Immunomonitoring of Tacrolimus in Healthy Volunteers: The First Step from PK- to PD-Based Therapeutic Drug Monitoring?

Therapeutic drug monitoring is routinely performed to maintain optimal tacrolimus concentrations in kidney transplant recipients. Nonetheless, toxicity and rejection still occur within an acceptable concentration-range. To have a better understanding of the relationship between tacrolimus dose, tacrolimus concentration, and its effect on the target cell, we developed functional immune tests for the quantification of the tacrolimus effect. Twelve healthy volunteers received a single dose of tacrolimus, after which intracellular and whole blood tacrolimus concentrations were measured and were related to T cell functionality. A significant correlation was found between tacrolimus concentrations in T cells and whole blood concentrations (r = 0.71, p = 0.009), while no correlation was found between tacrolimus concentrations in peripheral blood mononuclear cells (PBMCs) and whole blood (r = 0.35, p = 0.27). Phytohemagglutinin (PHA) induced the production of IL-2 and IFNγ, as well as the inhibition of CD71 and CD154 expression on T cells at 1.5 h post-dose, when maximum tacrolimus levels were observed. Moreover, the in vitro tacrolimus effect of the mentioned markers corresponded with the ex vivo effect after dosing. In conclusion, our results showed that intracellular tacrolimus concentrations mimic whole blood concentrations, and that PHA-induced cytokine production (IL-2 and IFNγ) and activation marker expression (CD71 and CD154) are suitable readout measures to measure the immunosuppressive effect of tacrolimus on the T cell

Immediate dental implant placement and restoration in the edentulous mandible in head and neck cancer patients: a systematic review and meta-analysis

PURPOSE OF REVIEW: Oral rehabilitation with dental implants in head and neck cancer (HNC) patients is challenging. After tooth removal prior to radiotherapy, immediate placement of dental implants during panendoscopy or surgery is thought to reduce the oral rehabilitation time improving patients' quality of life. RECENT FINDINGS: There is lack of consensus on the timing of dental implant placement and loading protocols. The aim of this study was to perform a systematic review of the literature regarding the performance and survival rate of immediately inserted dental implants placed prior to radiotherapy. Of 1003 articles, 10 were finally included comparing immediate vs. delayed placement of implants and comparing the effect of radiotherapy on immediately placed implants. Meta-analysis demonstrated a slightly higher survival of immediately placed implants compared with postponed placed implants [risk ratio: 0.92, 95% confidence interval (95% CI): 0.48-1.78, P = 0.81, I2 = 0%]. The other meta-analysis comparing radiotherapy vs. nonradiotherapy showed a clearly better survival of immediately placed implants not having received radiotherapy (risk ratio: 5.02, 95% CI: 0.92-27.38, P = 0.10, I2  = 56%). SUMMARY: Guidelines are recommended for immediate dental implant placement in the edentulous mandible in HNC patients prior to radiotherapy to allow homogeneity regarding the treatment protocols and thus comparison of treatment outcomes

Hydroxychloroquine Effects on TLR Signalling: Underexposed but Unneglectable in COVID-19

The main basis for hydroxychloroquine (HCQ) treatment in COVID-19 is the compound’s ability to inhibit viral replication in vitro. HCQ also suppresses immunity, mainly by interference in TLR signalling, but reliable clinical data on the extent and nature of HCQ-induced immunosuppression are lacking. Here, we discuss the mechanistic basis for the use of HCQ against SARS-CoV-2 in a prophylactic setting and in a therapeutic setting, at different stages of the disease. We argue that the clinical effect of prophylactic or therapeutic HCQ treatment in COVID-19 depends on the balance between inhibition of viral replication, immunosuppression, and off-target side effects, and that the outcome is probably dependent on disease stage and disease severity. This is supported by the initial outcomes of the well-designed randomized controlled trials: so far, evidence for a beneficial effect of HCQ treatment for COVID-19 is weak and conflicting

A Novel Approach for Immediate Implant-Based Oral Rehabilitation in a Sjögren's Syndrome Patient Using Virtual Surgical and Prosthetic Planning

Patients with Sjögren syndrome (SS) experience difficulties in wearing conventional dentures. After removal of all teeth, the oral rehabilitation is challenging and time consuming using conventional treatment protocols. Although implant-retained overdentures are beneficial for this specific patient group, the average total oral rehabilitation time (TORT) usually takes at least 9 months and needs to be reduced to increase patients' quality of life (QoL). In this paper, we report on a new treatment concept for immediate implant-based oral rehabilitation in a 77-year-old patient with partial edentulous SS. Because of persistent pain, discomfort, and retention problems with the conventional prosthetic devices, full clearance of the remaining mandibular dentition and immediate oral rehabilitation with an implant-retained overdenture were suggested. The treatment protocol included virtual surgical planning (VSP), combining a guided bone reduction of the mandibular alveolar process, immediate dental implant placement, and restoration using a prefabricated bar and placement of the overdenture. This method demands the use of ionizing 3D imaging optionally combined with an optical dental scan or a conventional impression. Furthermore, one needs to gain experience using VSP software. This novel treatment concept for immediate implant-based oral rehabilitation using VSP proved to be feasible and safe in a patient with SS, resulting in a significantly reduced TORT and improved QoL. Further research is needed to what extent this treatment concept could be beneficial to other patient groups, such as patients with head and neck cancer

Oral-Functioning Questionnaires in Patients with Head and Neck Cancer: A Scoping Review

Background: Oral-functioning impairment can negatively affect the quality of life (QoL) of head and neck cancer (HNC) patients after receiving radiotherapy (RT). Assessment of patient-reported oral functioning throughout treatment can improve patient care. This scoping review aims to propose a definition for oral functioning for HNC patients and to map out the available questionnaires measuring patient-reported oral functioning in RT-treated HNC patients. Methods: A literature search in relevant databases was performed. Each questionnaire was scored on the domains validity, reliability, and responsiveness. Furthermore, the items from the questionnaires were analyzed to define the common denominators for oral functioning in HNC patients. Results: Of the 6434 articles assessed, 16 met the inclusion criteria and employed 16 distinct instruments to evaluate QoL. No questionnaire covered all oral-health-related QoL items nor assessed all aspects of validity, reliability, and responsiveness. Chewing, speaking, and swallowing were the common denominators for oral functioning. Conclusions: Based on the included studies, we suggest using the VHNSS 2.0 questionnaire to assess oral functioning in HNC patients. Furthermore, we suggest to more clearly define oral functioning in HNC patients by focusing on masticatory function (chewing and grinding), mouth opening, swallowing, speaking, and salivation

Monitoring of Ex Vivo Cyclosporin a Activity in Healthy Volunteers Using T Cell Function Assays in Relation to Whole Blood and Cellular Pharmacokinetics

Therapeutic drug monitoring (TDM) of calcineurin inhibitors (i.e., tacrolimus and cyclosporin A) is standard of care after solid organ transplantation. Although the incidence of acute rejection has strongly decreased, there are still many patients who experience severe side effects or rejection after long-term treatment. In this healthy volunteer study we therefore aimed to identify biomarkers to move from a pharmacokinetic-based towards a pharmacodynamic-based monitoring approach for calcineurin inhibitor treatment. Healthy volunteers received a single dose of cyclosporine A (CsA) or placebo, after which whole blood samples were stimulated to measure ex vivo T cell functionality, including proliferation, cytokine production, and activation marker expression. The highest whole blood concentration of CsA was found at 2 h post-dose, which resulted in a strong inhibition of interferon gamma (IFNy) and interleukin-2 (IL-2) production and expression of CD154 and CD71 on T cells. Moreover, the in vitro effect of CsA was studied by incubation of pre-dose whole blood samples with a concentration range of CsA. The average in vitro and ex vivo CsA activity overlapped, making the in vitro dose–effect relationship an interesting method for prediction of post-dose drug effect. The clinical relevance of the results is to be explored in transplantation patients on calcineurin inhibitor treatment