downregulated in BC-related transcriptomic datasets, BC tissues, and cells. LIPE overexpression reduced BC cell proliferation, invasion, and migration, increased FFA and LPL levels and activity, and decreased fatty acid synthase (FASN) and atp-citrate lyase (ACLY) expression. It also reduced the proportion of CD206-positive cells and the levels of interleukin-10 (IL-10) and transforming growth factor beta 1 (TGF-β1), while increasing the level of IL-1β. In vivo, LIPE overexpression decreased tumor volume and weight, and reduced FASN, ACLY, CD206, and Ki-67 levels in BC tissues. CONCLUSION: LIPE regulates lipid metabolism and thereby influences macrophage polarization, affecting BC progression and providing new insights and targets for its mechanistic research and therapy.