Clear-cell renal cell carcinoma (ccRCC) is characterised by constitutive activation of hypoxia-inducible factors (HIFs) following VHL loss, which contributes to tumour progression and therapeutic resistance. Given the limitations of VEGFR-targeted therapies, we investigated the biological and potential therapeutic relevance of the HIF axis in ccRCC. Nuclear and cytoplasmic HIF1A and EPAS1/HIF2A expression were assessed by immunohistochemistry in tumours from 40 patients and correlated with clinicopathological parameters and cancer-specific survival. The functional effects of HIF pathway inhibitors (GN44028, KC7F2, and FM19G11) and sunitinib were analysed in VHL-mutant 786-O and VHL-wild-type Caki-1 cell lines using SRB viability assay, cell cycle analysis, wound closure assay, and RT-qPCR of HIF-related genes, with comparison to non-malignant HK-2 cells. TCGA-ccRCC data from advanced-stage patients (III–IV, n = 185) were analysed as a complementary transcriptomic context. Nuclear, but not cytoplasmic, HIF1A and EPAS1/HIF2A expression was associated with advanced stage and shorter survival in univariable analyses. GN44028 showed the most pronounced antiproliferative effect under tested conditions and was associated with broad suppression of HIF-related transcription, whereas sunitinib was associated with increased expression of selected HIF-related genes. GN44028 did not demonstrate clear selectivity over non-malignant HK-2 cells. Overall, nuclear HIF activation is associated with aggressive ccRCC biology, and broader HIF pathway modulation warrants further experimental investigation; however, the clinical findings remain exploratory, and therapeutic selectivity and translational relevance are not yet established.

Background: Non-melanoma skin cancers (NMSCs) of the head and neck represent a therapeutic challenge due to the region’s complex anatomy, functional considerations, and frequent involvement of high-risk anatomical zones. Local recurrence remains a clinically significant concern, however real-world data regarding recurrence patterns and associated risk factors in facial NMSCs are limited. Objectives: To evaluate the incidence of local recurrence of facial skin cancers after surgical treatment and to determine clinicopathological and anatomical actors associated with an increased risk of recurrence. Methods: In this single-center retrospective cohort study, consecutive patients undergoing surgical excision of facial NMSC were included. The treatment of choice was always surgical excision under general or local anesthesia, with an adequate margin of macroscopically unchanged tissue. Mohs surgery was not used, and none of the patients received immunosuppression. Clinical and pathological data were extracted from medical records. Histopathological examination constituted the basis for establishing the final clinical diagnosis and thus was not verified otherwise. The primary outcome was histologically confirmed local recurrence defined as the reappearance of a tumor of the same histopathological type at the same anatomical site as the previously excised lesion. Patients in the non-recurrence group were defined as those who did not experience any recurrence within a 5-year follow-up period after the initial surgical treatment. Fisher’s exact test and the Mann–Whitney U test were used for statistical analysis. Logistic regression was performed to explore factors associated with recurrence. Due to incomplete follow-up data for the non-recurrent group, we limited the timing analysis to recurrent cases only, as these limitations precluded the use of standard survival analysis. Results: A total of 302 lesions were analyzed, with recurrence status available for 291 tumors. The overall recurrence rate was 28.52%. Basal cell carcinoma (BCC) was the most common histopathological subtype. Recurrences occurred more frequently in anatomically high-risk areas, particularly the scalp, temple and nose. Infiltrative BCC subtypes demonstrated higher recurrence rates than nodular and superficial subtypes. Patients with recurrent tumors were younger than those without recurrence. A history of prior skin radiotherapy was associated with increased odds of recurrence. Tumor size and surgical margin width were not significantly associated with recurrence. Multivariate models showed limited discriminatory ability, suggesting that additional unmeasured factors contribute to recurrence risk. Conclusions: Local recurrence of non-melanoma skin cancers in the head and neck region remains a substantial clinical concern, particularly in high-risk anatomical sites and tumors with aggressive histopathological features. These findings highlight the importance of long-term follow-up and support further prospective studies to improve recurrence risk assessment and treatment strategies.