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Multinucleated giant cells (MNGCs) are frequently observed in the implantation areas of different biomaterials. The main aim of the present study was to analyze the long-term polarization pattern of the pro- and anti-inflammatory phenotypes of macrophages and MNGCs for 180 days to better understand their role in the success or failure of biomaterials. For this purpose, silk fibroin (SF) was implanted in a subcutaneous implantation model of Wistar rats as a model for biomaterial-induced MNGCs. A sham operation was used as a control for physiological wound healing. The expression of different inflammatory markers (proinflammatory M1: CCR-7, iNos; anti-inflammatory M2: CD-206, CD-163) and tartrate-resistant acid phosphatase (TRAP) and CD-68 were identified using immunohistochemical staining. The results showed significantly higher numbers of macrophages and MNGCs within the implantation bed of SF-expressed M1 markers, compared to M2 markers. Interestingly, the expression of proinflammatory markers was sustained over the long observation period of 180 days. By contrast, the control group showed a peak of M1 macrophages only on day 3. Thereafter, the inflammatory pattern shifted to M2 macrophages. No MNGCs were observed in the control group. To the best of our knowledge, this is study is the first to outline the persistence of pro-inflammatory MNGCs within the implantation bed of SF and to describe their long-term kinetics over 180 days. Clinically, these results are highly relevant to understand the role of biomaterial-induced MNGCs in the long term. These findings suggest that tailored physicochemical properties may be a key to avoiding extensive inflammatory reactions and achieving clinical success. Therefore, further research is needed to elucidate the correlation between proinflammatory MNGCs and the physicochemical characteristics of the implanted biomaterial.
Background and Aims. Systemic treatment with sorafenib has been the standard of care (SOC) in patients with advanced Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) for more than a decade. TACE has been reported to allow better local tumor control in selected patients with BCLC stage C HCC. Methods. A retrospective analysis of patients with BCLC stage C HCC that were treated with sorafenib and TACE was conducted; they were compared to BCLC stage C patients treated either with TACE or sorafenib in the same period of time outside a clinical trial. Results. A total of 201 patients with BCLC stage C were identified, who were treated with either sorafenib and TACE (group A; n = 54), sorafenib (group B; n = 82) or TACE (group C; n = 65). No significant difference in baseline characteristics was observed. Time to progression was 7.0 months (95% CI: 4.3–9.7), 4.1 months (95% CI: 3.6–4.7) and 5.0 months (95% CI: 2.9–7.1) in groups A, B and C, respectively, and overall survival was 16.5 months (95% CI: 15.0–18.1), 8.4 months (95% CI: 6.0–10.8) and 10.5 months (95% CI: 7.5–13.6), respectively (group A vs. group B: p < 0.001; group A vs. group C: p = 0.0023). Adverse events of grade 3/4 occurred in 34% of patients in group A. Conclusions. Although sorafenib is a SOC in patients with BCLC stage C HCC, TACE is frequently used as an additional locoregional treatment in selected patients. This combined approach resulted in a significant overall survival benefit in selected patients, although randomized trials have not yet proven this benefit.
Adapting movements rapidly to unanticipated external stimuli is paramount for athletic performance and to prevent injuries. We investigated the effects of a 4-week open-skill choice-reaction training intervention on unanticipated jump-landings. Physically active adults (n = 37; mean age 27, standard deviation 2.7 years, 16 females, 21 males) were randomly allocated to one of two interventions or a control group (CG). Participants in the two intervention groups performed a 4-week visuomotor open skill choice reaction training, one for the upper and one for the lower extremities. Before and after the intervention, two different types of countermovement jumps with landings in split stance position were performed. In the (1) pre-planned condition, we informed the participants regarding the landing position (left or right foot in front position) before the jump. In the (2) unanticipated condition, this information was displayed after take-off (350–600 ms reaction time before landing). Outcomes were landing stability [peak vertical ground reaction force (pGRF) and time to stabilization (TTS)], and landing-related decision-making quality (measured by the number of landing errors). To measure extremity-specific effects, we documented the number of correct hits during the trained drills. A two-factorial (four repeated measures: two conditions, two time factors; three groups) ANCOVA was carried out; conditions = unanticipated versus pre-planned condition, time factors = pre versus post measurement, grouping variable = intervention allocation, co-variates = jumping time and self-report arousal. The training improved performance over the intervention period (upper extremity group: mean of correct choice reaction hits during 5 s drill: +3.0 hits, 95% confidence interval: 2.2–3.9 hits; lower extremity group: +1.6 hits, 0.6–2.6 hits). For pGRF (F = 8.4, p < 0.001) and landing errors (F = 17.1, p < 0.001) repeated measures effect occurred. Significantly more landing errors occurred within the unanticipated condition for all groups and measurement days. The effect in pGRF is mostly impacted by between-condition differences in the CG. No between-group or interaction effect was seen for these outcomes: pGRF (F = 0.4, p = 0.9; F = 2.3, p = 0.1) landing errors (F = 0.5, p = 0.6; F = 2.3, p = 0.1). TTS displayed a repeated measures (F = 4.9, p < 0.001, worse values under the unanticipated condition, improvement over time) and an interaction effect (F = 2.4, p = 0.03). Healthy adults can improve their choice reaction task performance by training. As almost no transfer to unanticipated landing successfulness or movement quality occurred, the effect seems to be task-specific. Lower-extremity reactions to unanticipated stimuli may be improved by more specific training regimens.
The purpose of this narrative review is to discuss and highlight recently published studies regarding the surgical management of patients suffering from prostate cancer treatment complications. Focus will be put on the recalcitrant and more complex cases which might lead to urinary diversion as a definite, last resort treatment. It is in the nature of every treatment, that complications will occur and be bothersome for both patients and physicians. A small percentage of patients following prostate cancer treatment (radical prostatectomy, radiation therapy, or other focal therapies) will suffer side effects and thus, will experience a loss of quality of life. These side effects can persist for months and even years. Often, conservative management strategies fail resulting in recalcitrant recurrences. Prostate cancer patients with “end-stage bladder,” “devastated outlet,” or a history of multiple failed interventions, are fortunately rare, but can be highly challenging for both patients and Urologists. In a state of multiple previous surgical procedures and an immense psychological strain for the patient, urinary diversion can offer a definite, last resort surgical solution for this small group of patients. Ideally, they should be transferred to centers with experience in this field and a careful patient selection is needed. As these cases are highly complex, a multidisciplinary approach is often necessary in order to guarantee an improvement of quality of life.
Mitofusin 2 (MFN2) is a mitochondrial outer membrane GTPase, which modulates mitochondrial fusion and affects the interaction between endoplasmic reticulum and mitochondria. Here, we explored how MFN2 influences mitochondrial functions and inflammatory responses towards zymosan in primary human macrophages. A knockdown of MFN2 by small interfering RNA decreased mitochondrial respiration without attenuating mitochondrial membrane potential and reduced interactions between endoplasmic reticulum and mitochondria. A MFN2 deficiency potentiated zymosan-elicited inflammatory responses of human primary macrophages, such as expression and secretion of pro-inflammatory cytokines interleukin-1β, -6, -8 and tumor necrosis factor α, as well as induction of cyclooxygenase 2 and prostaglandin E2 synthesis. MFN2 silencing also increased zymosan-induced nuclear factor kappa-light-chain-enhancer of activated B cells and mitogen-activated protein kinases inflammatory signal transduction, without affecting mitochondrial reactive oxygen species production. Mechanistic studies revealed that MFN2 deficiency enhanced the toll-like receptor 2-dependent branch of zymosan-triggered responses upstream of inhibitor of κB kinase. This was associated with elevated, cytosolic expression of interleukin-1 receptor-associated kinase 4 in MFN2-deficient cells. Our data suggest pro-inflammatory effects of MFN2 deficiency in human macrophages.
Magnetic resonance-guided laser interstitial laser therapy (MRgLITT) and radiofrequency ablation (RFA) represent two minimally invasive methods for the treatment of drug-refractory mesial temporal lobe epilepsy (mTLE). We performed a systematic review and a meta-analysis to compare outcomes and complications between MRgLITT, RFA, and conventional surgical approaches to the temporal lobe (i.e., anterior temporal lobe resection [ATL] or selective amygdalohippocampectomy [sAHE]). Forty-three studies (13 MRgLITT, 6 RFA, and 24 surgery studies) involved 554, 123, 1504, and 1326 patients treated by MRgLITT, RFA, ATL, or sAHE, respectively. Engel Class I (Engel-I) outcomes were achieved after MRgLITT in 57% (315/554, range = 33.3%–67.4%), RFA in 44% (54/123, range = 0%–67.2%), ATL in 69% (1032/1504, range = 40%–92.9%), and sAHE in 66% (887/1326, range = 21.4%–93.3%). Meta-analysis revealed no significant difference in seizure outcome between MRgLITT and RFA (Q = 2.74, p = .098), whereas ATL and sAHE were both superior to MRgLITT (ATL: Q = 8.92, p = .002; sAHE: Q = 4.33, p = .037) and RFA (ATL: Q = 6.42, p = .0113; sAHE: Q = 5.04, p = .0247), with better outcome in patients at follow-up of 60 months or more. Mesial hippocampal sclerosis (mTLE + hippocampal sclerosis) was associated with significantly better outcome after MRgLITT (Engel-I outcome in 64%; Q = 8.55, p = .0035). The rate of major complications was 3.8% for MRgLITT, 3.7% for RFA, 10.9% for ATL, and 7.4% for sAHE; the differences did not show statistical significance. Neuropsychological deficits occurred after all procedures, with left-sided surgeries having a higher rate of verbal memory impairment. Lateral functions such as naming or object recognition may be more preserved in MRgLITT. Thermal therapies are effective techniques but show a significantly lower rate of Engel-I outcome in comparison to ATL and sAHE. Between MRgLITT and RFA there were no significant differences in Engel-I outcome, whereby the success of treatment seems to depend on the approach used (e.g., occipital approach). MRgLITT shows a similar rate of complications compared to RFA, whereas patients undergoing MRgLITT may experience fewer major complications compared to ATL or sAHE and might have a more beneficial neuropsychological outcome.
Background: We hypothesized that lymph node dissection (LND) at salvage radical prostatectomy may be associated with lower cancer-specific mortality (CSM) and we tested this hypothesis.
Methods: We relied on surveillance, epidemiology, and end results (2004–2016) to identify all salvage radical prostatectomy patients. Categorical, as well as univariate and multivariate Cox regression models tested the effect of LND (LND performed vs. not), as well as at its extent (log-transformed lymph node count) on CSM.
Results: Of 427 salvage radical prostatectomy patients, 120 (28.1%) underwent LND with a median lymph node count of 6 (interquartile range [IQR], 3–11). According to LND status, no significant or clinically meaningful differences were recorded in PSA at diagnosis, stage and biopsy Gleason score at diagnosis, except for age at prostate cancer diagnosis (LND performed 63 vs. 68 years LND not performed, p < .001). LND status (performed) was an independent predictor of lower CSM (hazard ratio [HR] 0.47; p = .03). Similarly, lymph node count (log transformed) also independently predicted lower CSM (HR: 0.60; p = .01). After the 7th removed lymph node, the effect of CSM became marginal. The effect of N-stage on CSM could not be tested due to insufficient number of observations.
Conclusions: Salvage radical prostatectomy is rarely performed and LND at salvage radical prostatectomy is performed in a minority of patients. However, LND at salvage radical prostatectomy is associated with lower CSM. Moreover, LND extent also exerts a protective effect on CSM. These observations should be considered in salvage radical prostatectomy candidates.
Background and Aims: Activation of the inflammasome NLRP3 (NOD-, LRR- and pyrin domain containing 3) contributes to the development of non-alcoholic fatty liver disease (NAFLD) and progression to non-alcoholic steatohepatitis (NASH). Therefore, this study explored the therapeutic effects of a novel and selective NLRP3 antagonist in a murine dietary model of NASH. Methods: Groups of 12-week-old ApoE-/- mice were fed ad lib for 7 weeks with a methionine/choline deficient (MCD) and western diet (WD). After 3 weeks of diet-induced injury, mice were injected i. p. with the NLRP3 antagonist IFM-514 (100 mg/kg body weight) or vehicle (0.5% carmellose) every day, 5 days/week for a further 4 weeks. Several markers of inflammation, fibrosis and steatosis were evaluated. Whole transcriptome sequencing and panel RNA expression analysis (NanoString) were performed. Results: IFM-514 inhibited IL-1β production in mice challenged with 20 mg/kg lipopolysaccharide, and in mouse and human inflammatory cells in vitro. IFM-514 inhibited hepatic inflammation in the in vivo non-alcoholic steatohepatitis model assessed by H&E staining and in the hepatic gene expression of inflammasome-related proinflammatory cytokines. This effect was associated with significant reduction in caspase-1 activation. Similarly, IFM-514 was efficacious in vivo in MDC-fed ApoE-/- mice, markedly reducing portal pressure, Sirius red staining and 4-hydroxyproline content compared to vehicle-treated mice. Moreover, IFM-514 significantly reduced hepatic steatosis in MCD-fed ApoE-/- mice, as evidenced by NAFLD scores, oil red O staining, hepatic triglycerides and gene expression. In WD treated animals, similar trends in inflammation and fibrosis were observed, although not sufficient IFM-514 levels were reached. Conclusion: Overall, IFM-514 reduced liver inflammation and fibrosis, with mild effects on liver steatosis in experimental murine NASH. Blocking of NLRP3 may be an attractive therapeutic approach for NASH patients.
Purpose: Dexamethasone (Dex) is the most common corticosteroid to treat edema in glioblastoma (GBM) patients. Recent studies identified the addition of Dex to radiation therapy (RT) to be associated with poor survival. Independently, Tumor Treating Fields (TTFields) provides a novel anti-cancer modality for patients with primary and recurrent GBM. Whether Dex influences the efficacy of TTFields, however, remains elusive. Methods: Human GBM cell lines MZ54 and U251 were treated with RT or TTFields in combination with Dex and the effects on cell counts and cell death were determined via flow cytometry. We further performed a retrospective analysis of GBM patients with TTFields treatment +/- concomitant Dex and analysed its impact on progression-free (PFS) and overall survival (OS). Results: The addition of Dex significantly reduced the efficacy of RT in U251, but not in MZ54 cells. TTFields (200 kHz/250 kHz) induced massive cell death in both cell lines. Concomitant treatment of TTFields and Dex did not reduce the overall efficacy of TTFields. Further, in our retrospective clinical analysis, we found that the addition of Dex to TTFields therapy did not influence PFS nor OS. Conclusion: Our translational investigation indicates that the efficacy of TTFields therapy in patients with GBM and GBM cell lines is not affected by the addition of Dex.
Objectives: To evaluate peri-implant tissue dimensions following nonsurgical (NS) and surgical therapy (S) employing different decontamination protocols of advanced ligature-induced peri-implantitis in dogs.
Material & Methods: Peri-implantitis defects (n = 5 dogs, n = 30 implants) were randomly and equally allocated in a split-mouth design to NS or S treatment using either an Er:YAG laser (ERL), an ultrasonic device (VUS), or plastic curettes + local application of metronidazole gel (PCM), respectively. Horizontal bone thickness (hBT) and soft tissue thickness (hMT) were measured at different reference points: (v0) at the marginal portion of the peri-implant mucosa (PM); (v1) at 50% of the distance from PM to bone crest (BC); (v2) at the BC; (v3) at the most coronal extension of the bone-to-implant contact. Vertical peri-implant tissue height was calculated from PM to BC.
Results: All of the treatment groups showed a gradual hMT increase from v0 to the v2 reference point, followed by a reduction from v2 to the v3 region. The S-VUS subgroup tended to be associated with higher hMT values at the v0 region than the NS-VUS subgroup (0.44 mm versus 0.31 mm). PM-BC distance varied from 2.22 to 2.83 mm in the NS group, and from 2.07 to 2.38 in the S group.
Conclusion: Vertical and horizontal peri-implant tissue dimensions were similar in different treatment groups.