IFN-γ-responsiveness of lymphatic endothelial cells inhibits melanoma lymphatic dissemination via AMPK-mediated metabolic control.

The integrity of the lymphatic system is critical for preventing the dissemination of tumor cells, such as melanoma, to distant parts of the body. IFN-γ is well studied as a negative regulator for lymphangiogenesis, which is strongly associated with cancer metastasis. However, the exact mechanisms underlying this process remain unclear. In the present study, we investigated whether IFN-γ signaling in lymphatic endothelial cells (LECs) affects tumor cell dissemination by regulating the barrier function of tumor-associated lymphatic vessels. Using LEC-specific IFN-γ receptor (IFN-γR) knockout mice, we found that the loss of IFN-γR in LECs increased the dissemination of melanoma cells into the draining lymph nodes. Notably, IFN-γ signaling in LECs inhibited trans-lymphatic endothelial cell migration of melanoma cells, indicating its regulation of lymphatic barrier function. Further investigations revealed that IFN-γ upregulated the expression of the tight junction protein Claudin-3 in LECs, while knockdown of Claudin-3 in LECs abolished IFN-γ-induced inhibition of trans-lymphatic endothelial migration activity. Mechanistically, IFN-γ inhibits AMPK signaling activation, which is involved in the regulation of fatty acid metabolism. Modulating fatty acid metabolism and AMPK activation in LECs also affected the lymphatic dissemination of melanoma cells, further confirming that this process is involved in IFN-γ-induced regulation of lymphatic barrier function. These results provide novel insights into how IFN-γ modulates tight junctions in LECs, inhibiting the dissemination of melanoma cells via the lymphatic vessels.

Assessing the Efficacy of Radioactive Iodine Seed Localisation in Targeted Axillary Dissection for Node-Positive Early Breast Cancer Patients Undergoing Neoadjuvant Systemic Therapy: A Systematic Review and Pooled Analysis.

Targeted axillary dissection (TAD), employing marked lymph node biopsy (MLNB) alongside sentinel lymph node biopsy (SLNB), is increasingly recognised for its efficacy in reducing false negative rates (FNRs) in node-positive early breast cancer patients receiving neoadjuvant systemic therapy (NST). One such method, 125I radioactive seed localisation (RSL), involves implanting a seed into a biopsy-proven lymph node either pre- or post-NST. This systematic review and pooled analysis aimed to assess the performance of RSL in TAD among node-positive patients undergoing NST. Six studies, encompassing 574 TAD procedures, met the inclusion criteria. Results showed a 100% successful deployment rate, with a 97.6% successful localisation rate and a 99.8% retrieval rate. Additionally, there was a 60.0% concordance rate between SLNB and MLNB. The FNR of SLNB alone was significantly higher than it was for MLNB (18.8% versus 5.3%, respectively; p = 0.001). Pathological complete response (pCR) was observed in 44% of cases (248/564). On average, the interval from 125I seed deployment to surgery was 75.8 days (range: 0-272). These findings underscore the efficacy of RSL in TAD for node-positive patients undergoing NST, enabling precise axillary pCR identification and facilitating the safe omission of axillary lymph node dissection.

Lymphatic Dissemination in Prostate Cancer: Features of the Transcriptomic Profile and Prognostic Models.

Radical prostatectomy is the gold standard treatment for prostate cancer (PCa); however, it does not always completely cure PCa, and patients often experience a recurrence of the disease. In addition, the clinical and pathological parameters used to assess the prognosis and choose further tactics for treating a patient are insufficiently informative and need to be supplemented with new markers. In this study, we performed RNA-Seq of PCa tissue samples, aimed at identifying potential prognostic markers at the level of gene expression and miRNAs associated with one of the key signs of cancer aggressiveness-lymphatic dissemination. The relative expression of candidate markers was validated by quantitative PCR, including an independent sample of patients based on archival material. Statistically significant results, derived from an independent set of samples, were confirmed for miR-148a-3p and miR-615-3p, as well as for the CST2, OCLN, and PCAT4 genes. Considering the obtained validation data, we also analyzed the predictive value of models based on various combinations of identified markers using algorithms based on machine learning. The highest predictive potential was shown for the "CST2 + OCLN + pT" model (AUC = 0.863) based on the CatBoost Classifier algorithm.

Novel Expression of Thymine Dimers in Renal Cell Carcinoma, Demonstrated through Immunohistochemistry.

Despite significant developments in renal cell carcinoma (RCC) detection and molecular pathology, mortality has been steadily rising. Advanced RCC remains an incurable disease. Better clinical management tools, i.e., RCC biomarkers, have yet to emerge. Thymine-dimers (TDs) were traditionally considered photo-dependent pre-mutagenic lesions, occurring exclusively during ultra-violet light exposure. Non-oxidative, direct, and preferential byproducts of DNA photochemical reactions, TDs, have recently shown evidence regarding UVR-independent formation. In this study, we investigate, for the first time, TD expression within RCC tumor tissue and tumor-adjacent healthy renal parenchyma using a TD-targeted IHC monoclonal antibody, clone KTM53. Remarkably, out of the 54 RCCs evaluated, 77.8% showed nuclear TD-expression in RCC tumor tissue and 37% in the tumor-adjacent healthy renal parenchyma. A comprehensive report regarding quantitative/qualitative TD-targeted immunostaining was elaborated. Two main distribution models for TD expression within RCC tumor tissue were identified. Statistical analysis showed significant yet moderate correlations regarding TD-positivity in RCC tissue/tumor-adjacent healthy renal parenchyma and TNM stage at diagnosis/lymphatic dissemination, respectively, indicating possible prognostic relevance. We review possible explanations for UVR-independent TD formation and molecular implications regarding RCC carcinogenesis. Further rigorous molecular analysis is required in order to fully comprehend/validate the biological significance of this newly documented TD expression in RCC.

Lymphatic Dissemination and Axillary Web Syndrome in Primary Cutaneous Tuberculosis Secondary to Needlestick Injury.

Cutaneous tuberculosis secondary to skin inoculation of Mycobacterium tuberculosis is uncommon but it can occur in the health care settings. Herein, we report an unusual case of primary cutaneous tuberculosis of the thumb following a needlestick injury. The infection progressed with a necrotic granuloma, lymphatic dysfunction as visualized by near-infrared fluorescence lymphatic imaging, and the development of an axillary web syndrome.

miRNAs expression signature potentially associated with lymphatic dissemination in locally advanced prostate cancer.

BACKGROUND: Prostate cancer is one of the most common and socially significant cancers among men. The aim of our study was to reveal changes in miRNA expression profiles associated with lymphatic dissemination in prostate cancer and to identify the most prominent miRNAs as potential prognostic markers for future studies. METHODS: High-throughput miRNA sequencing was performed for 44 prostate cancer specimens taken from Russian patients, with and without lymphatic dissemination (N1 - 20 samples; N0 - 24 samples). RESULTS: We found at least 18 microRNAs with differential expression between N0 and N1 sample groups: miR-182-5p, miR-183-5p, miR-96-5p, miR-25-3p, miR-93-5p, miR-7-5p, miR-615-3p, miR-10b, miR-1248 (N1-miRs; elevated expression in N1 cohort; p < 0.05); miR-1271-5p, miR-184, miR-222-3p, miR-221-5p, miR-221-3p, miR-455-3p, miR-143-5p, miR-181c-3p and miR-455-5p (N0-miRs; elevated expression in N0; p < 0.05). The expression levels of N1-miRs were highly correlated between each other (the same is applied for N0-miRs) and the expression levels of N0-miRs and N1-miRs were anti-correlated. The tumor samples can be divided into two groups depending on the expression ratio between N0-miRs and N1-miRs. CONCLUSIONS: We found the miRNA expression signature associated with lymphatic dissemination, in particular on the Russian patient cohort. Many of these miRNAs are well-known players in either oncogenic transformation or tumor suppression. Further experimental studies with extended sampling are required to validate these results.

Duodenal and rectal obstructions due to urothelial cancer infiltration from recurrent renal pelvic cancer in the bladder wall: An autopsy case.

Duodenal and rectal obstructions due to urological malignancies are relatively uncommon. We report an autopsy case of an 83-year-old man with a history of renal pelvic cancer who presented these obstructions. Autopsy revealed that urothelial cancer infiltrated the bladder wall, duodenal wall, rectal wall, and prostate and widely spread in the retroperitoneal lymphatic vessel. We concluded that renal pelvic cancer recurred in the bladder wall and then infiltrated into each organ because of lymphatic dissemination. The gastrointestinal obstructions due to urinary tract cancer were lethal. Further knowledge and clinical experience regarding these types of obstructions are crucial.

Prediction of lymphatic dissemination in endometrioid endometrial cancer: Comparison of three risk-stratification models in a single-institution cohort.

OBJECTIVES: To compare the performance characteristics of 3 risk-stratification models, referred to as Mayo, Helsinki and Milwaukee models, in predicting lymphatic dissemination in endometrial cancer. METHODS: A total of 1052 patients with stage I-III endometrioid endometrial cancer were included in the study. The areas under curve were compared with the receiver operating characteristic curve area comparison test. Chi-square and Fisher exact test were used for comparing categorical variables. The Kaplan-Meier method and multivariable Cox regression models were used for survival analyses. The median follow-up time was 55months (range 1-108). RESULTS: Areas under curve were 0.781, 0.830 and 0.829 for the Mayo, Helsinki (P=0.285 vs. Mayo) and Milwaukee (P=0.292 vs. Mayo) models, respectively, in predicting lymphatic dissemination. The rates of false negatives and false positives were similar for all models. The lymphadenectomy rate decreased in the order of Mayo model (71.5%)>Helsinki model (62.4%)>Milwaukee model (48.8%). In patients with stage I cancer, disease specific survival was better for those who satisfied low-risk criteria according to any of the models. In patients with stage II-III cancer, this difference in survival was significant only for the Milwaukee model. Both lymphatic dissemination and high-risk tumor features as per the risk models were independent predictors of survival. CONCLUSIONS: The studied models had a similar accuracy in predicting lymphatic dissemination in endometrial cancer. Lymphadenectomy rate was lowest for the Milwaukee model. Survival analyses suggest that variables included in the models predict patient outcome independently of tumor stage.

Immunohistochemical detection of lymph node-DTCs in patients with node-negative HNSCC.

This study was performed to systematically assess the prevalence, topography and prognostic impact of disseminated tumor cells (DTCs) in lymph nodes (LN) of patients with primary, regional and distant metastasis-free head and neck squamous cell carcinoma (HNSCC) who underwent resection with elective neck dissection. From the routinely processed resection specimen, we could prospectively analyze a total of 1.137 exactly mapped LNs of 50 pN0-HNSCC patients, classified as tumor free by routine histopathology. Three immunohistochemistry (IHC) assays using antibodies directed against CK5/14, a broad spectrum of CKs (1-8, 10, 14-16 and 19), and CD44v6, respectively, were applied on 4.190 LN sections to detect DTCs. The IHC results were correlated with clinicopathologic parameters and clinical follow-up data. We detected seven micrometastases (MM) in five patients and 31 DTCs in 12 patients. Overall, 15 (30%) patients were positive for DTCs or MMs. Strikingly, the anatomical distribution of LN affected with DTCs was not random, but was dependent on the lateralization of the primary tumor and clustered significantly most proximal to the primary tumor. None of the investigated patients developed loco-regional lymphatic or distant metastasis during the mean follow-up period of 71 months. Our results reveal clinically occult tumor cell dissemination as an early and frequent event in HNSCC. Considering that higher rates of recurrences in therapeutic LN dissection concepts have been reported than in elective neck dissection strategies, our DTC-data support to perform elective neck dissections, since they appear to be effective in preventing loco-regional lymphatic recurrence from LN DTCs or MMs.

Tumor diameter as a predictor of lymphatic dissemination in endometrioid endometrial cancer.

OBJECTIVES: To assess the utility of tumor diameter (TD) for predicting lymphatic dissemination (LD) and determining need for lymphadenectomy following diagnosis of endometrioid endometrial cancer. METHODS: Patients diagnosed with stage I-III endometrioid endometrial cancer during 2003-2013 who underwent pelvic or para-aortic lymphadenectomy during hysterectomy were studied. Intraoperative predictors of LD included TD, grade, myometrial invasion (MI), age, body mass index, and race/ethnicity. Candidate logistic regression models of LD were evaluated for model fit and predictive power. RESULTS: Of 737 cancer patients, 68 (9.2%) were node-positive. Single-variable models with only continuous TD (c-statistic 0.77, 95% CI 0.71-0.83) and dichotomous TD with 50-mm cut-off (TD50; c-statistic 0.73, 95% CI 0.67-0.78) were significantly more predictive than with the standard 20-mm cut-off (c-statistic 0.56, 95% CI 0.53-0.59). Overall, the most important LD predictors were TD50 and MI3rds (three-category form). The best candidate model (c-statistic 0.84, 95% CI 0.80-0.88) suggested odds of LD were five times greater for TD >50mm than ≤50mm (OR 4.91, 95% CI 2.73-8.82) and six and ten times greater for MI >33% to ≤66% (OR, 5.70; 95% CI, 2.25-14.5) and >66% (OR 10.2, 95% CI 4.11-25.4), respectively, than ≤33%. Best-model false-negative (0%) and positive (57.2%) rates demonstrated marked improvement over traditional risk-stratification false-negative (1.5%) and positive (76.2%) rates (c-statistic 0.77, 95% CI 0.72-0.82). CONCLUSIONS: Tumor diameter is an important predictor of LD. Our risk model, containing modified forms of MI and TD, yielded a lower false-negative rate and can significantly decrease the number of lymphadenectomies performed on low-risk women.

External validation of nomograms designed to predict lymphatic dissemination in patients with early-stage endometrioid endometrial cancer: a multicenter study.

OBJECTIVE: The objective of the study was to externally validate and assess the robustness of 2 nomograms designed to predict the probability of lymphatic dissemination (LD) for patients with early-stage endometrioid endometrial cancer. STUDY DESIGN: Using a prospective multicenter database, we assessed the discrimination, calibration, and clinical utility of 2 nomograms in patients with surgically treated early-stage endometrioid endometrial cancer. RESULTS: Among the 322 eligible patients identified, the overall LD rate was 9.9% (32 of 322). Predictive accuracy according to discrimination was 0.65 (95% confidence interval, 0.61-0.69) for the full nomogram and 0.71 (95% confidence interval, 0.68-0.74) for the alternative nomogram. The correspondence between observed recurrence rate and the nomogram predictions suggests a moderate calibration of the nomograms in the validation cohort. CONCLUSION: The nomograms were externally validated and shown to be partly generalizable to a new and independent patient population. Although these tools provide a more individualized estimation of LD, additional parameters are needed to allow higher accuracy for counseling patients in clinical practice.