Anterolateral and accessory anterolateral portals are safe to avoid subcutaneous nerve injury during subtalar arthroscopy-Definition of safe zones for standard lateral portals.

PURPOSE: Injury to the superficial peroneal nerve (SPN) or the sural nerve (SN) is a common complication in subtalar arthroscopy. The purpose of this anatomical study was to evaluate the distance to surrounding subcutaneous nerves in the vicinity of three standard arthroscopic portals for subtalar joint arthroscopy and through actual portal placement for arthroscopic procedures, in order to define anatomical safe zones. METHODS: Forty paired fresh-frozen foot-and-ankle specimens were used. Subtalar arthroscopy using a three-portal technique (anterolateral [AL], posterolateral [PL] and accessory anterolateral [AAL] portals) was performed. After completion of subtalar arthroscopy, the portals were marked, and all surrounding subcutaneous nerves, that is, the branches of the SPN and SN, were dissected. The distance of the nearest nerve at the level of the respective portal was measured and potential injury was recorded. RESULTS: The nearest nerve at the level of the AL portal was the intermediate dorsal cutaneous nerve at a mean of 15.4 ± 5.1 mm medial to the portal. The nearest nerve at the level of the AAL portal was the lateral dorsal cutaneous nerve at a mean of 17.7 ± 4.8 mm, being lateral to the portal. The nearest nerve at the level of the PL portal was the SN at a mean of 6.7 ± 4.7 mm anterior to the portal. Based on the measurements, safe zones were defined. CONCLUSIONS: Placement of the AL and AAL portals in subtalar arthroscopy is saved using standard anatomical landmarks and a thorough surgical technique. At the level of the PL portal, the SN is the most endangered structure in subtalar arthroscopy. Surgeons should be aware of the proximity of the SN to the PL portal and take the utmost care during portal placement and instrument insertion to avoid iatrogenic injury. The risk of nerve damage during portal placement may be reduced when positioning the portals in the defined safe zones. LEVEL OF EVIDENCE: Not applicable.

Immune cell distribution and DNA methylation signatures differ between tumor and stroma enriched compartment in pancreatic ductal adenocarcinoma.

The presence of abundant tumor stroma is a prominent characteristic of pancreatic ductal adenocarcinomas (PDAC) that potentially influences disease progression and therapy response. This study aims to investigate immune cell infiltration and epigenetic profiles in tumor cell enriched ("Tumor") and stroma cell enriched ("Stroma") regions within human PDAC tissue samples. By comparing those regions, we identified 25,410 differentially methylated positions (DMPs) distributed across 6,963 unique genes. Pathway enrichment analysis using the top 2,000 DMPs that were either hyper- or hypomethylated indicated that immune response pathways and the estrogen receptor pathway are epigenetically dysregulated in Tumor and Stroma regions, respectively. In terms of immune cell infiltration, we observed overall low levels of T cells in both regions. In Tumor regions however, occurrence of tumor-associated macrophages (TAMs) was higher than in Stroma regions (p = 0.02) concomitant with a dualistic distribution that stratifies PDAC patients into those with high and low TAM infiltration. By categorizing TAM levels into quartiles, our analysis revealed that PDAC patients with more than 1,515 TAMs per mm² exhibited significantly shorter overall survival (p = 0.036). Our data suggest that variations in inflammatory characteristics between the Tumor and Stroma defined compartments of PDAC may primarily stem from the presence of macrophages rather than lymphocytes. The abundance of TAMs within regions enriched with tumor cells correlates with patient survival, underscoring the potential significance of exploring therapeutic interventions targeting TAMs. Furthermore, directing attention towards the estrogen receptor pathway may represent a promising strategy to address the stroma cell component within the PDAC tumor microenvironment.

Frequent Overexpression of HER3 in Brain Metastases from Breast and Lung Cancer.

PURPOSE: HER3 belongs to a family of receptor tyrosine kinases with oncogenic properties and is targeted by a variety of novel anticancer agents. There is a huge unmet medical need for systemic treatment options in patients with brain metastases (BM). Therefore, we aimed to investigate HER3 expression in BM of breast (BCa) and non-small cell lung cancer (NSCLC) as the basis for future clinical trial design. EXPERIMENTAL DESIGN: We analyzed 180 BM samples of breast cancer or NSCLC and 47 corresponding NSCLC extracranial tissue. IHC was performed to evaluate protein expression of HER3, and immune cells based on CD3, CD8, and CD68. To identify dysregulated pathways based on differential DNA methylation patterns, we used Infinium MethylationEPIC microarrays. RESULTS: A total of 99/132 (75.0%) of BCa-BM and 35/48 (72.9%) of NSCLC-BM presented with HER3 expression. Among breast cancer, HER2-positive and HER2-low BM showed significantly higher rates of HER3 coexpression than HER2-negative BM (87.1%/85.7% vs. 61.0%, P = 0.004). Among NSCLC, HER3 was more abundantly expressed in BM than in matched extracranial samples (72.9% vs. 41.3%, P = 0.003). No correlation of HER3 expression and intratumoral immune cell density was observed. HER3 expression did not correlate with overall survival from BM diagnosis. Methylation signatures differed according to HER3 status in BCa-BM samples. Pathway analysis revealed subtype-specific differences, such as TrkB and Wnt signaling pathways dysregulated in HER2-positive and triple-negative breast cancer BM, respectively. CONCLUSIONS: HER3 is highly abundant in BM of breast cancer and NSCLC. Given the promising results of antibody-drug conjugates in extracranial disease, BM-specific trials that target HER3 are warranted. See related commentary by Kabraji and Lin, p. 2961.