Impact of smoking status on clinical outcomes in patients with metastatic renal cell carcinoma treated with first-line immune checkpoint inhibitor-based regimens.

BACKGROUND: Current tobacco smoking is independently associated with decreased overall survival (OS) among patients with metastatic renal cell carcinoma (mRCC) treated with targeted monotherapy (VEGF-TKI). Herein, we assess the influence of smoking status on the outcomes of patients with mRCC treated with the current first-line standard of care of immune checkpoint inhibitor (ICI)-based regimens. MATERIALS AND METHODS: Real-world data from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) were collected retrospectively. Patients with mRCC who received either dual ICI therapy or ICI with VEGF-TKI in the first-line setting were included and were categorized as current, former, or nonsmokers. The primary outcomes were OS, time to treatment failure (TTF), and objective response rate (ORR). OS and TTF were compared between groups using the log-rank test and multivariable Cox regression models. ORR was assessed between the 3 groups using a multivariable logistic regression model. RESULTS: A total of 989 eligible patients were included in the analysis, with 438 (44.3%) nonsmokers, 415 (42%) former, and 136 (13.7%) current smokers. Former smokers were older and included more males, while other baseline characteristics were comparable between groups. Median follow-up for OS was 21.2 months. In the univariate analysis, a significant difference between groups was observed for OS (P = .027) but not for TTF (P = .9), with current smokers having the worse 2-year OS rate (62.8% vs 70.8% and 73.1% in never and former smokers, respectively). After adjusting for potential confounders, no significant differences in OS or TTF were observed among the 3 groups. However, former smokers demonstrated a higher ORR compared to never smokers (OR 1.45, P = .02). CONCLUSION: Smoking status does not appear to independently influence the clinical outcomes to first-line ICI-based regimens in patients with mRCC. Nonetheless, patient counseling on tobacco cessation remains a crucial aspect of managing patients with mRCC, as it significantly reduces all-cause mortality.

Update on Biomarkers in Renal Cell Carcinoma.

Immune checkpoint inhibitors have significantly transformed the treatment paradigm for metastatic renal cell carcinoma (RCC), offering prolonged overall survival and achieving remarkable deep and durable responses. However, given the multiple ICI-containing, standard-of-care regimens approved for RCC, identifying biomarkers that predict therapeutic response and resistance is of critical importance. Although tumor-intrinsic features such as pathological characteristics, genomic alterations, and transcriptional signatures have been extensively investigated, they have yet to provide definitive, robust predictive biomarkers. Current research is exploring host factors through in-depth characterization of the immune system. Additionally, innovative technological approaches are being developed to overcome challenges presented by existing techniques, such as tumor heterogeneity. Promising avenues in biomarker discovery include the study of the microbiome, radiomics, and spatial transcriptomics.

Efficacy and safety of the enzymatic mixture - Lipase, collagenase and hyaluronidase - In the treatment of moderate to severe submental fat: A prospective cohort study.

Purpose: To study the effect of the enzymatic mixture: Lipase, Collagenase and Hyaluronidase in the treatment of submental fat. Methods: A monocentric prospective cohort study including 10 female patients, aged between 18 and 65 years old, who received treatment for submental fat with a mixture of Lipase, Collagenase, and Hyaluronidase. The treatment protocol consisted of one treatment session every 21 days for a total of 3 sessions. In each session, 4 ml of the enzymatic mixture (1 ml of Collagenase GH PB20, 1 ml of Hyaluronidase PB 3000 and 2 ml of Lipase PB 500) + 2 ml of Lidocaine 2% were injected in the submental fat (SMF). Efficacy was assessed four weeks after the last session. Co-Primary Outcome was defined as the improvement of ≥ 1-point in Clinician-Reported and Patient-Reported Sub-mental Fat Rating Scales (CR-SMFRS and PR-SMFRS). Secondary Outcomes included score reductions in Patient-Reported Sub-mental Fat Impact Scale (PR-SMFIS), ≥10% reduction in submental fat pad thickness by ultrasound, and Subject Self-Rating Scale (SSRS) responses of 4, 5, or 6. Results: The Co-Primary outcome was achieved in 9 out of 10 patients. A considerable reduction of 22.8% in the PR-SMFIS was observed. Furthermore, 9 out of 10 patients expressed overall satisfaction with the treatment. Submental fat reduction of more than 10% was observed in 9 out of 10 patients in neutral position and in all patients in flexed position. Adverse effects were only limited to local reactions. Conclusion: The enzymatic mixture of Lipase, Collagenase and Hyaluronidase is an effective and safe minimally-invasive method for the reduction of SMF that can be used alone or in conjunction with other treatment modalities.

Kinematic adaptations from self-selected to fast speed walking in patients with adult spinal deformity.

PURPOSE: To investigate kinematic adaptations from self-selected to fast speed walking in ASD patients. METHODS: 115 primary ASD and 66 controls underwent biplanar radiographic X-rays and 3D gait analysis to calculate trunk, segmental spine and lower limb kinematics during self-selected and fast speed walking. Kinematic adaptation was calculated as the difference (Δ) between fast and self-selected speed walking. ASD with 7 or more limited kinematic adaptation parameters were classified as ASD-limited-KA, while those with less than 7 limited kinematic adaptation parameters were classified as ASD-mild-KA. RESULTS: 25 patients were classified as ASD-limited-KA and 90 as ASD-mild-KA. ASD-limited-KA patients walked with a lesser increase of pelvic rotation (Δ = 1.7 vs 5.5°), sagittal hip movement (Δ = 3.1 vs 7.4°) and shoulder-pelvis axial rotation (Δ = 3.4 vs 6.4°) compared to controls (all p < 0.05). ASD-limited-KA had an increased SVA (60.6 vs - 5.7 mm), PT (23.7 vs 11.9°), PI-LL (9.7 vs - 11.7°), knee flexion (9.2 vs - 0.4°) and a decreased LL (44.0 vs 61.4°) compared to controls (all p < 0.05). Kinematic and radiographic alterations were less pronounced in ASD-mild-KA. The limited increase of walking speed was correlated to the deteriorated physical component summary score of SF-36 (r = 0.37). DISCUSSION: Kinematic limitations during adaptation from self-selected to fast speed walking highlight an alteration of a daily life activity in ASD patients. ASD with limited kinematic adaptations showed more severe sagittal malalignment with an increased SVA, PT, PI-LL, and knee flexion, a decreased LL and the most deteriorated quality of life. This highlights the importance of 3D movement analysis in the evaluation of ASD.

Impact of renal cell carcinoma molecular subtypes on immunotherapy and targeted therapy outcomes.

Saliby et al. show that a machine learning approach can accurately classify clear cell renal cell carcinoma (RCC) into distinct molecular subtypes using transcriptomic data. When applied to tumors biospecimens from the JAVELIN Renal 101 (JR101) trial, a benefit is observed with immune checkpoint inhibitor (ICI)-based therapy across all molecular subtypes.

Epigenomic signatures of sarcomatoid differentiation to guide the treatment of renal cell carcinoma.

Renal cell carcinoma with sarcomatoid differentiation (sRCC) is associated with poor survival and a heightened response to immune checkpoint inhibitors (ICIs). Two major barriers to improving outcomes for sRCC are the limited understanding of its gene regulatory programs and the low diagnostic yield of tumor biopsies due to spatial heterogeneity. Herein, we characterized the epigenomic landscape of sRCC by profiling 107 epigenomic libraries from tissue and plasma samples from 50 patients with RCC and healthy volunteers. By profiling histone modifications and DNA methylation, we identified highly recurrent epigenomic reprogramming enriched in sRCC. Furthermore, CRISPRa experiments implicated the transcription factor FOSL1 in activating sRCC-associated gene regulatory programs, and FOSL1 expression was associated with the response to ICIs in RCC in two randomized clinical trials. Finally, we established a blood-based diagnostic approach using detectable sRCC epigenomic signatures in patient plasma, providing a framework for discovering epigenomic correlates of tumor histology via liquid biopsy.