Metabolic syndrome detection with biomarkers in childhood cancer survivors.

PURPOSE: Augmented survival of childhood nephroblastoma and neuroblastoma has increased long-term side effects such as metabolic syndrome (MetS). Risk stratification is difficult after abdominal radiation because waist circumference underestimates adiposity. We aimed to develop a strategy for determining MetS in irradiated survivors using an integrated biomarker profile and vascular ultrasonography. METHODS: The NCEP-ATPIII MetS-components, 14 additional serum biomarkers and 9 vascular measurements were assessed in a single-centre cohort of childhood nephroblastoma (n = 67) and neuroblastoma (n = 36) survivors and controls (n = 61). Multivariable regression models were used to study treatment effects. Principal component analysis (PCA) was used to study all biomarkers in a combined analysis, to identify patterns and correlations. RESULTS: After 27.5 years of follow-up, MetS occurred more often in survivors (14%) than controls (3%). Abdominal radiotherapy and nephrectomy, to a lesser extent, were associated with MetS and separate components and with several biomarker abnormalities. PCA of biomarkers revealed a pattern on PC1 from favourable lipid markers (HDL-cholesterol, adiponectin) towards unfavourable markers (triglycerides, LDL-cholesterol, apoB, uric acid). Abdominal radiotherapy was associated with the unfavourable biomarker profile (ß = 1.45, P = 0.001). Vascular measurements were not of added diagnostic value. CONCLUSIONS: Long-term childhood nephro- and neuroblastoma survivors frequently develop MetS. Additional assessment of biomarkers identified in PCA - adiponectin, LDL, apoB, and uric acid - may be used especially in abdominally irradiated survivors, to classify MetS as alternative for waist circumference. Vascular ultrasonography was not of added value.

Metabolic syndrome as cardiovascular risk factor in childhood cancer survivors.

Over the past decades, survival rates of childhood cancer have increased considerably from 5 to 30% in the early seventies to current rates exceeding 80%. This is due to the development of effective chemotherapy, surgery, radiotherapy and stem cell transplantation, combined with an optimized stratification of therapy and better supportive care regimens. As a consequence, active surveillance strategies of late sequelae have been developed to improve the quality of survival. Several epidemiological studies have reported an increased incidence of (components of) metabolic syndrome (MetS) and cardiovascular disease in childhood cancer survivors (CCS). Growth hormone deficiency (GHD) after cranial radiotherapy (CRT) has been previously described as an important cause of MetS. New insights suggest a role for abdominal radiotherapy as a determinant for MetS as well. The role of other risk factors, such as specific chemotherapeutic agents, steroids, gonadal impairment, thyroid morbidity and genetics, warrants further investigation. This knowledge is important to define subgroups of CCS that are at risk to develop (subclinical) MetS features. These survivors might benefit from standard surveillance and early interventions, for example lifestyle and diet advice and medical treatment, thereby preventing the development of cardiovascular disease.

Bone mineral density after childhood cancer in 346 long-term adult survivors of childhood cancer.

SUMMARY: More than 45 % of long-term childhood cancer survivors (CCS) were diagnosed with osteopenia. Our data suggest that greater awareness for osteopenia is warranted in long-term CCS, especially in survivors who are older than 30 years, male, and underweight and were treated with cranial-spinal radiotherapy and/or steroids. INTRODUCTION: Osteopenia is a potential complication of childhood cancer treatment, but the magnitude of this problem in survivors is unknown. We examined (determinants of) bone mineral density (BMD) status in long-term survivors of adult childhood cancer. METHODS: This retrospective single-centre cohort study included 346 subjects with the most common types of childhood cancer. Subjects had a median age at diagnosis of 7.0 years (range 0.1-16.8 years), a median age at follow-up of 24.5 years (range 18.0-47.6 years) and a median follow-up time of 16.7 years (range 5.6-39.9 years). Total body BMD (BMDTB) and BMD of the lumbar spine (BMDLS) were measured by dual X-ray absorptiometry. Osteopenia was defined as BMD standardized deviation score (SDS) below -1. RESULTS: Survivors had a lower BMDTB and BMDLS (mean SDS -0.55; p<0.001 and -0.30; p<0.001, respectively) as compared to healthy peers. Osteopenia (BMDTB and/or BMDLS) was present in 45% of the survivors. Multivariate logistic regression analyses identified age at diagnosis<12 years, age>30 years at follow-up, male gender, underweight at follow-up and treatment with cranial-spinal radiotherapy or prednisone as independent prognostic factors for osteopenia. CONCLUSIONS: This large cohort of childhood cancer survivors identified osteopenia in 45% of CCS. This indicates that greater awareness is warranted, especially in survivors who are older than 30 years, male, have underweight and were treated with cranial-spinal radiotherapy and/or steroids.

Endocrine late sequelae in long-term survivors of childhood non-Hodgkin lymphoma.

BACKGROUND: Aim of this study was to investigate the long-term endocrine effects of treatment of childhood non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS: A single-center cohort of 84 survivors (22 females) was included in this retrospective study. Median age was 21 years (9-40 years) and time after cessation of therapy 12 years (4-30 years). Height, weight, percentage fat, lean body mass (LBM), bone mineral content (BMC), bone mineral density of total body (BMD(TB)) and bone mineral density of lumbar spine (BMD(LS)) were measured. Thyroid-stimulating hormone (TSH), free thyroxin (fT4), insulin-like growth factor-1 (IGF-1), inhibin B and anti-müllerian hormone (AMH) levels were measured. Results were compared with Dutch controls. RESULTS: Height was lower in survivors [mean standard deviation score (SDS) -0.36, P = 0.002], but further analysis showed that shorter stature was already present at diagnosis (mean SDS -0.28, P = 0.023). Body mass index, percentage fat, BMC, BMD(TB) and BMD(LS) were not different from controls. LBM was lower in survivors (mean SDS -0.47, P = 0.008). TSH, fT4 and IGF-1 were normal in all survivors. Three of 20 adult females had low AMH levels and 23 of 42 adult males had low inhibin B levels. CONCLUSIONS: Twelve years after cessation of treatment, NHL survivors did not develop adiposity, osteoporosis or thyroid disease. Male survivors may be at risk for infertility.

[Dissertations 25 years after date 25. Dentures: a question of grinning and bearing it]. / Proefschriften 25 jaar na dato 25. Een kunstgebit, een kwestie van doorbijten.

'Dentures: A question of grinning and bearing it' is not just the title of a 25-year-old thesis, but it also reflects the content well. Dissatisfaction with complete dentures is not only determined by the quality of the dentures and the oral conditions, but also and just as much by the patient's capacity to adapt to and accept the dentures. In order to treat an edentulous patient adequately, an oral healthcare provider should pay special attention to these aspects. After 25 years of further scientific study, this conclusion is still true. The current care standard for edentulous patients with atrophy of the residual mandibular alveolar ridge is an overdenture supported by 2 implants. For edentulous patients with a solid residual mandibular alveolar ridge, conventional complete dentures are the first choice of treatment. Only in cases of obvious remaining complaints, should an implant-supported overdenture be considered.

[Neutral zone. An anatomic space which is often neglected while fabricating removable complete dentures]. / Neutrale zone. Een bij vervaardiging van volledige gebitsprothesen vaak vervaarloosde anatomische ruimte.

When designing complete dentures, consideration should not only be given to the occlusal concept but also to the occlusal system as a whole. An important part of that system is the position of the artificial teeth. This prosthetic part of the occlusal system is directly related to the tongue, the floor of the mouth, the cheeks and the lips. The artificial teeth of the mandibular dentures have to be positioned in the so-called 'neutral zone' of the edentulous mandible. The neutral zone is the stress-free area between the tongue on one side and, on the other side, the mimic muscles, which are responsible for the movement of the lips and cheeks. Moreover, the maxillary posterior artificial teeth and the supporting acrylic surfaces of the maxillary denture have an important function in providing support for the upper lip and cheeks in order to prevent a 'denture look' appearance.

Components of the metabolic syndrome in 500 adult long-term survivors of childhood cancer.

BACKGROUND: Adult survivors of childhood cancer have been reported to have an increased risk of late sequels. A cluster of abnormalities that contribute to the metabolic syndrome may be expressed at a higher level and therefore result in an increased risk for diabetes mellitus and cardiovascular diseases. PATIENTS AND METHODS: We investigated a single-centre cohort of 500 adult survivors (228 females) of childhood cancer, median age 28 years (range 18-59 years) and median follow-up time 19 years (range 6-49 years). We measured total cholesterol, high-density lipoprotein-cholesterol, systolic and diastolic blood pressure, body mass index and the prevalence of diabetes mellitus. Data from the epidemiological Monitoring van Risicofactoren en Gezondheid in Nederland (MORGEN) study were used to calculate standard deviation scores as normative values. RESULTS: The criteria of the metabolic syndrome were met in 13% of the total cohort. Acute lymphoblastic leukaemia (ALL) survivors treated with cranial irradiation had an increased risk of developing the metabolic syndrome compared with ALL survivors not treated with cranial irradiation (23% versus 7%, P = 0.011), probably determined by higher prevalence of overweight and hypertension. CONCLUSION: Adult survivors of childhood cancer, especially those treated with cranial irradiation, are at increased risk of developing the metabolic syndrome.

[Indications for removable partial dentures]. / De indicaties voor een partiële gebitsprothese.

Since there are many ways of preserving a natural dentition, if necessary with support of solitary crowns and fixed partial dentures, sometimes on dental implants, removable partial dentures are nowadays primarily indicated in patients with complaints about missing teeth in the aesthetic zone, which cannot be solved in another way. In addition to this, a removable partial denture is indicated in patients with extremely reduced dentitions or large or multiple edentulous areas, in patients with severe periodontitis or excessive loss of alveolar bone, in patients who are physically or emotionally vulnerable, as an interim solution on the way to edentulousness, as a temporary solution waiting for more extensive treatment and for patients who cannot afford an alternative.

An eight-year follow-up to a randomized clinical trial of aftercare and cost-analysis with three types of mandibular implant-retained overdentures.

Mandibular implant overdentures increase satisfaction and the quality of life of edentulous individuals. Long-term aftercare and costs may depend on the type of overdentures. One hundred and ten individuals received one of 3 types of implant-retained overdentures, randomly assigned, and were evaluated with respect to aftercare and costs. The follow-up time was 8 years, with only seven drop-outs. No significant differences (Kruskal-Wallis test) were observed for direct costs of aftercare (p = 0.94). The initial costs constituted 75% of the total costs and were significantly higher in the group with a bar on 4 implants, compared with the group with a bar on 2 implants and the group with ball attachments on 2 implants (p = 0.018). The last group needed a significantly higher number of prosthodontist-patient aftercare contacts, mostly for re-adjustment of the retentive system. It can be concluded that an overdenture with a bar on 2 implants might be the most efficient in the long term.

[Incorporation of implant overdentures into the dental curriculum]. / De invoering van de overkappings- prothese op implantaten in het reguliere onderwijsprogramma.

This article is focusing on incorporation of implant overdentures into the dental curriculum. For mandibular edentulism, an implant-retained overdenture should nowadays be considered a first choice for prosthodontic care, if not the standard of care. Yet, it is not incorporated in practical teaching today. Curriculum change is always difficult. The needs of our patients specifically, and those of society generally, should be primarily drivers of innovation of the curriculum. Therefore, Dutch dental schools should make sure that graduated students are experts in analyzing edentulous patients' problems, in considering possible treatments, and in carrying out the standard of care.

An eight-year follow-up to a randomized clinical trial of participant satisfaction with three types of mandibular implant-retained overdentures.

Studies have shown that mandibular implant overdentures significantly increase satisfaction and quality of life of edentulous elders. Improved chewing ability appears to have a positive impact on nutritional state. Therefore, it is important to determine the best design of this prosthesis over the long term. In this randomized controlled trial, three groups of edentulous participants with atrophic mandibles wore 3 types of implant overdentures. During an eight-year follow-up, only seven of the 110 participants had dropped out of this study. Almost all participants were still satisfied with their overdentures. Participant satisfaction concerning retention and stability of the mandibular overdenture had decreased significantly in the two-implant ball attachment group, whereas the opinion of participants in the single- and triple-bar groups was still at the same level. The long-term results suggest that a mandibular overdenture retained by 2 implants with a single bar may be the best treatment strategy for edentulous people with atrophic ridges.

[The smile line, a literature search]. / De lachlijn, een literatuuronderzoek.

Beautiful teeth, visible when smiling, are in line with the present ideal of beauty. The display of teeth when smiling is determined by the smile line: the projection of the lower border of the upper lip on the maxillary teeth when smiling. On the basis of a literature search the determining methods of the smile line are discussed, demographic data of the position of the smile line are given, and factors of influence are examined. There is no unequivocal method for determining the position of the smile line. A rough distinction can be made between qualitative and (semi)-quantitative methods. The (semi)-quantitative methods have clear advantages for research purposes, but their reliability is unknown. It was demonstrated that among minimally 40% of subjects the maxillary gingiva was not visible when smiling. The mandibular gingiva was not visible when smiling among more than 90% of subjects. Furthermore, it appeared that among women the smile line was on average higher situated than among men and that it has not yet been proven that the smile line will be situated lower when growing older.

[Simulation of pigmented mucosa in complete dentures: development of an oral pigment index]. / Simulatie van de gepigmenteerde mucosa in gebitsprothesen: ontwikkeling van een classificatie.

In the non-Caucasian population the skin and oral tissues show pigmentation to a variable degree, but much more than in Caucasian. When a person becomes edentulous, the tissues containing oral pigmentation disappear. The patient's ethnic background gives no information to predict the characteristics of individual oral pigmentation; other sources have to be found. The mucosal pigmentation of 106 non-Caucasian, dentate people in Amsterdam and Los Angeles was investigated; a classification-chart of oral pigmentation with six types was designed. This tool makes it possible to help patient, dentist and dental technician to choose an accurate simulation of the contour of oral pigmentation in a denture. It is recommended to document the individual pigmentation before extractions are performed.

A clinical evaluation of implants in irradiated oral cancer patients.

In this prospective study, we determined the effects of the time interval between irradiation and implant therapy, implant location, bone-resection surgery, and irradiation dose on implant survival. We analyzed the survival of 446 implants inserted after radiotherapy over a period of up to 14 years in 130 consecutive patients treated for oral cancer. The 10-year overall Kaplan-Meier implant survival percentage is 78%. The difference in survival percentages of implants inserted < 1 year and >/= 1 year after irradiation (76% and 81%, respectively) is not significant. We concluded that implant survival is significantly influenced by the location (maxilla or mandible, 59% and 85%, respectively; p = 0.001), by the incidence of bone-resection surgery in the jaw where the implant was installed (p = 0.04), and by the irradiation dose at the implant site (< 50 Gray or >/= 50 Gray, p = 0.05).

Transforming growth factor-beta1 incorporation in an alpha-tricalcium phosphate/dicalcium phosphate dihydrate/tetracalcium phosphate monoxide cement: release characteristics and physicochemical properties.

The osteoconductive properties of calcium phosphate cements (CPCs) may be improved by the addition of growth factors, such as recombinant human transforming growth factor-beta1 (rhTGF-beta1). Previously we have shown that rhTGF-beta1 was released from cement enriched with rhTGF-beta1 and subsequently stimulated the differentiation of pre-osteoblastic cells from adult rat long bones. It is unknown whether the addition of rhTGF-beta1 changes the material properties of this alpha-tricalcium-phosphate (alpha-TCP)/tetracalcium-phosphate-monoxide (TeCP)/dicalcium-phosphate-dihydrate (DCPD) cement, and what the characteristics of the release of rhTGF-beta1 from this CPC are. Therefore, in the present study we determined the release of rhTGF-beta1 from cement pellets in vitro. The possible intervening effects of the CPC modification for intermixing rhTGF-beta1 on physicochemical properties were studied by assessing the compressive strength and setting time, as well as crystallinity, calcium to phosphorus ratio, porosity and microscopic structure. Most of the previously incorporated rhTGF-beta1 in the cement pellets was released within the first 48 h. For all concentrations of rhTGF-beta1 intermixed (100 ng-2.5 mg/g CPC), approximately 0.5% of the amount of rhTGF-beta1 incorporated initially was released in the first 2 h, increasing to 1.0% after 48 h. The release of rhTGF-beta1 continued hereafter at a rate of about 0.1% up to 1 week, after which no additional release was found. The initial setting time, nor the final setting time was changed in control cement without rhTGF-beta1 (standard CPC) or in cement modified for rhTGF-beta1 (modified CPC) at 20 degrees C and 37 degrees C. Setting times were more than six times decreased at 37 degrees C compared to 20 degrees C. The compressive strength was initially low for both standard CPC and modified CPC, after which it increased between 24 h and 8 weeks. The compressive strength for the modified CPC was significantly higher compared with standard at 1, 2, and 8 weeks after mixing. X-ray diffraction revealed that both standard and modified CPC changed similarly from the original components into crystalline apatite. The calcium to phosphorus ratio as determined by an electron microprobe did not differ at all time points measured for standard CPC and modified CPC. In both standard CPC and modified CPC the separated particles became connected by crystals, forming a structure in which the particles could hardly be recognised in a densifying matrix with some small pores. The present study shows that the calcium phosphate cement is not severely changed by modification for the addition of rhTGF-beta1. The addition of rhTGF-beta1 in CPC enhances the biologic response as shown in our previous study and did not interfere with the aimed physical and chemical properties as shown in this study. We conclude that the addition of rhTGF-beta1 enlarges the potential of the CPC in bone replacement therapy.

Transforming growth factor-beta1 incorporation in a calcium phosphate bone cement: material properties and release characteristics.

The bone regenerative properties of calcium phosphate cements (CPCs) may be improved by the addition of growth factors, such as recombinant human transforming growth factor-beta1 (rhTGF-beta1). Previously, we showed that rhTGF-beta1 in CPC stimulated the differentiation of preosteoblastic cells from adult rat long bones. The intermixing of rhTGF-beta1 in CPC, which was subsequently applied to rat calvarial defects, enhanced bone growth around the cement and increased the degradation of the cement. However, it is unknown whether the addition of rhTGF-beta1 changes the material properties of CPC and what the characteristics of the release of rhTGF-beta1 from CPC are. Therefore, we determined in this study the release of rhTGF-beta1, in vitro, from the cement pellets as implanted in the rat calvariae. The possible intervening effects of rhTGF-beta1 intermixing on the clinical compliance of CPC were studied through an assessment of its compressive strength and setting time, as well as its crystallinity, calcium-to-phosphorus ratio, porosity, and microscopic structure. We prepared CPC by mixing calcium phosphate powder (58% alpha-tricalcium phosphate, 25% anhydrous dicalcium phosphate, 8.5% calcium carbonate, and 8.5% hydroxyapatite) with a liquid (3 g/mL). The liquid for standard CPC consisted of water with 4% disodium hydrogen phosphate, whereas the liquid for modified CPC was mixed with an equal amount of 4 mM hydrochloride with 0.2% bovine serum albumin. The hydrochloride liquid contained rhTGF-beta1 in different concentrations for the release experiments. Most of the rhTGF-beta1 incorporated in the cement pellets was released within the first 48 h. For all concentrations of intermixed rhTGF-beta1 (100 ng to 2.5 mg/g of CPC), approximately 0.5% was released in the first 4 h, increasing to 1.0% after 48 h. Further release was only about 0.1% from 2 days to 8 weeks. CPC modification slightly increased the initial setting time at 20 degrees C from 2.6 to 5 min but had no effect on the final setting time of CPC at 20 degrees C or the initial and final setting times at 37 degrees C. The compressive strength was increased from 18 MPa in the standard CPC to 28 MPa in the modified CPC only 4 h after mixing. The compressive strength diminished in the modified CPC between 24 h and 8 weeks from 55 to 25 MPa. No other significant change was found with the CPC modification for rhTGF-beta1. X-ray diffraction revealed that standard and modified CPCs changed similarly from the original components, alpha-tricalcium phosphate and anhydrous dicalcium phosphate, into an apatite cement. The calcium-to-phosphorus ratio, as determined with an electron microprobe, did not differ for standard CPC and modified CPC. Standard and modified CPCs became dense and homogeneous structures after 24 h, but the modified CPC contained more crystal plaques than the standard CPC, as observed with scanning electron microscopy (SEM). SEM and back- scattered electron images revealed that after 8 weeks the cements showed equally and uniformly dense structures with microscopic pores (<1 microm). Both CPCs showed fewer crystal plaques at 8 weeks than at 24 h. This study shows that CPC is not severely changed by its modification for rhTGF-beta1. The prolonged setting time of modified cement may affect the clinical handling but is still within acceptable limits. The compressive strength for both standard and modified cements was within the range of thin trabecular bone; therefore, both CPCs can withstand equal mechanical loading. The faster diminishing compressive strength of modified cement from 24 h to 8 weeks likely results in early breakdown and so might be favorable for bone regeneration. Together with the beneficial effects on bone regeneration from the addition of rhTGF-beta1 to CPC, as shown in our previous studies, we conclude that the envisaged applications for CPC in bone defects are upgraded by the intermixing of rhTGF-beta1. Therefore, the combination of CPC and rhTGF-beta1 forms a promising synthetic bone graft.

Transforming growth factor-beta1 incorporated in calcium phosphate cement stimulates osteotransductivity in rat calvarial bone defects.

Bone regeneration of the alveolar crest around dental implants is an important factor in the success of implant use. Calcium phosphate cement can be used as a bone substitute and applied clinically as a paste to fill micro- and macroscopic bone defects. We have shown earlier that the intermixing of the recombinant human transforming growth factor-beta1 (rhTGF-beta1) in hardening calcium phosphate cement stimulated osteoblastic differentiation of rat primary bone cells in vitro. The aim of the present study was to examine whether the similar enrichment with rhTGF-beta1 affects the replacement of calcium phosphate cement by bone (osteotransduction) in calvarial critical size defects (csd) of adult rats. Two bone defects of 5 mm diameter were created bilaterally in each skull of 10 adult male rats. Both defects were filled with 53 mg of calcium phosphate cement without rhTGF-beta1 (control) at one side, and with 10 or 20 ng rhTGF-beta1 at the other side. After 8 weeks, defects with surrounding skull were analysed histologically and histomorphometrically. The addition of rhTGF-beta1 in the cement increased the amount of bone in rat skull defects. This finding coincidences with our in vitro observations, that intermixing of rhTGF-beta1 in calcium phosphate cement stimulates bone cell differentiation. Addition of rhTGF-beta1 stimulated bone formation as indicated by an increased bone volume of 50% and an increased bone/cement contact of 65%, in comparison to control defects with cement without rhTGF-beta1. In addition, rhTGF-beta1 reduced the remaining volume of cement, by 11% at 10 ng rhTGF-beta1, and by 20% at 20 ng rhTGF-beta1 in the cement. Defect closure was not affected. We conclude that the intermixing of rhTGF-beta1 in a fast-setting calcium phosphate cement stimulates bone growth and the osteotransduction of the cement. For bone regeneration procedures around endosseous implants, calcium phosphate cement with rhTGF-beta1 might be an appropriate combination for early osseointegration and implant use.

[Three treatment modalities for mandibular overdentures on implants. Clinical and radiological aspects]. / Drie behandelingsmethoden met implantaten in de edentate onderkaak. Klinische en röntgenologische aspecten.

The results are presented of 3 treatment modalities for overdentures on implants in the mandible: 2 implants with ball attachment, 2 implants interconnected with a bar and 4 implants interconnected with bars. The patients, in total 110, were at random treated and evaluated 3, 9 and 19 months after insertion of the implants. Six implants were lost out of 283 implants during the osseointegration period. There were hardly any differences found between the groups with respect to the clinical and radiologic parameters. De first group showed less bleeding around the implants after 19 months then the other groups. Around the medial implants there was significantly more bone resorption then around the distal implants and the implants in the other groups. No conclusions can be drawn with respect to the best treatment modality since the period of evaluation is too short and the other parameters like patients' experiences are not included.