BACKGROUND:High-grade soft tissue sarcomas (STSs) are heterogeneous tumours lacking robust prognostic or predictive biomarkers. Regnase-1, an immune RNase, enhances antitumour immunity by limiting immunosuppressive tumour microenvironment (TME) components (e.g., myeloid-derived suppressor cells (MDSCs)), but remains unexplored in STS. As CD68+ tumour-associated macrophages (TAMs) drive TME suppression and poor prognosis in non-translocation-driven STS, we evaluated Regnase-1 and CD68+ TAMs to assess Regnase-1 as an indicator of an immunologically activated TME. METHODS:Immunohistochemistry scoring of Regnase-1 and CD68+ TAMs was performed in 91 patients. Overall survival (OS) was assessed by Kaplan-Meier and Cox regression, and findings were validated in an independent "The Cancer Genome Atlas" Sarcoma (TCGA-SARC) cohort (n = 212). RESULTS:In UPS, Regnase-1-high predicted longer OS (17.0 months vs. not reached; p = 0.0247) and lower mortality (univariate hazard ratio (HR) = 0.3; p = 0.0343; multivariate HR = 0.4; p = 0.0413), but not after radiotherapy. CD68+ TAM-high predicted shorter OS (13.0 months vs. not reached; p = 0.0274) and higher mortality (HR = 2.0, 95% CI 1.1-3.7; p = 0.0325). Both Regnase-1 effects were reproduced in TCGA-SARC. Regnase-1-high tumours showed inflammatory/interferon enrichment, reduced TGF-β signalling, and SERPINE1 upregulation. CONCLUSIONS:Regnase-1 marked a pro-inflammatory TME and favourable outcome in UPS, but this effect may reverse upon radiotherapy.

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Lung cancer tissue diagnostics is complex, as therapy decisions in precision oncology rely on the integration of histomorphological, immunohistochemical, and molecular features. Yet pathological assessment remains largely visual and semi-quantitative and shows interobserver variability, while existing artificial intelligence (AI) tools cover only selected tasks, rarely reach generalizable expert-level performance, and lack prospective clinical validation. To address these challenges, we developed and clinically validated LUCAID, an agentic AI system for precision lung cancer pathology. An integrative agent couples diagnostic reasoning with nine modules that cover the full routine workflow, from quality control, tumor detection and segmentation, histological subtyping, tumor microenvironment profiling, tumor cellularity quantification, and predictive biomarker scoring (PD-L1, MET, TROP-2) to automated structured report generation. LUCAID enables users to interactively query the module outputs and generate reports that contextualize the results. Against large-scale expert ground-truth annotations, the analysis modules achieved F1 scores of 0.82-0.95. In prospective clinical validation, LUCAID reached 93.0

Background/Objectives: Perineural (PnI), lymphatic (LI), and vascular invasion (VI) in tumor specimens are supposed to worsen the clinical course of oral squamous cell carcinoma (OSCC) and negatively influence survival outcomes. Despite this, these histologic features have not been implemented in the international staging recommendation for OSCC and their prognostic role remains questionable due to inconsistent findings in the related literature. Methods: To investigate the impact of PnI, LI, and VI on oral cancer-specific (OCSS), recurrence-free (RFS), and overall survival (OS), we hypothesized that these histologic features are independent risk factors for poor survival and therefore considered within a prospectively maintained single-center cohort of patients with OSCC. LI and VI were assessed together and reported as lymphovascular invasion (LVI). Results: This study included 439 patients with primary OSCC. Sixty-nine Patients (21.9%) had at least one of the two risk factors. Within the 5-year follow-up period, 61 of these patients (64%) died, and 30 patients (31%) developed locoregional recurrences. Both perineural and lymphovascular invasion were strongly correlated with the presence of lymph node metastasis. PnI and LVI were investigated separately using an adjusted Cox’s proportional hazards regression model. In addition to higher tumor size and the presence of nodal disease (higher stage) the presence of LVI was associated with poor OS, OCSS, and RFS on multivariate analysis, while PnI was associated with reduced OS. In stage III/IV postoperative radiotherapy improved survival in patients with PnI but not with LVI. Conclusions: We conclude that the evidence of LVI in tumor specimens should be considered a high-risk factor when planning adjuvant treatment and monitoring patients with OSCC.

IntroductionTumor budding (TB) refers to the presence of small clusters of tumor cells at the invasive front of a malignant tumor. Single tumor cell invasion (SCI) is an extreme variant of TB, in which individual loose tumor cells are present at the invasive front. Both TB and SCI are important histomorphologic risk factors postulated to indicate loss of cellular cohesion. In this study, we investigated the influence of TB and SCI on different survival outcomes in patients with locally advanced oral squamous cell carcinoma (OSCC).MethodsWe included 129 patients with locally advanced OSCC (pT3-4) from a single-center, prospectively maintained cohort. We examined the association of TB and SCI with the presence of occult lymph node metastasis using a logistic regression model. Survival probabilities were estimated using the Kaplan-Meier method and cumulative incidence functions. The association of TB and SCI on overall survival (OS), oral cancer-specific survival (OCSS), and local recurrence-free survival (LRFS) was investigated using Cox’s proportional hazards regression models. ResultsTB was detected in 98 (76%) of the tumors, while SCI was observed in 66 (51%) patients. There was a significant association between TB and the occurrence of occult lymph node metastasis (OR=3.33, CI: 1.21-10.0). On multivariate analysis, TB had no detectable impact on survival outcomes. However, SCI showed a higher risk for local recurrence (Hazards ratio (HR): 3.33, CI: 1.19 – 9.27). DiscussionThis study demonstrates that TB and SCI in locally advanced OSCC function as an independent risk factor for occult lymph node metastases, as well as local recurrences. Both histomorphologic risk factors could serve as an additional parameter for stratifying therapy and escalating multimodal treatment approaches.

<p>HeLa and SW756 cells were stimulated with medium or OSM.</p>

<p>Low constitutive STAT3 activation in cervical cancer cell lines but not in primary cervical carcinoma cells or exocervical keratinocytes after prolonged exposure of Western blot analysis.</p>

Patients with lymphatic leukemia or systemic lymphoma may also present with clinical signs of ocular inflammation including inflammation of the anterior chamber membranes [1], [2]. Similar to lymphatic leukemia, myeloid leukemia, an oncogenic disease originating from the myeloid blood cell line (e.g., stemming from granulocytes, monocytes, erythrocytes and platelets), may present with various ocular features mostly affecting the posterior segment as a result of direct cellular invasion, non-perfusion of the retina or uvea or bleeding due to pancytopenia [3]. Clinical findings include optical nerve or retinal infiltration or uveitis [4]. Isolated presentation of anterior chamber affection is a rare feature and less common in myeloid leukemia than in lymphatic leukemia [5]. Therefore, it is not clear whether this affection is a tumorous infiltration or secondary inflammatory intraocular iridocyclitis due to systemic leukemia. To further illuminate this question, we report a case of acute myeloid leukemia with a massive unilateral whitish membrane and secondary hypopyon in the anterior chamber, which was investigated by immunohistological analysis.

<p>Pre- and Post-therapeutically staged tumors according to the International Federation of Gynecology and Obstetrics or TNM categories (S1); List of used antibodies (S2); Primers for amplification of cDNAs of IRF1 and IRF2 (S3).</p>

Figure S1. Selumetinib-resistant organoids show elevated mRNA levels of CEMIP but not Myc. Figure S2. CEMIP controls the expression of genes candidates linked to ErbB, RAS and LEF1 signaling and identification of upstream regulators of CEMIP. Figure S3. CEMIP is required for the maintenance of ex-vivo organoid cultures showing constitutive Wnt signaling. Figure S4. CEMIP promotes the acquired resistance to MEK1 inhibition in colon cancer cells. Figure S5. Ectopic expression of CEMIP in colon cancer cells enhances pERK1/2 and Myc levels and protects from cell death upon MEK1 inhibition. Figure S6. Acquisition of Selumetinib resistance in BRAFV600E-mutated colorectal cancer cells decreases E-cadherin levels and induces the nuclear expression of p65 and FRA-1. Figure S7. FRA-1 controls CEMIP expression in Selumetinib-resistant colon cancer cells. Figure S8. Vemurafenib decreases CEMIP expression in Selumetinib-resistant colon cancer cells. Figure S9. CEMIP expression is regulated by TCF4 in Selumetinib-resistant colon cancer cells. Figure S10. Generation of KRASG13D or G12A-mutated colon cancer cells showing some acquired resistance to Selumetinib. Figure S11. CEMIP promotes the acquired resistance to Selumetinib in BRAFV600E-mutated colorectal cancer cells. Figure S12. pERK1/2 levels decrease after a short treatment with Selumetinib but increase again after 24 hours of MEK1 inhibition and CEMIP contributes to MEK1-dependent ERK1/2 activation. Figure S13. Resistant BRAFV600E-mutated colorectal cancer cells with acquired resistance to MEK1 inhibition show more BRAF dimers. Figure S14. Myc deficiency mimicks CEMIP deficiency in Selumetinib-resistant ex-vivo organoids. Supplementary Table 1 is a list of all antibodies used in this study.

BackgroundAdenoma detection with polypectomy during total colonoscopy reduces the incidence of colorectal cancer (CRC) and colorectal cancer-associated mortality. The adenoma detection rate (ADR) is an established quality indicator, which is associated with a decreased risk for interval cancer. An increase in ADR could be demonstrated for several artificially intelligent, real-time computer-aided detection (CADe) systems in selected patients. Most studies concentrated on outpatient colonoscopies. This sector often lacks funds for applying costly innovations like CADe. Hospitals are more likely to implement CADe and information about the impact of CADe in the distinct patient cohort of hospitalized patients is scarce.MethodsIn this prospective, randomized-controlled study, we compared colonoscopies performed with or without computer-aided detection (CADe) system (GI Genius, Medtronic) performed at University Medical Center Schleswig-Holstein, Campus Luebeck. The primary endpoint was ADR.ResultsOverall, 232 patients were randomized with n = 122 patients in the CADe arm and n = 110 patients in the control arm. Median age was 66 years (interquartile range 51-77). Indication for colonoscopy was most often workup for gastrointestinal symptoms (88.4%) followed by screening, post-polypectomy and post-CRC surveillance (each 3.9%). Withdrawal time was significantly prolonged (11 vs. 10 min, p = 0.039), without clinical relevance. Complication rate was not different between the arms (0.8% vs. 4.5%; p = 0.072). The ADR was significantly increased in the CADe arm compared to the control (33.6% vs. 18.1%, p = 0.008). ADR increase was particularly strong for the detection in elderly patients aged >= 50 years (OR 6.3, 95% CI 1.7 - 23.1, p = 0.006).ConclusionThe use of CADe is safe and increases ADR in hospitalized patients.

<p>HeLa cells were transfected with 10 pmol/1.5 x 105 cells of human IRF1-specific siRNA (#8) or mock siRNA.</p>

1.5 x 105 HeLa cells/6-well were either left untransfected or were transfected with (A) 0 µg, 0.025 µg or 0.1 µg of pCMV-Flag2-IRF1 or (B) 0 µg, 0.6 µg or 0.8 µg of pCMV-Flag2-IRF2.

<p>79 human FFPE SCC were stained with anti-pTyr705-STAT3 Ab.</p>

<p>IRF1 is not induced by OSM or IL-6/sgp80 stimulation in NECK.</p>

<p>HeLa cells were transfected with 10 pmol/1.5 x 105 cells of human STAT3-specific siRNA (#8 or 9) or mock siRNA.</p>

HeLa cells were co-transfected with 1.85 µg pEFBos-STAT3F or pEFBos control vector and 0.35 µg EGFP expression vector.

Legends to Supplementary Figures S1-S8.

Background Anti-NMDA-receptor (anti-NMDAR) encephalitis is often associated with ovarian teratoma (OT). The best management of anti-NMDAR encephalitis patients with normal imaging studies (pelvic ultrasound/MRI) but clinically high risk of OT (e.g., female, adult, black) is unclear. We report on the surprising diagnostic quest in a young black woman with anti-NMDAR encephalitis, in whom invasive procedures could finally disclose two OTs that were hidden from the initial non-invasive diagnostics. Case report The patient presented with a one-week history of psychotic symptoms, developing oro-facial dyskinesia, seizures and coma, eventually requiring mechanical ventilation. NMDA-receptor antibodies were positive in serum and cerebrospinal fluid. Pelvic MRI and transabdominal ultrasound were normal. Exploratory laparoscopy was also unremarkable at first, but due to a suspicious echogenic mass (15 mm) in the right ovary on perioperative transvaginal ultrasound, an ovarian incision was performed which led to the detection of a first OT and its removal via ovarian-preserving cystectomy. Following a severe therapy-refractory clinical course despite aggressive immunotherapy and tumor removal, 6 months later bilateral oophorectomy was performed as ultima ratio, disclosing a second micro-OT (6 mm) in the left ovary. Unfortunately, the patient has not improved clinically yet. Conclusions In therapy-refractory anti-NMDAR encephalitis with high risk of OT, small and bilateral OTs hidden from primary non-invasive diagnostics should be considered, which may trigger further invasive diagnostic procedures.

Osteosarcomas are the most common primary malignant bone tumors and are classified by the WHO into several intramedullary and surface subtypes. One of these is the rare parosteal osteosarcoma. Liposarcomas are the second most common soft tissue sarcoma and are classified into several types ranging from intermediate to high grade tumors. In one of our recent patients we found an unusual combination of a parosteal osteosarcoma and a large fatty component, which fluorescence-in-situ-hybridization revealed as liposarcoma. Radiologists, pathologists, and surgeons should consider the possibility of bone and soft tissue malignancies consisting of different components, as this may be of paramount importance for oncologically complete resection.