Group 1 ITI Consensus Report: The role of bone dimensions and soft tissue augmentation procedures on the stability of clinical, radiographic, and patient-reported outcomes of implant treatment.

OBJECTIVES: The aims of Working Group 1 were to address the role (i) of the buccolingual bone dimensions after implant placement in healed alveolar ridge sites on the occurrence of biologic and aesthetic complications, and (ii) of soft tissue augmentation (STA) on the stability of clinical, radiographic, and patient-related outcomes of implant treatments. MATERIALS AND METHODS: Two systematic reviews were prepared in advance of the Consensus Conference and were discussed among the participants of Group 1. Consensus statements, clinical recommendations, recommendations for future research, and reflections on patient perspectives were based on structured group discussions until consensus was reached among the entire group of experts. The statements were then presented and accepted following further discussion and modifications as required by the plenary. RESULTS: Dimensional changes of the alveolar ridge occurred after implant placement in healed sites, and a reduction in buccal bone wall thickness (BBW) of 0.3 to 1.8 mm was observed. In healed sites with a BBW of <1.5 mm after implant placement, increased vertical bone loss, and less favorable clinical and radiographic outcomes were demonstrated. Implants with buccal dehiscence defects undergoing simultaneous guided bone regeneration, showed less vertical bone loss, and more favorable clinical and radiographic outcomes, compared to non-augmented dehiscence defects during initial healing. At healthy single implant sites, probing depths, bleeding and plaque scores, and interproximal bone levels evaluated at 1 year, remained stable for up to 5 years, with or without STA. When single implant sites were augmented with connective tissue grafts, either for soft tissue phenotype modification or buccal soft tissue dehiscence, stable levels of the soft tissue margin, and stable or even increased soft tissue thickness and/or width of keratinized mucosa could be observed from 1 to 5 years. In contrast, non-augmented sites were more prone to show apical migration of the soft tissue margin in the long-term. Favorable aesthetic and patient-reported outcomes after STA were documented to be stable from 1 to 5 years. CONCLUSIONS: It is concluded that dimensional changes of the alveolar ridge occur after implant placement in healed sites and that sites with a thin BBW after implant placement are prone to exhibit less favorable clinical and radiographic outcomes. In addition, it is concluded that STA can provide stable clinical, radiographic, aesthetic, and patient-reported outcomes in the medium and long-term.

Cerebral abscesses with odontogenic origin: a population-based cohort study.

OBJECTIVES: Recent studies have indicated that cerebral abscess (CA) patients with odontogenic origin are on the rise. However, CA patients are often poorly characterized and with an unknown etiologic background. The purpose of this study is to identify and characterize CA patients that may have an odontogenic origin based on microbiologic, radiographic, and/or clinical findings. MATERIALS AND METHODS: This is a population-based cohort study analyzing retrospective and prospective data from CA patients. Radiographic examinations of panoramic radiographs (PRs) or computed tomography (CT) scans were conducted. CA patients characterized with odontogenic origin required the fulfilment of the following criteria on admission: (1) Oral pathologic conditions were the only bacterial infections present, (2) oral microorganisms were isolated in the purulent exudate from the brain, and (3) radiographically and/or clinical recordings of oral pathologic conditions. RESULTS: A total of 44 patients could be included in this study of which 25 (57%) were characterized as having CA with a likely odontogenic origin. Type two diabetes (T2D) (p = 0.014) and microorganisms of the Streptococcus anginosus group (SAG) (p < 0.01) were overrepresented in patients with CAs of odontogenic origin. CONCLUSIONS: Odontogenic infections may cause CAs to a greater extent than previously assumed. T2D was overrepresented among patients with odontogenic CA. When microorganisms of the SAG were isolated from the brain pus, CA patients had a predisposing odontogenic or sinus infection. CLINICAL RELEVANCE: The identification of patients with a likely odontogenic CA will contribute to understanding the etiology of the infectious disease and highlighting the importance of preserving oral health.

Soft tissue management at implants: Summary and consensus statements of group 2. The 6th EAO Consensus Conference 2021.

OBJECTIVES: The task of working Group 2 at the 6th Consensus Meeting of the European Association for Osseointegration was to comprehensively assess the effects of soft tissue augmentation procedures at dental implant sites on clinical, radiographic and patient-reported outcome measures (PROMs) including an overview on available outcome measures and methods of assessment. MATERIALS AND METHODS: Three systematic reviews and one critical review were performed in advance on (i) the effects of soft tissue augmentation procedures on clinical, radiographic and aesthetic outcomes, (ii) reliability and validity of outcome measures and methods of assessment and (iii) PROMs applied in clinical studies for soft tissue augmentation procedures at dental implant sites. Major findings, consensus statements, clinical recommendations and implications for future research were discussed in the group and approved during the plenary sessions. RESULTS: The four reviews predominantly revealed: Soft tissue augmentation procedures in conjunction with immediate and delayed implant placement result in superior aesthetic outcomes compared to no soft tissue augmentation in the zone of aesthetic priority. Soft tissue augmentation procedures have a limited effect on marginal bone level changes compared to implant sites without soft tissue augmentation. Clinically relevant parameters (gingival index, mucosal recession) and plaque control improve at implant sites when the width of keratinised mucosa is increased. A variety of aesthetic indices have been described with good reliability. Pink Esthetic Score and Complex Esthetic Index are the most validated aesthetic indices for single implants, though. Superimposed digital surface scans are most accurate to assess profilometric tissue changes. PROMs following soft tissue augmentation procedures have been assessed using various forms of questionnaires. Soft tissue augmentation had a limited effect on PROMs. CONCLUSIONS: Soft tissue augmentation procedures are widely applied in conjunction with implant therapy. Depending on the indication of these interventions, clinical, radiographic and aesthetic outcomes may improve, whereas the effect on PROMs is limited.

Can High-Sensitivity Troponins Predict Future Hypertension? A Systematic Literature Review.

Hypertension (HT) is associated with cardiovascular events and increased mortality, and identification of persons at risk in due time is therefore important. Finding a biomarker to identify those at risk will enable early preventive treatment, and high-sensitivity cardiac troponin (hs-cTn) seems to be a highly relevant candidate. To gather the existing knowledge on the association between hs-cTn and future HT, a systematic literature review was conducted following the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) reporting guidelines and using the PICOS system. Medline was searched until August 2018. Of 45 extracted papers, eleven papers were eligible for the study. None were randomized controlled trials. Three studies assessed hs-cTnI, eight studies assessed hs-cTnT. All studies found statistically significant associations between hs-cTn concentrations and future HT, but the studies included different types of blood pressure (diastolic, systolic, diurnal). Due to differences in troponin assay construction and test capability, a direct comparison of test performance in terms of specificity, sensitivity and predictive values was not possible, and a specific hs-cTn cutoff value for HT prediction could therefore not be defined. Furthermore, a number of conditions known to affect troponin concentrations (e.g. gender, renal function, and co-morbidities) were not sufficiently studied. All retrieved studies found significant associations between hs-cTn concentrations and future HT; although the findings are promising, the studies were too heterogeneous, and many conditions affecting troponin concentrations needs investigation at these low concentrations before hs-cTn can be considered a useful HT predictor.

Autotransplantation of teeth to the anterior maxilla: A systematic review of survival and success, aesthetic presentation and patient-reported outcome.

BACKGROUND/AIM: Autotransplantation of teeth to the anterior maxilla may be indicated after trauma or in patients with congenitally missing teeth. The aim of this systematic review was to report the current evidence concerning survival and success rate, aesthetic outcome, and patient-reported outcome of autotransplanted teeth to the anterior maxilla. MATERIALS AND METHODS: A MEDLINE search followed by an additional hand search was performed to identify relevant literature. All levels of evidence except case reports were considered. Any publication reporting on 10 or more autotransplanted teeth to the anterior maxilla, and written in English were eligible for this systematic review. RESULTS: The systematic search identified 95 abstracts. Thirty-seven full-text articles were evaluated of which 17 could finally be included. Data on survival and success rate of the transplants could be extracted from 11 studies. Survival rates ranged between 93% and 100% (weighted mean: 96.7%, median: 100%) after 9 months to 22 years of observation (median: 8.75 years). No consensus regarding definition of success criteria of the transplants could be found in the literature. Two and four studies contained data on aesthetic and patient-reported outcomes, respectively. In general, they reported favourable aesthetic results and high patient satisfaction. CONCLUSION: The current available evidence suggests a high survival rate after autotransplantation of teeth to the anterior maxilla. However, the level of evidence is low. Limited data on aesthetic and patient-reported outcomes warrant additional research in this field.

Can hyaluronan injections augment deficient papillae at implant-supported crowns in the anterior maxilla? A randomized controlled clinical trial with 6 months follow-up.

OBJECTIVES: The present randomized controlled trial aimed to assess the effect of hyaluronan (HY) injections to augment deficient interproximal papillae at implant-supported crowns in the anterior maxilla. METHODS: Twenty-two patients with a deficient papilla in the anterior maxilla next to an implant-supported crown were randomly assigned to receive twice either HY (test) or saline solution (control) injection. The following parameters were recorded prior to injection (baseline) and 3 and 6 months after injection: distance between the papilla tip and contact point (PT-CP), modified papilla index score (MPIS), and standard clinical periodontal parameters. Pain level after injection was recorded on a visual analogue scale (VAS). The deficient area was evaluated on clinical photographs, and the esthetic appearance was recorded on a VAS. Differences in mucosal volume were assessed after 3 months by intraoral scans. The bone level was assessed on periapical radiographs. RESULTS: No differences were observed between groups, neither at baseline nor at 3 and 6 months post-treatment. Mean PT-CP ranged between 1.8 mm and 2.3 mm without significant differences between groups or over time within groups; MPIS was 2 for all patients at all time points. Similarly, insignificant differences between groups or time points were observed for deficient area, gingival volume changes, bone level, and esthetic appearance. There were no differences in pain level between groups during injection, but discomfort after injection lasted longer in the test group. CONCLUSIONS: Injection of HY adjacent to maxillary anterior implant-supported crowns did not result in any clinical conspicuous volume augmentation of deficient papillae.

Adverse reaction after hyaluronan injection for minimally invasive papilla volume augmentation. A report on two cases.

OBJECTIVES: To report two cases of adverse reaction after mucosal hyaluronan (HY) injection around implant-supported crowns, with the aim to augment the missing interdental papilla. MATERIAL AND METHODS: Two patients with single, non-neighbouring, implants in the anterior maxilla, who were treated within the frames of a randomized controlled clinical trial testing the effectiveness of HY gel injection to reconstruct missing papilla volume at single implants, presented an adverse reaction. Injection of HY was performed bilaterally using a 3-step technique: (i) creation of a reservoir in the mucosa directly above the mucogingival junction, (ii) injection into the attached gingiva/mucosa below the missing papilla, and (iii) injection 2-3 mm apically to the papilla tip. The whole-injection session was repeated once after approximately 4 weeks. RESULTS: Both patients presented with swelling and extreme tenderness with a burning sensation on the lip next to the injection area, after the second injection session. In one of the cases, a net-like skin discoloration (livedo reticularis) was also noted. The symptoms lasted for up to 7 days, and in both cases, symptoms resolved without any signs of skin or mucosal necrosis or any permanent damage. CONCLUSION: Most likely, water attraction over time by the highly hygroscopic HY, exerted progressively an external vascular compression and at least partial occlusion of neighbouring blood vessels. An infection or an allergic reaction seems unlikely, since all symptoms gradually disappeared within a week irrespective use of antimicrobials, while an allergic reaction most likely would not have been restricted to one side.

The resection angle in apical surgery: a CBCT assessment.

OBJECTIVES: The primary objective of the present radiographic study was to analyse the resection angle in apical surgery and its correlation with treatment outcome, type of treated tooth, surgical depth and level of root-end filling. MATERIALS AND METHODS: In the context of a prospective clinical study, cone beam computed tomography (CBCT) scans were taken before and 1 year after apical surgery to measure the angle of the resection plane relative to the longitudinal axis of the root. Further, the surgical depth (distance from the buccal cortex to the most lingual/palatal point of the resection plane) as well as the level of the root-end filling relative to the most coronal point of the cut root face was determined. Treated teeth were categorized into four groups (maxillary and mandibular anterior and posterior teeth). The final material comprised 62 treated roots in 55 teeth. RESULTS: The mean calculated resection angle of all roots was 17.7° ± 11.4° (range -9.6° to 43.4°). Anterior maxillary roots presented the highest mean angle (25.8° ± 10.3°) that was significantly different from the mean angle in posterior maxillary roots (10.7° ± 9.4°; p < 0.001) and from the mean angle in posterior mandibular roots (15.1 ± 9.8°; p < 0.05). In roots with a shallow resection angle (≤20°), the rate of healed cases was higher than in roots with an acute resection angle (>20°), however without reaching statistical significance (p = 0.0905). Angles did not correlate either with the surgical depth or with the retrofilling length. CONCLUSIONS: Statistically significant differences were observed comparing resection angles of different tooth groups. However, the angle had no significant effect on treatment outcome. CLINICAL RELEVANCE: Contrary to common belief, the resection angle in maxillary anterior teeth was greater than in the other teeth. The surgeon is advised to pay attention to the resection angle when bevelling maxillary anterior teeth in apical surgery.

Osteoclast-like cells on deproteinized bovine bone mineral and biphasic calcium phosphate: light and transmission electron microscopical observations.

OBJECTIVES: The occurrence of multinucleated giant cells (MNGCs) on bone substitute materials has been recognized for a long time. However, there have been no studies linking material characteristics with morphology of the MNGCs. The aim was to analyze the qualitative differences of MNGCs on two commercially available calcium phosphate bone substitute materials retrieved from bone defects. MATERIAL AND METHODS: Six defects were prepared bilaterally in the mandibular body of three mini pigs. The defects were randomly grafted with either deproteinized bovine bone mineral (DBBM) or biphasic calcium phosphate (BCP). After a healing period of four weeks, bone blocks were embedded in LR White resin. Three consecutive sections per defect were analyzed as follows: two with light microscopy using toluidine blue and tartrate-resistant acid phosphatase (TRAP) staining and one with transmission electron microscopy. RESULTS: Multinucleated giant cells appeared on both biomaterials. On BCP, MNGCs had a flat morphology and were not observed in resorption lacunae. On DBBM, the MNGCs appeared more round and were often found in shallow concavities. MNGCs on both biomaterials demonstrated a varying degree of TRAP staining, with a tendency toward higher staining intensity of MNGCs on BCP. At the ultrastructural level, signs of superficial dissolution of BCP together with phagocytosis of minor fragments were observed. MNGCs on the surface of DBBM demonstrated sealing zones and ruffled borders, both features of mature osteoclasts. CONCLUSION: MNGCs demonstrated distinctly different histological features depending on the bone substitute material used. Further research is warranted to understand the clinical implications of these morphological observations.

Impact of bone graft harvesting techniques on bone formation and graft resorption: a histomorphometric study in the mandibles of minipigs.

BACKGROUND: Harvesting techniques can affect cellular parameters of autogenous bone grafts in vitro. Whether these differences translate to in vivo bone formation, however, remains unknown. OBJECTIVE: The purpose of this study was to assess the impact of different harvesting techniques on bone formation and graft resorption in vivo. MATERIAL AND METHODS: Four harvesting techniques were used: (i) corticocancellous blocks particulated by a bone mill; (ii) bone scraper; (iii) piezosurgery; and (iv) bone slurry collected from a filter device upon drilling. The grafts were placed into bone defects in the mandibles of 12 minipigs. The animals were sacrificed after 1, 2, 4 and 8 weeks of healing. Histology and histomorphometrical analyses were performed to assess bone formation and graft resorption. An explorative statistical analysis was performed. RESULTS: The amount of new bone increased, while the amount of residual bone decreased over time with all harvesting techniques. At all given time points, no significant advantage of any harvesting technique on bone formation was observed. The harvesting technique, however, affected bone formation and the amount of residual graft within the overall healing period. Friedman test revealed an impact of the harvesting technique on residual bone graft after 2 and 4 weeks. At the later time point, post hoc testing showed more newly formed bone in association with bone graft processed by bone mill than harvested by bone scraper and piezosurgery. CONCLUSIONS: Transplantation of autogenous bone particles harvested with four techniques in the present model resulted in moderate differences in terms of bone formation and graft resorption.

Development of assay platforms for in vitro screening of Treg modulating potential of pharmacological compounds.

CD4 + CD25+ regulatory T cells (Tregs) are believed to be pivotal in controlling chronic inflammation as well as in opposing the effect of cancer immunotherapy. Therefore, identification of novel drug compounds that interfere with Treg function is of high priority together with research that investigates Treg modulation by current drugs. For such research as well as for novel cell based therapies based on Treg infusions, rapid in vitro assays as well as functional assays based on inhibitory capacity of Tregs are required. Here, we report on such assays using highly pure fluorescence-activated cell sorting (FACS) sorted CD4 + CD25(high)CD127(dim/-)CD45RA+ naïve Treg cells followed by in vitro expansion. We report on the use of these cells in a short-term assay based on Treg mediated inhibition of the early effector T cell activation markers CD69 and CD154. Additionally, we investigate the use of highly pure Tregs in a functional assay based on Treg mediated inhibition of effector T cell proliferation. We report highly reproducible Treg function in assays that test the effect of well-known model compounds such as CpG-A, anti-IL-6R (tocilizumab), anti-TNF-α (adalimumab) or a combination of IL-6 and TNF-α. In conclusion, these assays have the potential for use in pharmacological screening and discovery in relation to drug development in immunology.

Medication-related osteonecrosis of the jaw and successful implant treatment in a patient on high-dose antiresorptive medication: A case report.

OBJECTIVES: Oral rehabilitation can be a challenge in patients on high-dose antiresorptive medication (HDAR), especially if the alveolar anatomy has changed due to previous medication-related osteonecrosis of the jaw (MRONJ) resection. In healthy patients, dental implant treatment has found wide acceptance in prosthetic rehabilitation as it increases the patient's oral health-related quality of life. However, it is considered contraindicated in patients on HDAR due to the risk of MRONJ, although a recent feasibility study indicates that implant treatment may indeed be an option in these patients. The aim of the present case report is to illustrate the risk of MRONJ in a patient with cancer on HDAR and to discuss the reasons behind the outcomes of the implant treatment. MATERIALS AND METHODS: A patient with prostate cancer with bone metastases on high-dose denosumab therapy with previous MRONJ had four implants inserted bilaterally in the maxilla (14, 13, 23, 24). Two identical implant-supported screw-retained cantilever bridges were fabricated. The patient was followed for more than 1 year. RESULTS AND CONCLUSION: Peri-implantitis, and/or MRONJ, was diagnosed around two of the implants (23, 24), probably induced by crestal bone trauma from a healing abutment and/or a misfitting prosthetic reconstruction. A peri-implantitis operation was performed, but without the desired response, and the two implants (23, 24) were later removed in an MRONJ resection. The implants on the other side of the maxilla (14, 13) remained without complications. Dental implant treatment is feasible in patients on HDAR, but comorbidities (e.g., diabetes mellitus) and polypharmacy (e.g., chemotherapy and steroids) may add to the risk of implant failure. Minimal trauma surgery and prosthodontics are crucial to increase the chance of successful healing in an HDAR patient.

A 10-year Follow-up Study of 119 Teeth Treated with Apical Surgery and Root-end Filling with Mineral Trioxide Aggregate.

INTRODUCTION: The objective of this clinical study was to assess the long-term outcome (clinical signs/symptoms and radiographic healing) of teeth treated with apical surgery and mineral trioxide aggregate (MTA) for root-end filling. METHODS: One hundred ninety-five patients were recalled 1, 5, and 10 years after apical surgery for clinical and radiographic examinations. Three calibrated observers evaluated the periapical radiographs independently. The evolution of the cases over time was analyzed. Healing classification of teeth was divided into "healed" versus "not healed" teeth using well-established clinical and radiographic healing criteria. The potential influence of sex, age, type of treated tooth, type of MTA, and first-time versus repeat surgery on healing outcome was statistically analyzed. RESULTS: The inception cohort included 195 teeth. The dropout rate after 10 years amounted to 39% (n = 76). Of the 119 teeth available for the 10-year analysis, 97 teeth were classified as healed (81.5%). No significant differences were found with regard to the rate of healed cases for the subcategories of the parameters of age, sex, type of MTA, and first-time or repeat surgery. Concerning the type of treated tooth, the rate of healed maxillary molars (95.2%) differed significantly (P = .035) from the rate of healed maxillary premolars (66.7%). The predictive value of the cases classified as healed at 1 year and remaining so over the 10-year observation period was 86.8%. CONCLUSIONS: This 10-year follow-up study of teeth treated with apical surgery and MTA as root-end filling material showed an acceptable rate of healed cases. Many of the lost teeth had been extracted because of longitudinal root fractures during the observation period.

Increased expression and activity of group IIA and X secretory phospholipase A2 in peritumoral versus central colon carcinoma tissue.

Secretory phospholipase A2 (sPLA2) type IIA and X was analyzed in tumors from 22 patients with colon adenocarcinomas in order to determine the involvement and activity of sPLA2 in colon cancer. Evaluation of immunoreactive sPLA2 IIA by Western blotting showed a significantly higher level in the periphery of the tumors, compared to central tumor regions. Increased levels of sPLA2 IIA protein correlated with a two-fold increase in sPLA2 enzymatic activity in the peripheral regions compared to central regions. Nineteen out of 22 tumors showed high levels of sPLA2 IIA, whereas 7 out of the 22 tumors showed sPLA2 type X. These data demonstrate that both sPLA2 type IIA and X are present in human colon cancer and suggest a role for sPLA2 in colon cancer tumor immunology and tumorigenesis.

Advanced strategies in liposomal cancer therapy: problems and prospects of active and tumor specific drug release.

Tumor specific drug delivery has become increasingly interesting in cancer therapy, as the use of chemotherapeutics is often limited due to severe side effects. Conventional drug delivery systems have shown low efficiency and a continuous search for more advanced drug delivery principles is therefore of great importance. In the first part of this review, we present current strategies in the drug delivery field, focusing on site-specific triggered drug release from liposomes in cancerous tissue. Currently marketed drug delivery systems lack the ability to actively release the carried drug and rely on passive diffusion or slow non-specific degradation of the liposomal carrier. To obtain elevated tumor-to-normal tissue drug ratios, it is important to develop drug delivery strategies where the liposomal carriers are actively degraded specifically in the tumor tissue. Many promising strategies have emerged ranging from externally triggered light- and thermosensitive liposomes to receptor targeted, pH- and enzymatically triggered liposomes relying on an endogenous trigger mechanism in the cancerous tissue. However, even though several of these strategies were introduced three decades ago, none of them have yet led to marketed drugs and are still far from achieving this goal. The most advanced and prospective technologies are probably the prodrug strategies where non-toxic drugs are carried and activated specifically in the malignant tissue by overexpressed enzymes. In the second part of this paper, we review our own work, exploiting secretory phospholipase A2 as a site-specific trigger and prodrug activator in cancer therapy. We present novel prodrug lipids together with biophysical investigations of liposome systems, constituted by these new lipids and demonstrate their degradability by secretory phospholipase A2. We furthermore give examples of the biological performance of the enzymatically degradable liposomes as advanced drug delivery systems.

Delivery of TLR7 agonist to monocytes and dendritic cells by DCIR targeted liposomes induces robust production of anti-cancer cytokines.

Tumor immune escape is today recognized as an important cancer hallmark and is therefore a major focus area in cancer therapy. Monocytes and dendritic cells (DCs), which are central to creating a robust anti-tumor immune response and establishing an anti-tumorigenic microenvironment, are directly targeted by the tumor escape mechanisms to develop immunosuppressive phenotypes. Providing activated monocytes and DCs to the tumor tissue is therefore an attractive way to break the tumor-derived immune suppression and reinstate cancer immune surveillance. To activate monocytes and DCs with high efficiency, we have investigated an immunotherapeutic Toll-like receptor (TLR) agonist delivery system comprising liposomes targeted to the dendritic cell immunoreceptor (DCIR). We formulated the immune stimulating TLR7 agonist TMX-202 in the liposomes and examined the targeting of the liposomes as well as their immune activating potential in blood-derived monocytes, myeloid DCs (mDCs), and plasmacytoid DCs (pDCs). Monocytes and mDCs were targeted with high specificity over lymphocytes, and exhibited potent TLR7-specific secretion of the anti-cancer cytokines IL-12p70, IFN-α 2a, and IFN-γ. This delivery system could be a way to improve cancer treatment either in the form of a vaccine with co-formulated antigen or as an immunotherapeutic vector to boost monocyte and DC activity in combination with other treatment protocols such as chemotherapy or radiotherapy. STATEMENT OF SIGNIFICANCE: Cancer immunotherapy is a powerful new tool in the oncologist's therapeutic arsenal, with our increased knowledge of anti-tumor immunity providing many new targets for intervention. Monocytes and dendritic cells (DCs) are attractive targets for enhancing the anti-tumor immune response, but systemic delivery of immunomodulators has proven to be associated with a high risk of fatal adverse events due to the systemic activation of the immune system. We address this important obstacle by targeting the delivery of an immunomodulator, a Toll-like receptor agonist, to DCs and monocytes in the bloodstream. We thus focus the activation, potentially avoiding the above-mentioned adverse effects, and demonstrate greatly increased ability of the agonist to induce secretion of anti-cancer cytokines.

Synthesis and biological activity of anticancer ether lipids that are specifically released by phospholipase A2 in tumor tissue.

The clinical use of anticancer lipids is severely limited by their ability to cause lysis of red blood cells prohibiting intravenous injection. Novel delivery systems are therefore required in order to develop anticancer ether lipids (AELs) into clinically useful anticancer drugs. In a recent article (J. Med. Chem. 2004, 47, 1694) we showed that it is possible to construct liposome systems composed of masked AELs that are activated by secretory phospholipase A2 in cancerous tissue. We present here the synthesis of six AELs and evaluate the biological activity of these bioactive lipids. The synthesized AEL 1-6 were tested against three different cancer cell lines. It was found that the stereochemistry of the glycerol headgroup in AEL-2 and 3 has a dramatic effect on the cytotoxicity of the lipids. AEL 1-4 were furthermore evaluated for their ability to prevent phosphorylation of the apoptosis regulating kinase Akt, and a correlation was found between their cytotoxic activity and their ability to inhibit Akt phosphorylation.

Triggered activation and release of liposomal prodrugs and drugs in cancer tissue by secretory phospholipase A2.

The selectivity of anticancer drugs in targeting the tumour tissue presents a major problem in cancer treatment. In this article we review a new generation of smart liposomal nanocarriers that can be used for enhanced anticancer drug and prodrug delivery to tumours. The liposomes are engineered to be particularly degradable to secretory phospholipase A2 (sPLA2), which is a lipid hydrolyzing enzyme that is significantly upregulated in the extracellular microenvironment of cancer tumours. Thus, when the long circulatory liposomal nanocarriers extravasate and accumulate in the interstitial tumour space, sPLA2 will act as an active trigger resulting in the release of cytotoxic drugs in close vicinity of the target cancer cells. The sPLA2 generated lysolipid and fatty acid hydrolysis products will furthermore be locally released and function as membrane permeability promoters facilitating the intracellular drug uptake. In addition, the liposomal membrane can be composed of a novel class of prodrug lipids that can be converted selectively to active anticancer agents by sPLA2 in the tumour. The integrated drug discovery and delivery technology offers a promising way to rationally design novel tumour activated liposomal nanocarriers for better cancer treatment.

Secretory phospholipase A2 as a tumor-specific trigger for targeted delivery of a novel class of liposomal prodrug anticancer etherlipids.

The use of many common clinically relevant chemotherapeutics is often limited due to insufficient delivery to the tumor and dose-limiting systemic toxicities. Therefore, therapeutics that specifically target tumor cells and are nontoxic to normal cells are required. Here, we report the development of a novel class of liposomes composed of lipid prodrugs, which use the increased secretory phospholipase A2 type IIA (sPLA2) activity of the tumor microenvironment as a trigger for the release of anticancer etherlipids (AEL). Treatment of sPLA2-secreting tumor cells in vitro with liposomes consisting of proAELs resulted in growth inhibition comparable with addition of the AELs alone. Using a specific sPLA2 inhibitor, we showed the low cytotoxicity of the nonhydrolyzed proAEL liposomes and have proven the sPLA2 dependency of the activation of proAELs to cytotoxic AELs. In addition, we showed that our proAEL liposomes circumvent the inherent hemolytic toxicities associated with the use of etherlipids, thereby allowing i.v. administration of such therapeutics as nontoxic prodrug liposomes. Furthermore, using a sPLA2-secreting human colon cancer xenograft model, we showed that the proAEL liposomes are capable of inducing a tumor growth delay in vivo. Taken together, these data support the validity of this novel tumor-selective liposomal prodrug delivery strategy. This new approach also provides a promising system for tumor-selective delivery and release of conventional chemotherapeutics encapsulated in the sPLA2-degradable prodrug liposomes.

Changes of Root Length and Root-to-Crown Ratio after Apical Surgery: An Analysis by Using Cone-beam Computed Tomography.

INTRODUCTION: Apical surgery is an important treatment option for teeth with post-treatment periodontitis. Although apical surgery involves root-end resection, no morphometric data are yet available about root-end resection and its impact on the root-to-crown ratio (RCR). The present study assessed the length of apicectomy and calculated the loss of root length and changes of RCR after apical surgery. METHODS: In a prospective clinical study, cone-beam computed tomography scans were taken preoperatively and postoperatively. From these images, the crown and root lengths of 61 roots (54 teeth in 47 patients) were measured before and after apical surgery. Data were collected relative to the cementoenamel junction (CEJ) as well as to the crestal bone level (CBL). One observer took all measurements twice (to calculate the intraobserver variability), and the means were used for further analysis. The following parameters were assessed for all treated teeth as well as for specific tooth groups: length of root-end resection and percentage change of root length, preoperative and postoperative RCRs, and percentage change of RCR after apical surgery. RESULTS: The mean length of root-end resection was 3.58 ± 1.43 mm (relative to the CBL). This amounted to a loss of 33.2% of clinical and 26% of anatomic root length. There was an overall significant difference between the tooth groups (P < .05). There was also a statistically significant difference comparing mandibular and maxillary teeth (P < .05), but not for incisors/canines versus premolars/molars (P = .125). The mean preoperative and postoperative RCRs (relative to CEJ) were 1.83 and 1.35, respectively (P < .001). With regard to the CBL reference, the mean preoperative and postoperative RCRs were 1.08 and 0.71 (CBL), respectively (P < .001). The calculated changes of RCR after apical surgery were 24.8% relative to CEJ and 33.3% relative to CBL (P < .001). Across the different tooth groups, the mean RCR was not significantly different (P = .244 for CEJ and 0.114 for CBL). CONCLUSIONS: This CBCT-based study demonstrated that the RCR is significantly changed after root-end resection in apical surgery irrespective of the clinical (CBL) or anatomic (CEJ) reference levels. The lowest, and thus clinically most critical, postoperative RCR was observed in maxillary incisors. Future clinical studies need to show the impact of resection length and RCR changes on the outcome of apical surgery.