The use of bisphosphonates in the management of bone involvement from solid tumours and haematological malignancies - a European survey.

Bone metastases in patients with solid tumours (ST) and bone lesions in patients with haematological malignancies (HM) are common. Associated skeletal-related events (SREs) cause severe pain, reduced quality of life and place a burden on health care resources. Bone-targeted agents can reduce the risk of SREs. We evaluated the management of bone metastasis/lesions in five European countries (France, Germany, Italy, Spain and the UK) by an observational chart audit. In total, 881 physicians completed brief questionnaires on 17 193 patients during the observation period, and detailed questionnaires for a further 9303 individuals. Patient cases were weighted according to the probability of inclusion. Although a large proportion of patients with bone metastases/lesions were receiving bisphosphonates, many had their treatment stopped (ST, 19%; HM, 36%) or will never be treated (ST, 18%; HM, 13%). The results were generally similar across the countries, although German patients were more likely to have asymptomatic bone lesions detected during routine imaging. In conclusion, many patients who could benefit from bone-targeted agents do not receive bisphosphonates and many have their treatment stopped when they could benefit from continued treatment. Developing treatment guidelines, educating physicians and increasing the availability of new agents could benefit patients and reduce costs.

Modification of the bilateral sagittal split osteotomy (BSSO) in a study using pig mandibles.

In a bilateral sagittal split osteotomy (BSSO) mechanical irritation of the inferior alveolar nerve (IAN) (e.g. by chiselling) should be avoided to prevent neural damage. A modification of the Obwegeser-Dal Pont operation technique was studied by splitting 100 pig mandibles ex vivo. An additional osteotomy at the caudal border of the mandible was used to facilitate the sagittal split by means of a locus of minor resistance. The chisel was inserted distal to the second molar and far away from the IAN. The mandible was split by torque. The modified technique reduced the required torque to split the mandible about 30% compared with the original technique (paired t-test, t(69)=-12.89; p<0.05). 75% of all mandibles split by the modified technique were classified as bad splits compared with 100% using the original technique using the same protocol without the additional osteotomy.

HPLC-based quantification of haemagglutinin in the production of egg- and MDCK cell-derived influenza virus seasonal and pandemic vaccines.

The haemagglutinin (HA) content is an important specification of influenza vaccines. Recently, a reversed-phase high performance liquid chromatography (RP-HPLC) method for quantification of HA in PER.C6 cell culture-based whole virus vaccines has been reported, having a high sensitivity, precision, broad range, and high sample throughput [Kapteyn JC, Drissi Saidi M, Dijkstra R, Kars C, Tjon CMS-K, Weverling GJ et al. Haemagglutinin quantification and identification of influenza A&B strains propagated in PER.C6 cells: a novel RP-HPLC method. Vaccine 2006;24:3137-44]. This RP-HPLC assay is based on measuring the peak area of HA1, the hydrophilic subunit of HA, which turned out to be proportional to the amount of HA analyzed. Here, we present data demonstrating that this RP-HPLC method is also highly suitable for HA quantification of active and BPL- or formaldehyde-inactivated egg-based and MDCK cell-based whole virus samples, including egg allantoic harvest, and in final (monovalent) subunit vaccines, including those for pandemic H5N1 strains and for virosomal vaccines. In addition, the RP-HPLC assay was demonstrated to be a very powerful tool in the early stages of seasonal influenza vaccine production, when homologous serial radial immunodiffusion (SRID) reagents are not yet available, enabling fast and reliable viral growth studies in eggs in order to select the best growing virus strains or reassortants for the production of the seasonal trivalent influenza vaccine. Because of its high sensitivity, the RP-HPLC assay has shown its enormous value in supporting small scale MDCK-based (H5N1) influenza virus production models. Finally, the observed differences between HA1 molecules from various HA subtypes in UV absorbance, FLD response, and in the actual retention times in RP-HPLC are discussed in relation to the primary structure of the HA1 molecules studied.

Prosthodontic rehabilitation of oral function in head-neck cancer patients with dental implants placed simultaneously during ablative tumour surgery: an assessment of treatment outcomes and quality of life.

The aim of this prospective study was to assess treatment outcome and impact on quality of life of prosthodontic rehabilitation with implant-retained prostheses in head-neck cancer patients. Fifty patients were evaluated by standardized questionnaires and clinical assessment. All received the implants during ablative tumour surgery in native bone in the interforaminal area. About two-thirds of the patients (n=31) needed radiotherapy post-surgery. Both in irradiated and non-irradiated bone two implants were lost 18-24 months after installation. Peri-implant tissues had a healthy appearance. No cases of osteoradionecrosis occurred. In 15 patients no functional implant-retained lower dentures could be made for various reasons. The other 35 patients all functioned well, with an improvement in quality of life. Major improvement was observed in the non-irradiated patients. In the irradiated patients, less improvement in many functional items was observed, while items related to the oral sequelae of radiotherapy did not improve. Similar to the quality-of-life assessments, denture satisfaction was improved and tended to be higher in non-irradiated than irradiated patients. Implant-retained lower dentures can substantially improve the quality of life related to oral functioning and denture satisfaction in head-neck cancer patients. This effect is greater in non-irradiated than irradiated cancer patients.

Phase change of a confined subcooled simple liquid in a nanoscale cavity.

The phase transition of a simple liquid bounded between two parallel walls a few nanometers apart is investigated with molecular dynamics simulations. Vapor nucleation in a liquid confined in a microchannel of only a few nanometers in size cannot be achieved by increasing the temperature at the wall. Already small changes in temperature cause a large rise in pressure, in terms of orders of magnitude. On the other hand, using the fact that some fluids thermally contract on cooling, e.g., the argon liquid investigated here, reducing the temperature places the fluid in the liquid-vapor coexistence regime. If the bottom wall temperature is further reduced, the fluid will crystallize starting from the bottom surface, creating a "frozen" bubble in the crystallized state. It was found that the confining walls and not the quenching rate primarily affect the crystallization process. However, the fastest cooling rate investigated herein led to a decrease of the boiling initiation temperature. At a lower cooling rate, the vapor nucleation temperature was the same as the equilibrium boiling temperature for the confined liquid. Small temperatures in the confined system result in dominating attraction forces at the fluid-wall interface exposing the fluid to tensile stress. The increased influence of the walls results in a significant decrease of the boiling as well as freezing temperatures.

The use of implant retained mandibular prostheses in the oral rehabilitation of head and neck cancer patients. A review and rationale for treatment planning.

Surgical treatment of malignancies in the oral cavity (tongue, floor of the mouth, alveolus, buccal sulcus, oropharynx) often results in an unfavourable anatomic situation for prosthodontic rehabilitation. The outcome is a severe disturbance of oral functioning despite the improved surgical techniques for reconstruction that are currently available. Radiotherapy, which often is applied postsurgically, worsens oral functioning in many cases. Main problems that may hamper proper prosthodontic rehabilitation of these patients include a severe reduction of the neutral zone, an impaired function of the tongue, and a very poor load-bearing capacity of the remaining soft tissues and mandibular bone. Many of these problems can, at least in part, be diminished by the use of endosseous oral implants. These implants can contribute to the stabilisation of the prostheses and intercept the main part of the occlusal loading. Surgical interventions after radiotherapy are preferably avoided because of compromised healing, which may lead to development of radionecrosis of soft tissues and bone as well as to increased implant loss. If surgical treatment after radiotherapy is indicated, measures to prevent implant loss and development of radionecrosis have to be considered e.g. antibiotic prophylaxis and/or pre-treatment with hyperbaric oxygen (HBO). To avoid this problem, implant insertion during ablative surgery has to be taken into consideration if postoperative radiotherapy is scheduled or possibly will be applied. This approach is in need of a thorough pre-surgical examination and multidisciplinary consultation for a well-established treatment planning. The primary curative intent of the oncological treatment and the prognosis for later prosthodontic rehabilitation have to be taken into account too.

[Dentoalveolar traumatology]. / Dentoalveolaire traumatologie.

The dentist will be confronted unexpectedly with a dentoalveolar trauma patient. This patient has to be seen immediately and has to be treated adequately. The risk of overlooking trauma-related signs when examining these patients, can be minimized by following a strict protocol. This article describes a protocol for examination and treatment of a patient with a dentoalveolar trauma. The prognosis after treatment of the trauma is discussed. Also some recommendations regarding aftercare and prevention are presented.

[Reconstructive preprosthetic surgery 1. Corrections of soft tissues and bone]. / Reconstructieve preprothetische chirurgie 1. Correcties van weke delen en bot.

The aim of reconstructive preprosthetic surgery is the creation of an environment of hard and soft tissue which is favourable to the function of an aesthetically optimal prosthesis, with or without oral implants. In this paper, various preprosthetic surgical treatments for correcting soft and hard tissues are discussed.

[Reconstructive preprosthetic surgery 2. Pre-implantologic surgery]. / Reconstructieve preprothetische chirurgie 2. Preïmplantaire chirurgie.

Reconstructive preprosthetic surgery is, amongst others, aimed at the creation of an environment which is favourable to the construction of an implant supported prosthesis. Not in all cases the pre-existent volume of bone is sufficient to place an implant in the planned position. In this paper various techniques to augment local bone defects for reliable implant placement are described.

[Dentoalveolar surgery for the dentist: removal of teeth and root tips]. / Dentoalveolaire chirurgie voor de tandarts: verwijdering van gebitselementen en wortelresten.

The indication for surgical removal of teeth or roottips is often made in dental practice. In some cases a general practitioner will decide to perform the surgical procedure himself, while in other cases he will refer the patient to an oral and maxillofacial surgeon. Level of difficulty of the treatment and the experience, the time available, the availability for postoperative care, and the personal interest of the dentist are factors involved in decision making. It is likely that with increased experience, the dentist will be able to perform more complicated treatments. This article supports this process. Surgical removal of teeth and roottips is systematically described, with emphasis on technical aspects. Presurgical management, removal of singlerooted and multirooted teeth, woundcare and postoperative management are the subjects covered.

[Dentoalveolar surgery for the dentist: removal of third molar]. / Dentoalveolaire chirurgie voor de tandarts: verwijdering van derde molaren.

In contrast to removal of other teeth and roottips, a third molar is mostly removed for preventive reasons. There is still debate about the correct indications for removal of third molars. As soon as the decision to remove a third molar surgically is made, the dentist has to decide between performing the surgical procedure himself or referring the patient to an oral and maxillofacial surgeon. Level of difficulty of the treatment and experience, available time, availability for postoperative care, and personal interest of the dentist are issues influencing this decision. This article describes systematically the indications, for instance using preoperative radiodiagnostics, the factors determining the technical surgical plan, as well as the practical surgical procedures.

Comparison of coagulation activity tests in vitro for selected biomaterials.

Testing of coagulation induced by external communicating medical devices is an International Standardisation Organization (ISO) requirement for products exposed to human blood. Four categories of tests are indicated by ISO 10993/4: a clotting test (partial thromboplastin time; PTT), thrombin generation, fibrinogen deposition, or measurement of coagulation split products. We evaluated the specificity of these tests on various polymers and found only thrombin generation and fibrinogen binding sensitive and reproducible tests while thrombin generation correlated best with the classical PTT. The thrombin generation assay is therefore the method of choice for testing coagulation induced by biomaterials and medical devices.

Targeting influenza virosomes to ovarian carcinoma cells.

Reconstituted influenza virus envelopes (virosomes) containing the viral hemagglutinin (HA) have attracted attention as delivery vesicles for cytosolic drug delivery as they possess membrane fusion activity. Here, we show that influenza virosomes can be targeted towards ovarian carcinoma cells (OVCAR-3) with preservation of fusion activity. This was achieved by incorporating poly(ethylene glycol) (PEG)-derivatized lipids into the virosome membrane. This PEG layer serves as shield to prevent interaction of HA with ubiquitous sialic acid residues and as spatial anchor for antibody attachment. Coupling of Fab' fragments of mAb 323/A3 (anti-epithelial glycoprotein-2) to the distal ends of PEG lipids resulted in specific binding of virosomes to OVCAR-3 cells. These antibody-redirected virosomes fused with membranes of OVCAR-3 cells in a pH-dependent fashion.

Treatment outcome of bone-anchored craniofacial prostheses after tumor surgery.

BACKGROUND: Percutaneous endosseous implants have acquired an important place in the prosthetic rehabilitation of patients with craniofacial defects. The objective of this study was to evaluate the clinical outcome of the use of endosseous implants in the orbital and auricular region as well as to assess the satisfaction of patients with implant-retained craniofacial prostheses after tumor surgery. METHODS: The clinical outcome and patient satisfaction of implant-retained prostheses in the auricular and orbital region were evaluated in a group of 26 patients with facial defects after tumor surgery by using standardized questionnaires and a clinical assessment. Twelve patients (n = 31 implants) received the implants during ablative tumor surgery, from which 7 patients (n = 20 implants) were treated with radiation therapy after surgery (mean, 65 grays [Gy]). Fourteen patients (n = 44 implants) received the implants after the tumor surgery, from which 5 patients (n = 21 implants) were irradiated after ablative surgery (mean, 54.4 Gy), but before implant placement. RESULTS: No implants were lost in patients who had not undergone irradiation (100%), whereas 5 implants were lost in the irradiated group (87.8%). The overall implant survival rate was 93.3%. The peri-implant tissues had a healthy appearance, and no cases of osteoradionecrosis occurred. When compared with patients treated with conventional adhesive retained facial prostheses, satisfaction was higher in patients treated with implant-retained facial prostheses. CONCLUSIONS: From this study, it is concluded that implant-retained facial prostheses are better tolerated than adhesive retained prostheses and offer an improvement in the quality of life. Radiotherapy is not a contraindication for the use of osseointegrated implants in the maxillofacial region, but the loss of implants is higher than in nonirradiated sites.

Role of hemagglutinin surface density in the initial stages of influenza virus fusion: lack of evidence for cooperativity.

Membrane fusion mediated by influenza virus hemagglutinin (HA) is believed to proceed via the cooperative action of multiple HA trimers. To determine the minimal number of HA trimers required to trigger fusion, and to assess the importance of cooperativity between these HA trimers, we have generated virosomes containing coreconstituted HAs derived from two strains of virus with different pH dependencies for fusion, X-47 (optimal fusion at pH 5.1; threshold at pH 5.6) and A/Shangdong (optimal fusion at pH 5.6; threshold at pH 6.0), and measured fusion of these virosomes with erythrocyte ghosts by a fluorescence lipid mixing assay. Virosomes with different X-47-to-A/Shangdong HA ratios, at a constant HA-to-lipid ratio, showed comparable ghost-binding activities, and the low-pH-induced conformational change of A/Shangdong HA did not affect the fusion activity of X-47 HA. The initial rate of fusion of these virosomes at pH 5.7 increased directly proportional to the surface density of A/Shangdong HA, and a single A/Shangdong trimer per virosome appeared to suffice to induce fusion. The reciprocal of the lag time before the onset of fusion was directly proportional to the surface density of fusion-competent HA. These results support the notion that there is no cooperativity between HA trimers during influenza virus fusion.

Induction of cytotoxic T lymphocyte activity by fusion-active peptide-containing virosomes.

Priming of cytotoxic T lymphocyte (CTL) activity with exogenous antigen requires introduction of the antigen into the MHC class I presentation pathway of antigen-presenting cells. In the present study, we used fusogenic reconstituted envelopes (virosomes), derived from influenza virus, as a carrier system for delivery of a synthetic soluble peptide corresponding to a major murine CTL epitope of the influenza virus nucleoprotein (NP). Virosomes containing encapsulated NP-peptide efficiently sensitized target cells for recognition by influenza-specific CTLs generated through priming of mice with infectious virus. Intramuscular immunization of mice with peptide-containing virosomes induced a potent class I MHC-restricted CTL response against influenza-infected target cells. By contrast, an equal dose of NP-peptide encapsulated in fusion-inactivated virosomes did not induce CTL activity, indicating an essential role of the membrane fusion activity of the virosomes in the induction of the response. Likewise, NP-peptide encapsulated in liposomes, NP-peptide mixed with empty virosomes and NP-peptide in IFA failed to induce a CTL response. These results demonstrate that fusion-active virosomes represent a promising delivery system for induction of class I MHC-restricted CTL activity with non-replicating viral antigens.

Gene transfer mediated by fusion protein hemagglutinin reconstituted in cationic lipid vesicles.

Hemagglutinin, the membrane fusion protein of influenza virus, is known to mediate a low-pH-dependent fusion reaction between the viral envelope and the limiting membrane of the endosomal cell compartment following cellular uptake of the virus particles by receptor-mediated endocytosis. Here we exploited this activity of hemagglutinin to achieve efficient gene delivery to cultured cells. Hemagglutinin was reconstituted in the presence of the monocationic lipid dioleoyldimethylammonium chloride (DODAC) to permit plasmid binding to the virosome surface. Virosomes with 30 mol% DODAC exhibited a distinct binding capacity for plasmid without causing aggregation. The virosome fusion activity was not affected by the cationic lipid DODAC as demonstrated by low-pH-dependent lipid mixing with erythrocyte ghosts. Efficient cell transfection of BHK-21 cells was observed with virosomes containing 30 mol% DODAC and plasmid encoding for beta-galactosidase (pCMV beta-gal) associated to their surface. The transfection activity observed was dependent on the functional activity of hemagglutinin. Contrary to DNA/cationic lipid complexes the transfection was not dependent on the cationic lipid to DNA charge ratio. Importantly, transfection of BHK-21 cells with pCMV beta-gal by DODAC-containing virosomes did not show any significant signs of cytotoxicity that is commonly observed with DNA/cationic lipid complexes. Together with the high levels of expression of the transgene this highlights the potential of DODAC-containing virosomes as a novel approach in nonviral gene transfer.

The mandibular staple bone plate: a long-term retrospective evaluation.

PURPOSE: Clinical and radiographic parameters and denture satisfaction were evaluated in a long-term retrospective study of patients treated with the mandibular staple bone plate. PATIENTS AND METHODS: Fifty-six edentulous patients were treated with the mandibular staple bone plate to stabilize their lower denture. The mean evaluation period was 103 months (range, 84 to 139 months). Peri-implant mucosa and bone height were scored, together with quality of the prosthesis and prosthodontic maintenance care. Denture satisfaction was assessed by using two questionnaires. RESULTS: Four staple bone plates were removed during the evaluation period, and one appeared to be fractured. The remaining 51 staple bone plates were functional without any signs of major complications (survival rate, 91%). No further alveolar resorption in the interforaminal region of the mandible took place during the evaluation period. Patients were very satisfied with the prosthetic construction. CONCLUSIONS: The mandibular staple bone plate is a good modality to stabilize the lower denture. However, endosseous implant systems are preferred because of comparable success rates with a more simple operative procedure.

[Complaints and complications associated with removal of the mandibular third molar. A prospective clinical study]. / Nabezwaren en complicaties na verwijdering van de derde molaar in de onderkaak. Een prospectief klinisch onderzoek.

OBJECTIVE: To study the incidence of complaints and complications after removal of the mandibular third molar and to evaluate the influence of this procedure on functioning of the patient during the first post-surgical week. DESIGN: Prospective, clinical. SETTING: Department of Oral and Maxillofacial Surgery, University Hospital Groningen. METHODS: Patients referred for removal of a mandibular third molar were asked to return one week after the procedure and to keep a daily record of the use of pain medication, duration of the pain and intensity of the pain. RESULTS: Removal of mandibular third molars resulted in an overall complication rate of 12%. Pain medication was used more frequently and for a longer period by patients with post-surgical complications. Due to complaints following the removal of the mandibular third molar, the mean absence from work was one and a half day. Work was generally resumed with decreased perceived efficiency. CONCLUSION: After this commonly performed procedure in dento-alveolar surgery most of the patients were hampered as a result of pain during the first four post-surgical days. Over 10% of the patients developed complications leading to more frequently and prolonged use of pain medication. Removal of the mandibular third molar gave rise to complaints which influenced the patients relatively strong in their daily functioning.