<p><b>A,</b> LD enhances CD8<sup>+</sup> T-cell activities. <b>B–F,</b> The expression levels of CD4<sup>+</sup>, CD8<sup>+</sup> T cells, Tregs, IFNγ, and TNFα in each group [each bar represents mean ± SD (<i>n</i> = 5–7); **<sup>,</sup>***, <i>P</i> < 0.01, 0.001 vs. MOC1+IgG; <sup>#</sup>,<sup>###</sup>, <i>P</i> < 0.05, 0.001 vs. MOC1+αPD-1; <sup>$</sup><sup>,</sup><sup>$$$</sup>, <i>P</i> < 0.05, 0.001 αPD-1 vs. IgG].</p>
Computer-assisted jaw reconstruction (CAJR) has benefits in reducing operation time and improving reconstruction accuracy, compared to conventional freehand jaw reconstruction. However, no information is available regarding learning curves in CAJR with the use of 3D-printed patient-specific surgical plates (PSSP). The purpose of this study was to assess surgical outcomes and learning curve for the first 58 consecutive CAJR using 3D-printed PSSP performed by a single surgical team in a single institution.In a prospective study, consecutive patients who underwent free flap CAJR using 3D-printed PSSP were included. The determination of proficiency, based on the cumulative sum of surgical success (no major adjustment of 3D-printed PSSP, flap survival) passing the acceptable boundary line of cumulative sum analysis, was the primary outcome. To find out any potential factors influencing the learning curve, baseline characteristics of patients were compared before and after proficiency achievement. Secondary outcomes included inflexion points of the total operation time, blood loss, length of hospital stay, and bone graft deviation, measured by the cumulative sum analysis.From December 2016 to November 2020, 58 consecutive cases underwent surgery performed by a single surgical team. The overall surgical success rate was 94.8% (55/58). A three-stage learning curve of primary outcome was observed. The proficiency was achieved after 23 cases. The proportions of advanced tumor staging and concomitant surgery after obtaining proficiency were significantly higher than those before achieving proficiency (p = 0.046 and p < 0.001, respectively). Mean values of operation time, intraoperative blood loss, length of hospital stay, and bone graft deviation were 532.5 ± 119.2 min, 1,006.8 ± 547.2 ml, 16.1 ± 6.3 days, and 0.9 ± 1.2 mm, respectively. Two trends of learning curve were observed in the CUSUM analyses of total operation time, length of hospital stay, and bone graft deviation, in which the first and second inflexion points occurred between 8 and 17 cases and between 43 and 46 cases, respectively.Our results revealed a three-stage learning curve of CAJR with the use of PSSP, including initial learning, plateau, and overlearning. Based on CUSUM analysis, the surgical proficiency was achieved after 23 cases, and total operation time, length of hospital stay, and bone graft deviation stabilized after 8-17 cases.
Although computer-assisted surgery using fibula flap has been widely applied for oncologic jaw reconstruction in recent years, the inaccurate positioning of the fibula harvest guide brings sliding and rotational errors, which leads to compromised accuracy in simultaneous implant placement and dental rehabilitation. This study aimed to develop a novel three-dimensional (3D)-printed patient-specific fibula malleolus cap to increase oncologic reconstruction accuracy.In this prospective comparative study with a recent historical control cohort, patients in need of oncologic jaw reconstruction with fibula free flaps were recruited. In the study group, the fibula was harvested with the guide of the malleolus cap, whereas in the control group, without the malleolus cap. Deviations of location and angulation of distal fibula osteotomies, jaw reconstruction segments, and simultaneous dental implants were compared.Twenty patients were recruited, with 10 in each arm. The application of the malleolus cap significantly reduced the deviations in locations and angles of distal fibula osteotomies, from 9.5 to 4.1 mm and 25.3° to 8.7°. For the simultaneous dental implants placed in the fibula flaps, there was a significant increase in the accuracy of implant platform locations (the average deviation from 3.2 to 1.3 mm), apex locations (from 3.8 to 1.5 mm), and angles (from 11.3° to 4.6°). No significant difference was detected in the accuracy of fibula reconstruction segments.We developed a novel fibula malleolus cap to overcome the sliding and rotational errors during fibula flap harvesting for oncologic jaw reconstruction, with increased accuracy in simultaneous dental implants. This is a step forward to achieve a satisfactory functional outcome of jaw reconstruction with dental rehabilitation.
Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication associated with antiresorptive medications managing osteoporosis, such as bisphosphonates (BPs). To date, there is very limited evidence from prospective, controlled studies to support or refute the controversial prevention regimen that if a discontinuation of BPs before dentoalveolar surgery, so called "drug holiday", is effective in reducing the risk of MRONJ development in patients with osteoporosis. We proposed an experimental animal study, aiming to investigate the prevention of MRONJ following tooth extractions in osteoporotic condition, with the implementation of a BP drug holiday.Twenty rats were subjected to bilateral ovariectomy. After establishing the osteoporotic condition, all rats were exposed to weekly injections of zoledronate acid (ZA) for 8 weeks. After ZA treatment, 10 rats were subjected to dental extraction and defined as control group, and the rest 10 rats assigned to the DH group had a drug holiday of 8 weeks prior to dental extraction. Eight weeks after the dentoalveolar surgery, bone turnover biomarker in serum, occurrence of MRONJ-like lesion and histomorphometric assessment of osteonecrosis in mandible, and bone microarchitecture indices in femur, were examined.Eight weeks after dental extraction, the DH group showed a recovered osteoclastic activity, indicated by significantly increased number of osteoclasts in the mandibles and serum level of C-terminal telopeptides of type I collagen, as compared to the control group. No significant differences were observed in the gross-view and histological occurrences of MRONJ-like lesions between the two groups.There was no significant difference in bone microarchitecture in the femur between the control and DH groups before ZA therapy and 8 weeks after dental extraction.Our data provided the first experimental evidence in the osteoporotic animal model that the implementation of a BP holiday in prior to dental extractions could partially recover osteoclastic activity, but could not alleviate the development of MRONJ-like lesion or exacerbate the osteoporotic condition in the femur. Longer-term drug holiday, or combination of drug holiday and other prophylaxes to prevent MRONJ in patients with osteoporosis could be worth exploring in future studies, to pave the way for clinical managements.This in vivo prospective study reported that a recovery of osteoclastic activity by a BP drug holiday for 8 weeks in osteoporosis rats did not alleviate the development of MRONJ-like lesion followed by dental extractions. It contributes to the understanding of regimens to prevent MRONJ.
<p>Coculturing with TG neurons activates TGFβ-SMAD2 pathway and upregulates PD-L1 expression of OSCC cells. <b>A,</b> KEGG pathway enrichment analysis of the coculture group 1. <b>B,</b> KEGG pathway enrichment analysis of the coculture group 2. <b>C,</b> Expression levels of TGFβ1, TGFβ2, TGFβ3, and PD-L1 determined by qRT-PCR (*<sup>,</sup>**, <i>P</i> < 0.05, 0.01 vs. control group). <b>D,</b> The TGFβ1 level in the supernatants of each group determined by ELISA (***, <i>P</i> < 0.001 vs. control group). <b>E</b> and <b>F,</b> Expression levels of TGFβ1, p-SMAD2, SMAD2, and PD-L1 determined by Western blot analysis (*<sup>,</sup>**, <i>P</i> < 0.05, 0.01 vs. control group).</p>
<p><b>A,</b> LD enhances CD8<sup>+</sup> T-cell activities. <b>B–F,</b> The expression levels of CD4<sup>+</sup>, CD8<sup>+</sup> T cells, Tregs, IFNγ, and TNFα in each group [each bar represents mean ± SD (<i>n</i> = 5–7); **<sup>,</sup>***, <i>P</i> < 0.01, 0.001 vs. MOC1+IgG; <sup>#</sup>,<sup>###</sup>, <i>P</i> < 0.05, 0.001 vs. MOC1+αPD-1; <sup>$</sup><sup>,</sup><sup>$$$</sup>, <i>P</i> < 0.05, 0.001 αPD-1 vs. IgG].</p>
<p>Galunisertib reserves the tumor cell aggressiveness and downregulates TGFβ signaling and PD-L1 expression of tumor cells in the neuron-tumor coculture system. <b>A,</b> SCC-15 cell viability after treated with different concertation of galunisertib (**<sup>,</sup>***<sup>,</sup>****, <i>P</i> < 0.01, 0.001, 0.0001 vs. 0 µmol/L group) at each timepoint, top; MOC1 cell viability in complete DMEM/F12 (control group) or coculture medium from coculture group 1 (coculture group 2) after treated with 10 µmol/L galunisertib (*, <i>P</i> < 0.05, bottom). <b>B–F,</b> Migration and invasion activity of SCC-15 cells detected by migration assay, invasion assay, and wound healing assay (quantitative data from three independent experiments are shown in the right, respectively, **<sup>,</sup>***, <i>P</i> < 0.01, 0.001). <b>G–J,</b> Expression levels of TGFβ1, p-SMAD2, SMAD2, and PD-L1 determined by Western blot analysis (*<sup>,</sup>**, <i>P</i> < 0.05, 0.01).</p>
<p>Supplementary Figure 3. Galunisertib reserves the tumor cell aggressiveness and downregulates TGFbeta signaling and PD-L1 expression of tumor cells in the neuron-tumor coculture system.</p>
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