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BACKGROUND: In melanoma patients, microscopic tumor in the sentinel lymph-node biopsy (SLN) increases the risk of distant metastases, but the transition from tumor in the SLN to metastatic disease remains poorly understood. METHODS: Fluorescent staining for CD3, CD20, CD11c, and DNA was performed on SLN tissue and matching primary tumors. Regions of interest (ROI) were then chosen geometrically (e.g., tumor) or by fluorescent cell subset markers (e.g., CD11c). Each ROI was further analyzed using NanoString Digital Spatial Profiling high-resolution multiplex profiling. Digital counts for 59-panel immune-related proteins were collected and normalized to account for system variation and ROI area. RESULTS: Tumor regions of SLNs had variable infiltration of CD3 cells among patients. The patient with overall survival (OS) > 8 years had the most CD11c- and CD3-expressing cells infiltrating the SLN tumor region. All patients had CD11c (dendritic cell, DC) infiltration into the SLN tumor region. Selecting ROI by specific cell subtype, we compared protein expression of CD11c cells between tumor and non-tumor/normal tissue SLN regions. Known markers of DC activation such as CD86, HLA-DR, and OX40L were lowest on CD11c cells within SLN tumor for the patient with OS < 1 year and highest on the patient with OS > 8 years. CONCLUSION: We demonstrate the feasibility of profiling the protein expression of CD11c cells within the SLN tumor. Identifying early regulators of melanoma control when the disease is microscopically detected in the SLN is beneficial and requires follow-up studies in a larger cohort of patients.
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Metástase Linfática/imunologia , Melanoma/imunologia , Biópsia de Linfonodo Sentinela/métodos , Microambiente Tumoral/imunologia , Feminino , Humanos , MasculinoRESUMO
Purpose: Meniscal injuries are common in knee surgery and often require preservation techniques to prevent secondary osteoarthritis. Despite advancements in repair techniques, some patients undergo partial meniscectomy, which can lead to postmeniscectomy syndrome. To address these challenges, meniscal substitution techniques like scaffolds have been developed. However, a comprehensive synthesis of the existing evidence through an umbrella review is lacking. Methods: A comprehensive search was conducted in the MEDLINE, Embase and Scopus databases to identify relevant systematic reviews and meta-analyses. Studies were screened based on predefined inclusion and exclusion criteria. The quality of included studies was assessed using the AMSTAR-2 tool. Results: A total of 17 studies met the inclusion criteria and were included in the review. Most studies focused on the use of collagen-based scaffolds, with fewer studies evaluating synthetic scaffolds. The majority of studies (52.9%) were rated as having 'Critically Low' overall confidence, with only one study (5.9%) rated as 'High' confidence and most studies exhibiting methodological limitations, such as small sample sizes and lack of long-term follow-up. Despite these limitations, the majority of studies reported positive short-term outcomes, including pain relief and functional improvement, following scaffold implantation. However, some studies noted a relatively high failure rate. Radiographically, outcomes also varied, with some studies reporting morphological deterioration of the implant seen on MRI, while others noted possible chondroprotective effects. Conclusions: Meniscal scaffold-based approaches show promise in the management of meniscal deficiency; however, the current evidence is limited by methodological shortcomings. One notable gap in the literature is the lack of clear guidelines for patient selection and surgical technique. Future research should focus on conducting well-designed randomized controlled trials with long-term follow-up to further elucidate the benefits and indications of these techniques in clinical practice. Additionally, efforts should be made to develop consensus guidelines to standardize the use of meniscal scaffolds and improve patient outcomes. Despite limited availability, synthesizing the literature on meniscal scaffold-based approaches is crucial for understanding research, guiding clinical decisions and informing future directions. Level of Evidence: Level IV.
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Background: The optimal duration and choice of antibiotic for fracture-related infection (FRI) is not well defined. This study aimed to determine whether antibiotic duration (≤6 vs >6 weeks) is associated with infection- and surgery-free survival. The secondary aim was to ascertain risk factors associated with surgery- and infection-free survival. Methods: We performed a multicenter retrospective study of patients diagnosed with FRI between 2013 and 2022. The association between antibiotic duration and surgery- and infection-free survival was assessed by Cox proportional hazard models. Models were weighted by the inverse of the propensity score, calculated with a priori variables of hardware removal; infection due to Staphylococcus aureus, Staphylococcus lugdunensis, Pseudomonas or Candida species; and flap coverage. Multivariable Cox proportional hazard models were run with additional covariates including initial pathogen, need for flap, and hardware removal. Results: Of 96 patients, 54 (56.3%) received ≤6 weeks of antibiotics and 42 (43.7%) received >6 weeks. There was no association between longer antibiotic duration and surgery-free survival (hazard ratio [HR], 0.95; 95% CI, .65-1.38; P = .78) or infection-free survival (HR, 0.77; 95% CI, .30-1.96; P = .58). Negative culture was associated with increased hazard of reoperation or death (HR, 3.52; 95% CI, 1.99-6.20; P < .001) and reinfection or death (HR, 3.71; 95% CI, 1.24-11.09; P < .001). Need for flap coverage had an increased hazard of reoperation or death (HR, 3.24; 95% CI, 1.61-6.54; P = .001). Conclusions: The ideal duration of antibiotics to treat FRI is unclear. In this multicenter study, there was no association between antibiotic treatment duration and surgery- or infection-free survival.
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Introduction: B cells are key regulators of immune responses in melanoma. We aimed to explore differences in the histologic location and activation status of B cell follicles in sentinel lymph nodes (SLN) of melanoma patients. Methods: Flow cytometry was performed on fresh tumor draining lymph nodes (LN). Paraffin slides from a separate cohort underwent NanoString Digital Spatial Profiling (DSP)®. After staining with fluorescent markers for CD20 (B cells), CD3 (T cells), CD11c (antigen presenting cells) and a nuclear marker (tumor) was performed, regions of interest (ROI) were selected based on the location of B cell regions (B cell follicles). A panel of 68 proteins was then analyzed from the ROIs. Results: B cell percentage trended higher in patients with tumor in LN (n=3) compared to patients with nSLN (n=10) by flow cytometry. B cell regions from a separate cohort of patients with tumor in the (pSLN) (n=8) vs. no tumor (nSLN) (n=16) were examined with DSP. Within B cell regions of the SLN, patients with pSLN had significantly higher expression of multiple activation markers including Ki-67 compared to nSLN patients. Among 4 patients with pSLN, we noted variability in arrangement of B cell follicles which were either surrounding the tumor deposit or appeared to be infiltrating the tumor. The B cell follicle infiltrative pattern was associated with prolonged recurrence free survival. Conclusion: These data suggest a role for B cell follicles in coordinating effective adaptive immune responses in melanoma when low volume metastatic disease is present in tumor draining LN.
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Melanoma , Neoplasias Cutâneas , Biologia , Humanos , Excisão de Linfonodo , Metástase Linfática , Melanoma/patologia , Biópsia de Linfonodo Sentinela , Neoplasias Cutâneas/patologiaRESUMO
BACKGROUND: We previously reported results from a phase 1 study testing intratumoral recombinant poliovirus, lerapolturev, in 12 melanoma patients. All 12 patients received anti-PD-1 systemic therapy before lerapolturev, and 11 of these 12 patients also received anti-PD-1 after lerapolturev. In preclinical models lerapolturev induces intratumoral innate inflammation that engages antitumor T cells. In the current study, prelerapolturev and postlerapolturev tumor biopsies and blood were evaluated for biomarkers of response. METHODS: The following analyses were performed on tumor tissue (n=11): (1) flow cytometric assessment of immune cell density, (2) NanoString Digital Spatial profiling of protein and the transcriptome, and (3) bulk RNA sequencing. Immune cell phenotypes and responsiveness to in vitro stimulation, including in vitro lerapolturev challenge, were measured in peripheral blood (n=12). RESULTS: Three patients who received anti-PD-1 therapy within 30 days of lerapolturev have a current median progression-free survival (PFS) of 2.3 years and had higher CD8+T cell infiltrates in prelerapolturev tumor biopsies relative to that of 7 patients with median PFS of 1.6 months and lower CD8+T cell infiltrates in prelerapolturev tumor biopsies. In peripheral blood, four patients with PFS 2.3 years (including three that received anti-PD-1 therapy within 30 days before lerapolturev and had higher pretreatment tumor CD8+T cell infiltrates) had significantly higher effector memory (CD8+, CCR7-, CD45RA-) but lower CD8+PD-1+ and CD4+PD-1+ cells compared with eight patients with median PFS 1.6 months. In addition, pretreatment blood from the four patients with median PFS 2.3 years had more potent antiviral responses to in vitro lerapolturev challenge compared with eight patients with median PFS 1.6 months. CONCLUSION: An inflamed pretreatment tumor microenvironment, possibly induced by prior anti-PD-1 therapy and a proficient peripheral blood pretreatment innate immune response (antiviral/interferon signaling) to lerapolturev was associated with long term PFS after intratumoral lerapolturev in a small cohort of patients. These findings imply a link between intratumoral T cell inflammation and peripheral immune function. TRIAL REGISTRATION NUMBER: NCT03712358.