Case Western Reserve University

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.

Distinguishing non-epileptic events from epileptic seizures remains a clinical challenge, particularly when occurring exclusively during sleep. Sleep-related rhythmical movement disorder (SRRMD) is a benign condition typically seen in early childhood, characterised by stereotyped, rhythmical repetitive movements involving large muscle groups, predominantly during Stage II of non-REM sleep. These movements can closely mimic features of sleep parasomnias, hypermotor seizures or psychogenic non-epileptic seizures (PNES), complicating the diagnostic approach. We present a case of an adolescent female with comorbid SRRMD and PNES and a clinical approach to distinguish between them.

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.

Joint learning on diverse ultrasonic source scenarios presents a challenge in preserving stable generalization due to the combination of heterogeneity of different sources and the inconsistency of joint learning features. Previous joint learning studies, which are not source-resilient frameworks, may not preserve stable generalization when trained on diverse source scenarios. Furthermore, the limited variations in single-source data and the interference from ultrasound imaging, which are common in ultrasonic source scenarios, further decrease generalization. To address these problems, we proposed a source-resilient joint learning framework consisting of three stages: 1) Source transforming, where our 1-to-N transformation unifies diverse source scenarios for source-resiliency. 2) Our feature enhancement modules model the source-resilient joint learning network, including a manifold-constraint normalization module (MCNM) for addressing heterogeneity by minimizing manifold-based loss, a task-consistent attention module (TCAM) shares the multi-scale features with self-attention to address inconsistency, and an adaptive feature-shifting module (AFSM) for feature-level augmentation to overcome single-source data. 3) Our ultrasound-hybrid linear mapping (USmapping) cascades speckle randomization and mask-guiding Monge-Kantorovitch linear mapping to achieve ultrasonic style randomization for addressing the interference of ultrasonic data. Our framework was evaluated on eight ultrasound datasets from various scanners at multiple centers and surpassed previous comparable studies in both segmentation (DSC$WAvg$ of 75.7%) and classification (AUROC$WAvg$ of 68.8%) tasks. Our framework has the potential to serve as a general framework for enhancing the performance of joint learning under diverse ultrasonic source scenarios.