Long-term outcomes and prognostic factors of surgical treatment of peri-implantitis - A retrospective study.

AIM: To evaluate long-term outcomes and prognostic factors of non-reconstructive surgical treatment of peri-implantitis. MATERIALS AND METHODS: One hundred forty-nine patients (267 implants) were surgically treated for peri-implantitis and followed for an average of 7.0 (SD: 3.6) years. The primary outcome was implant loss. Additional bone loss and surgical retreatment were secondary outcomes. Patient/implant characteristics, as well as clinical and radiographic parameters collected prior to initial surgery, were evaluated as potential predictors of implant loss. Flexible parametric survival models using restricted cubic spline functions were used; 5- and 10-year predicted rates of implant loss were calculated according to different scenarios. RESULTS: Fifty-three implants (19.9%) in 35 patients (23.5%) were lost during the observation period. Implant loss occurred after a mean period of 4.4 (SD: 3.0) years and was predicted by implant surface characteristics (modified surface; HR 4.5), implant length (HR 0.8 by mm), suppuration at baseline (HR 2.7) and disease severity (baseline bone loss: HR 1.2 by mm). Estimates of 5- and 10-year implant loss ranged from 1% (best prognostic scenario; initial bone loss <40% of implant length, turned implant surface and absence of suppuration on probing (SoP)) to 63% (worst prognostic scenario; initial bone loss ≥60% of implant length, modified implant surface and SoP) and from 3% to 89%, respectively. Surgical retreatment was performed at 65 implants (24.3%) in 36 patients (24.2%) after a mean time period of 4.5 (3.1) years. In all, 59.5% of implants showed additional bone loss, were surgically retreated or lost. CONCLUSIONS: Recurrence of disease is common following surgical treatment of peri-implantitis. The strongest predictor for implant loss was implant surface characteristics. Implant length as well as suppuration and disease severity at baseline were also relevant factors.

Combined treatment with crizotinib and temsirolimus is an effective strategy in mantle cell lymphoma and can overcome acquired resistance to temsirolimus.

Constitutive activation of the PI3K/AKT/mTOR-pathway plays an important role in the pathogenesis of mantle cell lymphoma (MCL), leading to approval of the mTOR inhibitor temsirolimus for relapsed or refractory MCL. Yet, despite favorable initial response rates, early relapses under treatment have been observed. Therefore, understanding the underlying mechanisms of temsirolimus resistance and developing strategies to overcome it is highly warranted. Here, we established a new temsirolimus-resistant MCL cell line to evaluate the molecular background of resistance to this drug. Transcriptome profiling and gene set enrichment analysis comparing temsirolimus-sensitive and -resistant cell lines showed significant upregulation of PI3K/AKT/mTor-, RAS signaling- and the RTK-dependent PDGFR-, FGFR-, Met- and ALK-signaling-pathways in the resistant cells. Furthermore, MET, known as important proto-oncogene and mediator of drug resistance, was among the most upregulated genes in the resistant cells. Importantly, Met protein was overexpressed in both, MCL cells with acquired as well as intrinsic temsirolimus resistance, but could not be detected in any of the temsirolimus sensitive ones. Combined pharmacological inhibition of mTOR and Met signaling with temsirolimus and the RTK inhibitor crizotinib significantly restored sensitivity to temsirolimus. Furthermore, this combined treatment proved to be synergistic in all MCL cell lines investigated and was also active in primary MCL cells. In summary, we showed for the first time that overexpression of MET plays an important role for mediating temsirolimus resistance in MCL and combined treatment with temsirolimus and crizotinib is a very promising therapeutic approach for MCL and an effective strategy to overcome temsirolimus resistance.