Background Cancer metastasis, the leading cause of cancer mortality, is fundamentally dependent on the formation of a pre-metastatic niche (PMN), a distant microenvironment proactively reprogrammed by the primary tumor to support malignant seeding. The early microscopic and spatially heterogeneous events driving PMN formation have historically evaded detection by standard clinical imaging and bulk omics technologies. Advances & Insights The advent of highly multiplexed spatial multi-omics, integrating spatial transcriptomics, proteomics, metabolomics, and extracellular vesicle cargo-omics, has successfully bridged this diagnostic gap. By enabling high-resolution molecular mapping within intact tissue architectures, these platforms have decoded the organ-specific evolution of the PMN. Key findings highlight how integrin-guided, tumor-derived extracellular vesicles and localized cellular crosstalk actively reprogram resident immune populations and cancer-associated fibroblasts to establish immunosuppressive and metabolically favorable environments. Clinical Translation Distilling these high-dimensional spatial discoveries into targeted multiplex immunofluorescence panels and AI-driven digital pathology models provides a transformative roadmap for precision oncology. This framework enables the proactive assessment of metastatic risk and the therapeutic interception of the PMN during the minimal residual disease phase, effectively neutralizing the microenvironment prior to tumor engraftment.
In recent years, the mechanisms of abnormal metabolite accumulation in tumor development have become an emerging research field. Cells within the tumor microenvironment (TME) sustain tumor proliferation via metaboalic reprogramming. Such metabolic remodeling triggers aberrant oncometabolite accumulation, which drives tumor progression, distant metastasis and therapeutic resistance through the modulation of tumor cell proliferation, angiogenesis and immune evasion. Notably, fumarate and itaconate, originating from different subcellular localizations, modulate protein function primarily covalent or non-covalent interactions. Functionally, the modified target proteins can be roughly divided into four categories that drive tumor progression: key metabolic enzymes, epigenetic regulators, immune-related molecules and resistance-associated proteins, which respectively modulate metabolic rewiring, epigenetic reprogramming, the immunosuppressive microenvironment and therapeutic resistance. Herein, we systematically summarize the oncogenic mechanisms of these two oncometabolites, propose viable strategies to address technical hurdles in studying non-enzymatic protein modifications and offer new directions for the clinical treatment of tumors through targeted inhibition of fumarate and itaconate.
Small cell carcinoma (SCC) of the anal canal is a rare and highly aggressive neuroendocrine malignancy, and its infrequency has limited the development of evidence-based treatment approaches. As a result, management of extrapulmonary SCC (EPSCC) is often extrapolated from small cell lung cancer (SCLC), given the similar disease biology and the lack of formal approval for many SCLC-directed agents. We report the case of a 60-year-old woman who presented with metastatic SCC of the anal canal and whose disease course illustrates both the challenges and therapeutic uncertainties inherent in treating this diagnosis. Given the absence of established standards, she was treated with SCLC-based regimens and achieved a partial radiographic and clinical response to platinum-based chemotherapy in combination with the immune checkpoint inhibitor atezolizumab. Upon subsequent progression, she was treated with lurbinectedin and tarlatamab, a bispecific T-cell engager targeting delta-like ligand 3 (DLL3), reflecting evolving treatment paradigms in SCLC. Her response suggests that novel therapies developed for pulmonary small cell disease may offer benefit in select extrapulmonary cases. This case highlights the need for continued reporting of clinical experiences and prospective investigation to better define the role of emerging therapies in rare and aggressive extrapulmonary neuroendocrine malignancies.
Male breast cancer is rare. Encapsulated Papillary Carcinoma (EPC) is an uncommon, low-grade subtype that presents as a solitary cystic tumor. EPC comprises 2%-3% of male breast cancers and is difficult to diagnose due to challenges in biopsy and its similarity to benign lesions. We present a case of EPC in an middle-aged male with complicated preoperative imaging findings. A 58-year-old male presented with a stable, non-painful left breast mass noticed six years ago. Initially diagnosed as a lipoma, the ultrasound revealed a suspicious BIRADS 4 mass. CT imaging showed a mass with small lymph nodes. An intraoperative frozen section raised suspicion of malignancy, and the diagnosis of EPC was confirmed on definitive paraffin-section histopathology. The patient underwent surgery, and histopathology revealed positive hormone receptors and negative surgical margins. Postoperative recovery was uneventful except for a minor hematoma. EPC is an uncommon breast cancer subtype that arises from the cystic wall, with a low recurrence rate after surgery. Diagnosis is challenging due to low atypia and difficulty obtaining biopsy samples. EPC, often hormone receptor-positive, is typically treated with surgical resection, and mastectomy may be needed depending on tumor location. After complete excision with clear margins, pure EPC is managed analogously to ductal carcinoma in situ and does not routinely require systemic adjuvant therapy; endocrine therapy is considered on an individualized basis, and adjuvant treatment is otherwise guided by any invasive component. EPC is an uncommon and diagnostically challenging malignancy with a favorable prognosis when confined to the cyst wall. Complete surgical excision with clear margins is the primary treatment; for pure EPC, no systemic adjuvant therapy is routinely required, and endocrine therapy is considered on an individualized basis. With management aligned to current guidelines, EPC generally results in favorable outcomes.
Background Peritoneal metastasis from colorectal cancer (pmCRC) is a major form of distant spread and generally confers a poor prognosis. This study aimed to evaluate its global research activity, hotspots, and emerging trends through a bibliometric analysis. Methods We searched the Web of Science Core Collection, PubMed, and Scopus for English-language pmCRC articles and reviews published from January 1, 2000, to March 31, 2026. Bibliometric analyses were performed using tools such as CiteSpace (v6.3), VOSviewer (v1.6.20), and R software (v4.5.0). Results A total of 1,611 publications were included. The United States produced the highest number of publications (n = 304), followed closely by China (n = 289) and the Netherlands (n = 203). Catharina Hospital emerged as the most productive institution (74 publications), while Ignace H.J.T. De Hingh was identified as the leading contributor based on publication volume and co-authorship linkage strength. Annals of Surgical Oncology was the most influential journal (161 publications). Keyword cluster analysis revealed four major research themes: surgical treatment, molecular mechanisms, chemotherapy, and prognosis. Citation burst analysis showed that “multicenter” had the highest burst strength, while “circulating tumor DNA” and “machine learning” have emerged as recent ongoing hotspots. Conclusions This bibliometric analysis provides an overview of pmCRC research over the past two decades. The field has evolved from optimizing surgical techniques toward molecular exploration and precision medicine. Emerging hotspots, including ctDNA, machine learning, and multicenter trials, point toward dynamic multi-omics monitoring and collaborative clinical validation.
BACKGROUND:Surgical choice between Dixon and Miles procedures in low rectal cancer (LRC) remains controversial, especially for tumors located 3-5 cm from the anal verge-a clinical "gray zone." This study aims to compare oncologic outcomes between procedures and identify prognostic factors. METHODS:We retrospectively analyzed 1,215 LRC patients (≤6 cm from anal verge) treated from 2008 to 2020. Patients in the 3-5 cm range (n = 601) formed the Borderline Group. MRI-based risk factors (mrMRF, mrEMVI) and survival outcomes were assessed using Kaplan-Meier and Cox regression models. RESULTS:MRI-based risk stratification revealed distinct survival differences. Patients with MRI-defined high-risk features derived significant oncologic benefit from the Miles procedure. In the mrMRF-positive subgroup, Miles surgery was associated with improved disease-free survival (DFS; HR = 0.28, P = 0.004) and overall survival (OS; HR = 0.21, P < 0.001) compared with Dixon. Similarly, in mrEMVI-positive patients, Miles resulted in superior DFS (HR = 0.38, P = 0.012) and OS (HR = 0.25, P < 0.001). Multivariate analysis further confirmed that Miles was an independent predictor of favorable survival in these high-risk subgroups, whereas outcomes were comparable between procedures in MRI low-risk patients. CONCLUSION:For borderline LRC cases (3-5 cm from anal verge), Dixon and Miles surgeries yield similar outcomes overall. However, Miles surgery is preferable in patients with MRI-defined high-risk features, supporting MRI-guided surgical decision-making. These findings highlight the clinical utility of an MRI-guided, risk-adapted surgical strategy for borderline low rectal cancer.
Background Complete circumferential lymphadenectomy (CCL) around the superior mesenteric artery (SMA) is not routinely performed during pancreaticoduodenectomy (PD) for patients with pancreatic head cancer, and its clinical value remains unclear. Objective To investigate the positive rate of left side lymph nodes along the SMA (14cd-LNs), identify the associated risk factors and clinical outcomes, and evaluate the feasibility and potential clinical benefit of CCL in patients with pancreatic head cancer. Methods Patients who underwent PD for pancreatic head cancer at the Pancreatic Center of the First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital) between January 2020 and March 2023 were prospectively collected and retrospectively reviewed. Baseline characteristics, pathological findings, perioperative outcomes, and long-term oncological outcomes were evaluated. Univariate and multivariable logistic regression analyses were performed to identify risk factors. Statistical analyses were conducted using Stata 18.0. Results A total of 260 patients were identified, 132 (50.77%) performed CCL. Compared with the non-CCL group, CCL prolonged the median operation time (287.5 min vs. 248.0 min, P < 0.001), and postoperative hospital stay (17.0d vs. 13.0d, P < 0.001), but did not increase the postoperative mortality and morbidity. In the CCL group, the positive rate of 14cd-LNs was 28.79% (38/132), and 14cd-LNs metastasis indicated poorer prognosis (14cd-LNs negative vs. 14cd-LNs positive, median disease-free survival: 23.2 months vs. 11.5 months, P = 0.003; median overall survival: NR vs. 20.6 months, P = 0.003). Uncinate invasion-positive (OR=2.88, 95%CI: 1.07 to 7.76, P = 0.036), and tumor size≥4 cm (OR=4.27, 95%CI: 1.63-11.21, P = 0.003) were independent risk factors of 14cd-LNs metastasis. CCL significantly reduced postoperative 9-month local recurrence compared to non-CCL (25.00% vs 10.91%, P = 0.008), and emerged as an independent influencing factor of 9-month local recurrence (OR=0.31, 95%CI: 0.12-0.78, P = 0.013), but failed to provide survival benefits, neither disease-free survival (18.4 vs. 13.7 m, P = 0.280) nor overall survival (25.5 vs. 28.1 m, P = 0.930) across the whole cohort. For patients with low-risk 14cd-LNs metastasis (uncinate invasion-negative and tumor size <4.0 cm), CCL improved their disease-free survival (27.2 vs.12.8 m, P = 0.019) and overall survival (NR vs. 31.7 m, P = 0.062). Conclusions 14cd-LNs metastasis occurs at a considerable frequency in patients with pancreatic head cancer and is associated with poor prognosis. CCL provides improved locoregional control and may confer survival benefit in patients with low-risk 14cd-LNs metastasis.
The metabolic activities of cancer cells undergo complete transformation because they need to maintain their growth while resisting metabolic challenges and environmental dangers from their tumour surroundings. The metabolic changes that occur in cells depend on specific oncogenes together with tumour suppressor genes and stress-response pathways, which control essential bioenergetic and biosynthetic functions. This review presents the current scientific knowledge about genetic regulators, which include MYC, KRAS, PI3K-AKT-mTOR, EGFR, p53, PTEN, and LKB1-AMPK, that control glucose, amino acid, lipid, nucleotide, and mitochondrial metabolism in different human cancers. The research demonstrates that these pathways connect through common metabolic pathways, which produce metabolic flexibility and create complex metabolic patterns that drive tumour diversity and development and resistance to treatment. We present new systems-level frameworks that exceed pathway-based descriptions to show the intricate nature of cancer metabolism. The review investigates how artificial intelligence (AI) and machine learning methods, combined with multi-omics data and genome-scale metabolic models, enable scientists to enhance metabolic phenotyping and discover specific tumour weaknesses and forecast treatment results and combination methods. The study begins with a discussion of present-day obstacles that impede clinical application of research results, which include data inconsistency and the challenges of understanding and testing models. Then it presents upcoming research paths that will develop AI-powered metabolic assessment into biologically understandable and clinically usable tools. The review creates a comprehensive framework that connects genetic control mechanisms with metabolic network functions and AI-driven precision oncology.
Programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) constitute a core immune checkpoint axis that restrains T cell activation. Under physiological conditions, the interaction between PD-1 and PD-L1 maintains peripheral tolerance and prevents tissue damage from excessive immune responses. In tumor microenvironment, this axis is frequently activated through upregulation of PD-L1 on cancer cells, causing T cell dysfunction and tumor immune escape. PD-1/PD-L1 blockades reactivate exhausted T cells to kill cancer cells. However, some cancer patients fail to respond to PD-1/PD-L1 inhibitors, and the underlying mechanisms remain incompletely revealed. Thus, it is important to unveil the regulatory mechanisms that govern PD-1 and PD-L1 expression in tumor microenvironment. This review systematically summarizes the regulation of PD-1/PD-L1 expression at the genetic, epigenetic, transcriptional, and posttranscriptional levels. Beyond expression levels, posttranslational modifications and membrane trafficking determine PD‑L1 surface availability and sensitivity to PD-1/PD-L1 inhibitors. In this review, the rapidly expanding clinical trials of PD-1/PD-L1 blockades and future research directions are also discussed.
Clostridioides difficile infection (CDI) is a frequent and consequential healthcare-associated complication in patients with hematologic malignancies (HMs), particularly in the setting of bone marrow transplant (BMT); however, national data comparing the impact of CDI across HM hospitalizations with and without BMT remain significantly limited. To evaluate associations between CDI and key inpatient outcomes like in-hospital mortality, length of stay (LOS), and total hospital charges, this retrospective cross-sectional analysis was conducted using the Nationwide Inpatient Sample. Multivariable models were fitted using survey-weighted logistic regression for mortality and Poisson regression with a log link for LOS and charges, adjusting for demographic and clinical covariates to calculate adjusted odds ratios and incidence rate ratios. Among an estimated 2.86 million adult HM hospitalizations, most involved neither exposure, while smaller proportions involved BMT only, CDI only, or both. In adjusted analyses, CDI was independently associated with higher odds of in-hospital death and substantially increased LOS and hospital charges. BMT was associated with markedly higher mortality and pronounced increases in LOS and charges. Hospitalizations complicated by concurrent CDI and BMT demonstrated the greatest burden across outcomes, with significantly increased mortality risk and the largest increases in LOS and charges (all p < 0.001). These findings indicate that CDI was associated with worse clinical and economic outcomes in hospitalized HM patients, with the highest risk observed when CDI occurs in post-transplant settings. Targeted prevention, early diagnosis, and prompt treatment of CDI therefore represent high-yield opportunities to reduce inpatient morbidity, mortality, and resource utilization in this vulnerable population.
Introduction Cancer-related anemia (CRA) adversely affects quality of life and clinical outcomes. Despite extensive research, uncertainty remains regarding the optimal use of erythropoiesis-stimulating agents (ESAs), iron, and transfusions. This scoping review synthesizes efficacy and safety evidence and compares international management guidelines. Methods A systematic search of PubMed and Embase identified English-language studies on CRA published from 2000 up to November 30, 2024. Randomized controlled trials were reviewed to assess treatment efficacy and safety, and international guidelines were analyzed to compare management recommendations. Results Fifty-six randomized controlled trials and 10 international guidelines were included. ESAs and iron supplementation were effective in improving hemoglobin concentration and reducing transfusion requirements, particularly in context-dependent settings. Combination therapy with ESAs and iron consistently demonstrated superior hematologic responses compared with ESA monotherapy without additional safety concerns. Both conventional and newer intravenous (IV) and oral iron formulations showed benefit across different clinical contexts, with faster responses generally favoring IV iron in some settings, while emerging evidence supports oral iron as a viable alternative in absolute iron deficiency. Emerging therapies, including sotatercept and selected adjunctive approaches, showed preliminary signals of efficacy in limited studies, warranting further investigation.Guidelines generally restrict ESAs to chemotherapy-induced anemia or high-risk patients. For iron therapy, discrepancies exist regarding indications and administration route; most guidelines prioritize IV over oral iron for both functional iron deficiency and absolute iron deficiency. Significant regional gaps in guideline availability were identified, particularly in Africa, South America, Asia-Pacific, and the Middle East. Conclusion CRA management relies on ESAs, iron supplementation, and transfusions, but guideline heterogeneity and regional discrepancies necessitate harmonization and individualized approaches. Updated, globally representative recommendations and further research in under-studied populations are essential.
Tumor lysis syndrome (TLS) arises from the uncontrolled release of intracellular contents into the bloodstream. Generally associated with hematologic malignancies, TLS has also been reported in aggressive solid cancers. Corticosteroids are known triggers of cell lysis in leukemias and lymphomas, but less evidence exists to suggest steroids cause TLS in solid malignancies. We present a case of a 43-year-old smoker with dyspnea, cough, and chest pain. Endobronchial biopsy confirmed the diagnosis of extensive-stage small-cell carcinoma. He remained intubated due to airway edema and was started on dexamethasone. Prior to steroid administration, his blood chemistry values were within reference ranges. The following day, he met both laboratory and clinical Cairo-Bishop criteria for TLS. Despite IV hydration and rasburicase, he worsened and was transitioned to comfort care. This case suggests one of the clearest associations between steroid administration and TLS in a solid tumor. We systematically explored PubMed for cases of TLS in solid tumors and evaluated these for steroid use prior to diagnosis. Of the 252 included articles, 20 described corticosteroid use before the onset of TLS, with only 10 explicitly suggesting steroids may have been causative. While rare in solid tumors, TLS should be considered in any aggressive solid malignancy. A high index of suspicion is essential as early recognition and management of TLS are associated with improved outcomes. We encourage particular attention to be paid after steroids have been administered.
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a well-known group of malignancies characterized by hypervascularization, and much of the focus in this field has been on angiogenesis. Rather than simply an increase in microvessel density, angiogenesis of GEP-NENs is a far more sophisticated process regulated by angiogenic factors, genes, and cells. These angiogenesis-related factors are not only involved in tumorigenesis and progression but also serve as biomarkers with prognostic values and targets for antiangiogenic therapy. Extensive research has been conducted on the role of various angiogenesis-related factors in angiogenesis, their prognostic values, and antiangiogenic therapy has become a critical part of the treatment of GEP-NENs. However, the occurrence of drug resistance and unsatisfactory prognosis reminds us that our understanding of angiogenesis of GEP-NENs is insufficient, and we are in urgent need to optimize existing antiangiogenic therapies. This review focuses on angiogenesis-related factors, their roles in angiogenesis, as well as their values in predicting the prognosis of patients, and introduces the corresponding angiogenic therapies. By summarizing current research findings, we aim to shed light on the mechanism of angiogenesis of GEP-NENs and to elucidate prospects for more accurate prediction of prognosis and individualized antiangiogenic therapies.
Hormone-related cancers represent a significant global health concern, contributing to substantial mortality rates worldwide. The intricate interplay of steroidogenesis, the biochemical pathway governing hormone synthesis, plays a pivotal role in the development and progression of these malignancies. Dysregulation of key steroidogenic enzymes can disrupt physiological and biological processes, thereby driving malignant transformation. Post-translational modifications of these enzymes play an important role in modulating their activity, stability, and subcellular localization, thereby potentially influencing cancer progression. This study provides a comprehensive analysis of the functionality and regulatory mechanisms of four key steroidogenic enzymes, Desmolase, 17α-hydroxylase, 3β-HSD (3β-hydroxysteroid dehydrogenase), and 17β-HSD (17β-hydroxysteroid dehydrogenase), along with a transporter protein (steroidogenic acute regulatory protein [StAR]). We present an integrated overview of their expression patterns, domain architectures, reported post-translational modification sites, and the kinases involved. By elucidating these molecular details, our work highlights novel avenues for targeted therapy in hormone-related cancer research.
R0 resection and maximal preservation of anal function without a permanent stoma remains challenging in patients with a rectal neuroendocrine neoplasm (R-NEN) within 5 cm of the anal verge and lymph node metastasis in the iliac vascular region. A 22-year-old man presented with a 1-year history of paroxysmal palpitations and cold sweats. Colonoscopy revealed a 2-cm mass with well-defined margins located 5 cm from the anal verge. Biopsy revealed a neuroendocrine tumor. Endoscopic submucosal dissection and pathology revealed a G2 R-NEN with negative margins but vascular invasion. Enhanced MRI and whole-body PET/CT identified metastases in the left iliac and right common iliac vascular regions with presacral lymph node involvement. The patient underwent precision functional sphincter-preserving surgery combined with colonic J-pouch anal anastomosis without a stoma. The patient started oral short-peptide enteral nutrition on postoperative day (POD)3 and advanced to a liquid diet on POD8 and a semi-liquid diet on POD10. He was discharged on POD12, with no anastomotic leakage observed within 30 days. Histopathology confirmed stage T1bN1M0 disease. At the 7-month follow-up, the patient reported satisfactory anal, urinary, and sexual function and had maximal global health and quality of life scores. The favorable outcomes in this young case of G2 R-NEN suggests that precision functional sphincter-preserving surgery integrated with a colonic J-pouch may be a clinical reference for achieving oncological radicality while optimizing physiological outcomes. This strategy offers an alternative to traditional radical surgery for young patients and those with high functional demands. However, its safety, functional durability, and oncological efficacy require confirmation in larger, prospective multicenter studies with longer follow‑up.
Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but can cause excessive immune activation, leading to severe adverse events, including intensive care unit (ICU) admission. Existing evidence on critical illness after ICI use is limited, largely single center, and focused on immune related adverse events. This study evaluates the risk of inpatient and ICU admissions after ICI initiation using two large national databases. We retrospectively analyzed MarketScan Commercial and Multi-state Medicaid Research Databases (2016-2022) to identify adults with solid organ malignancies treated with ICIs and determined if ICU admission was required within 90 days of ICI administration. The primary diagnosis for ICU admission was identified and categorized. Associations between cancer type, ICI type, and ICU admission were analyzed. About 33,040 patients received ICIs during the study period. About 48.9% were male and 51.1% female. Pembrolizumab was the most used (49.3%), followed by nivolumab (31.9%), and ipilimumab (9.4%). Lung cancer was the most common malignancy (40.8%), followed by genitourinary (16%), melanoma (13%), gastrointestinal (12%), and breast (10%). About 22.0% (n = 7,216) of patients were hospitalized, and 8.7% (n = 2,872) required ICU admission. Infection was the most frequent reason for ICU admission, followed by respiratory causes. The odds of being admitted to the ICU were higher with combination ICI (OR = 1.51, P < .001) compared to ICI monotherapy. In conclusion, among patients with solid organ malignancies, nearly 9% required ICU admission within 90 days of ICI initiation, most commonly for infectious causes. These findings highlight the need for heightened vigilance for critical illness in patients treated with ICIs.
