Cleveland Clinic

Immunotherapy with checkpoint inhibitors targeting the PD1/PD-L1 and CTLA4 pathways has limited activity in patients with microsatellite stable (MSS) colorectal adenocarcinoma (CRC). In a prior study, the combination of cetuximab and pembrolizumab failed to improve outcomes for patients with advanced RAS wild-type (RASwt) CRC. In this post hoc secondary analysis, we show that the cetuximab and pembrolizumab-treated patients with TP53 mutant (p53mt) tumors had significantly higher progression-free survival (PFS) and a decrease in tumor burden compared to patients with TP53 wild-type (p53wt) tumors but no difference in overall survival compared to patients with p53wt tumors. The gene set enrichment analysis showed a uniform upregulation of multiple metabolic and immune gene sets, including NK-mediated immunity and IL-12 pathway, while the IL6 pathway was downregulated. There were no overlapping transcriptional alterations between the p53mt and p53wt groups with treatment that remain constant despite the therapeutic intervention. Functional overlap with treatment in both groups in the proliferative, immune, and metabolic pathways were identified. In the baseline tumor samples, the number of PD-L1+ tumor cells was significantly higher in p53mt tumors while the number of OX40-/AE1_AE3-/PD-L1- non-tumor cells, positive for either LAG3, CTLA4 or TIM3, was significantly higher in p53wt tumors. In conclusion, TP53 status was prognostic of improved PFS with cetuximab plus pembrolizumab in RASwt CRC. Future studies evaluating immune-oncology agents in patients with MSS, RASwt CRC should include TP53 as an integrated biomarker and evaluate its performance as a positive predictive biomarker (ClinicalTrials.gov NCT02713373).

While standard treatments for mandibular osteoradionecrosis (MORN) exist for mild/superficial and severe/full thickness disease, there is no consensus on treatment for advanced, partial thickness disease. In this niche, the anterolateral thigh fascia lata (ALTFL) "rescue" flap has managed MORN successfully. This study aimed to compare ALTFL with fibula free flap (FFF) reconstruction to determine differences in outcomes, complications, and postoperative logistics. A retrospective chart review of patients undergoing ALTFL or FFF for MORN between 2008 and 2024 was carried out. Fifty-one patients with Grade III (n = 26) or IV (n = 25) MORN underwent FFF (n = 22) or ALTFL (n = 29). ALTFL patients were older but did not differ in preoperative MORN treatment or risk factors compared to FFF. Median operative time for ALTFL was significantly less than FFF in both Grade III (298 min vs. 516 min) and IV (298 min vs. 599 min), without differences in subsites of mandible involved. Hospitalization for ALTFL was significantly shorter than FFF for both Grade III (2 days vs. 7 days) and IV (4.5 days vs. 7 days) without differences in peri-operative complications, flap failure or MORN resolution. Tracheotomy was performed more often for patients undergoing FFF for Grade III MORN. Patients who underwent ALTFL were more likely to return to a diet beyond soft within the follow-up period. The ALTFL rescue flap offers reduced morbidity and improved resource allocation compared to FFF for the treatment of advanced, partial thickness MORN with similar outcomes.

To describe the use, indications, and outcomes of a limited transoral approach for segmental mandibulectomy reconstruction with minimal access vessel isolation and anastomoses in patients with mandibular osteoradionecrosis. Retrospective review of patients who have undergone FFF reconstruction of segmental mandibulectomy via transoral plating and inset at our institution from 2022 to 2024. Nine patients (median age of 66, 100% male) with mandibular ORN underwent FFF reconstruction via transoral approach with minimal access vessels isolation. The majority of patients failed conservative management of ORN, with eight patients receiving prior antibiotic therapy and seven undergoing hyperbaric oxygen therapy. Preoperative fracture/nonunion and fistula were noted in seven and four patients, respectively. The median length of hospitalization following this procedure was 6 days (range: 4-9). One patient developed nonunion in the postoperative period and required revision with anterolateral thigh fascia lata free flap and iliac crest bone grafting. An additional patient required takeback for hematoma and successful vascular salvage; however, complications were otherwise minimal, with no other patients experiencing operating room takeback, readmission within 30 days, hematoma, fistulas, or flap compromise. All patients demonstrated clinical and radiographic arrest of ORN at most recent follow-up. Median follow-up length was 13.9 months (range 7.7-34). Mandibular reconstruction using a transoral approach with FFF provides a promising alternative to the traditional transcervical approach for patients with osteoradionecrosis, potentially reducing morbidity and improving outcomes.

Glioblastoma (GBM) is a highly aggressive brain tumor characterized by extensive crosstalk between glioblastoma stem cells (GSCs) and immunosuppressive microglia, with our previous work identifying CLOCK and TFPI2 as key regulators of this interaction. Here, we uncover a ‘symbiotic exclusivity’ pattern between CLOCK and TFPI2, showing that, despite mutually exclusive amplifications, they sustain symbiotic regulatory interactions in GBM. The CLOCK-BMAL1 complex transcriptionally upregulates TFPI2, while TFPI2-driven hypoxia inducible factor 1 α (HIF-1α) signaling activates nuclear factor k B (NF-kB) P65 to upregulate the CLOCK-BMAL1 complex, creating a positive feedback loop to promote stemness, immunosuppression, and tumor progression. Disrupting the CLOCK-TFPI2 interplay through dual inhibition of their downstream effectors reduces GSC stemness and immunosuppressive microglia, activates antitumor immunity, and synergizes with anti-PD1 therapy to achieve complete tumor regression in 50%–62.5% of tumor-bearing mice. This study uncovers a promising therapeutic strategy for a broader subset of patients with GBM with high expression of either CLOCK or TFPI2, and provides a framework for identifying ‘symbiotic exclusivity’ genes in cancer.

BackgroundBrepocitinib is a first-in-class, oral, selective TYK2–JAK1 inhibitor that blocks cytokine signaling, which has been implicated in dermatomyositis.MethodsIn this phase 3, double-blind, randomized, placebo-controlled trial, adults with dermatomyositis were assigned in a 1:1:1 ratio to receive once-daily oral brepocitinib at a dose of 30 mg, brepocitinib at a dose of 15 mg, or placebo for 52 weeks. Standard therapies were continued, and glucocorticoids were tapered. The primary end point was the Total Improvement Score, a validated composite myositis index (with scores ranging from 0 to 100 and higher scores indicating greater improvement) at week 52. Key secondary end points, including skin disease activity, glucocorticoid tapering, and physical function, were tested in a multiplicity-controlled sequence.ResultsA total of 241 patients underwent randomization: 81 to receive brepocitinib 30 mg, 81 to receive brepocitinib 15 mg, and 79 to receive placebo. At week 52, the mean Total Improvement Score was 46.5, 37.5, and 31.2, respectively (difference with brepocitinib 30 mg vs. placebo, 15.3; 95% confidence interval [CI], 6.7 to 24.0; P<0.001; difference with brepocitinib 15 mg vs. placebo, 6.3; 95% CI, −2.4 to 14.9). Brepocitinib 30 mg was superior to placebo across all nine key secondary end points, including skin disease activity, systemic glucocorticoid tapering, and functional disability, with improvements observed as early as week 4. Serious infections were more frequent in the brepocitinib 30-mg group than in the placebo group (10% vs. 1%). No deaths occurred during the trial.ConclusionsIn adults with dermatomyositis that was resistant to previous therapy, the use of brepocitinib at a dose of 30 mg (but not at a dose of 15 mg) resulted in significant benefits with respect to a composite myositis index, skin disease severity, glucocorticoid tapering, and functional disability. (Funded by Priovant Therapeutics; ClinicalTrials.gov number, NCT05437263.)

To evaluate the utility of tumour size, R.E.N.A.L. (Radius, Exophytic/Endophytic, Nearness to collecting system or sinus, Anterior/Posterior, Location), PADUA (Preoperative Aspects and Dimensions Used for an Anatomical), and SPARE (Simplified PADUA R.E.N.A.L.) nephrometry scoring systems (NSs) in predicting the likelihood of achieving trifecta and pentafecta outcomes, as well as the risk of postoperative acute kidney injury (AKI) and kidney disease progression at 12 months following robot-assisted partial nephrectomy (RAPN). Retrospective review was performed on Institutional Review Board-approved, prospectively maintained database to identify all cases of primary, non-metastatic renal masses who underwent RAPN between 2011 and 2024. All preoperative radiological images were reviewed by a single resident physician, who characterised all tumours based on the NSs. Trifecta outcome was defined as cases with warm ischaemia time of <25 min, negative surgical margin, and absence of complications. Pentafecta included the trifecta outcomes with the addition of >90% renal function preservation and absence of kidney disease progression at 12 months. Logistic regression and receiver operating characteristic (ROC) analyses were completed to determine the predictive ability for the tumour size and each of the NSs. Based on 1787 patients, trifecta and pentafecta were achieved in 52.7% and 22.2%, respectively. All three NSs were established as significant predictors of trifecta, pentafecta, and postoperative AKI, with all demonstrating comparable yet limited predictive performance (area under the ROC curve [AUC] 0.573-0.645). Tumour diameter (AUC 0.649-0.665) was shown to outperform the NSs in predicting the likelihood of achieving trifecta and pentafecta, as well as the risk of AKI. None of the NSs were identified as predictors of kidney disease progression at 12 months. Although lower R.E.N.A.L., PADUA, and SPARE NSs were associated with achieving surgical success and reduced risk of AKI, their predictive performance was modest and can be outperformed by a simpler and more objective measure, such as tumour diameter. Future studies remain necessary to re-evaluate the broader clinical utility of NSs in predicting surgical and functional outcomes, in addition to its original purpose as standardized tools for the anatomical characterization of renal tumours.

Dennis M. Tang is a consultant for Aerin Medical, Acclarent, 3D Matrix, SoundHealth, and Regeneron. He is a speaker for Regeneron and Paratek. He receives research support from Acclarent. The data that support the findings of this study are available from the corresponding author upon reasonable request.