Distribution of orthognathic surgery among the Swedish population: a retrospective register-based study.

OBJECTIVE: The aim of this study was to provide a nationally representative assessment of orthognathic procedures performed in hospitalised patients in Sweden and study regional differences in prevalence, demographic parameters and hospitalisation time. MATERIAL AND METHODS: From the Swedish National Board of Health and Welfare's register, all the patients undergoing orthognathic surgery between 2010 and 2014 were identified. Outcome variables were categorised into: (1) Surgical methods and regional distribution (2) Demographic variations (3) Hospitalisation time. RESULTS: The population-prevalence-rate of orthognathic procedures over the 5-year period was 6.3 (SD 0.4) per 100,000 persons, a regional difference in the prevalence was found. Most common were Le Fort I osteotomies (43.4%) and bilateral sagittal split osteotomies (41.6%), 39% of the patients had bimaxillary surgery. The majority of the surgery was performed in the age group 19-29 (68.8%). The mean hospital stay was 2.2 days (SD = 0.9, range 1.7-3.4). A significant regional difference (p ≤ 0.001) was found in hospitalisation time for single-jaw versus bimaxillary surgery. CONCLUSIONS: Regional differences in the distribution of orthognathic surgery and demographic variations were found in Sweden in 2010-2014. The underlying causes of variations are still unknown and request further investigation.

Inter-centre comparison of data on surgery and speech outcomes at 5 years of age based on the Swedish quality registry for patients born with cleft palate with or without cleft lip.

BACKGROUND: The objective of the Swedish cleft lip and palate registry (CLP registry) is to promote quality control, research and improvement of treatment, by the comparison of long-term results. The aim was to compare data from the CLP registry among the six treatment centres, regarding data on surgery and speech outcomes at 5 years of age. METHODS: The participants were 430 children born in Sweden from 2009 to 2014, with cleft palate with or without cleft lip and without known syndromes and/or additional malformations. The number of primary and secondary palatal surgeries up to 5 years of age, timing of the last primary palatal surgery, percentage consonants correct, percentage non-oral speech errors and perceived velopharyngeal competence at 5 years were assessed. Multivariable binary logistic regression adjusted for sex and cleft type was used to compare results between the six centres. RESULTS: At one centre (centre 4), the palate was closed in one to three stages, and at the remaining centres in one or two stages. At centre 4, more children underwent a higher number of palatal surgeries, and the last primary palatal surgery was performed at a higher age. Children in centre 4 were also less likely to achieve ≥86% correct consonants (OR = 0.169, P = < 0.001), have no non-oral speech errors (OR = 0.347, P = < 0.001), or have competent or marginally incompetent velopharyngeal competence (OR = 0.244, P = < 0.001), compared to the average results of the other centres. No clear association between patient volume and speech outcome was observed. CONCLUSIONS: The results indicated the risk of a negative speech result if the last primary palatal surgery was performed after 25 months of age. Whether the cleft in the palate was closed in one or two stages did not affect speech outcome. The Swedish CLP registry can be used for open comparisons of treatment results to provide the basis for improvements of treatment methods. If deviating negative results are seen consistently at one centre, this information should be acted upon by further investigation and analysis, making changes to the treatment protocol as needed.

Coverage, reporting degree and design of the Swedish quality registry for patients born with cleft lip and/or palate.

BACKGROUND: The objective of the Swedish cleft lip and palate (CLP) registry is to promote quality control, research and improvement of treatment, by comparison of the long-term results of surgery, orthodontics and speech from all six Swedish CLP centres. The purpose of the study was to investigate the coverage and reporting degree of the Swedish CLP registry, and to describe the design of the registry and discuss questions of reliability and validity of the data included. METHODS: All six Swedish CLP centres participate in the registry. All children in Sweden with cleft lip and/or cleft palate, born from 2009 onwards, are included in the registry. Baseline data such as cleft type (ICD-10 diagnosis), heredity, birth weight and additional deformities and/or syndromes, as well as pre-surgical treatment, are recorded at first visit. Data on surgical treatment are recorded continuously. Treatment outcome regarding dentofacial development and speech are recorded at follow-ups at 5, 10, 16 and 19 years of age. Data on dentofacial development are also recorded 1 year after orthognathic surgery. In addition, data on babbling and speech are recorded at 18 months of age. Coverage degree and reporting degree of surgery was assessed by comparison with registrations in the Swedish Central patient registry. Reporting degree of orthodontic and speech registrations at 5 years of age was assessed by comparison with registrations at baseline. RESULTS: The average coverage degree for children born 2009 to 2018 was 95.1%. For cleft-related surgeries, the average reporting degree was 92.4%. Average reporting degree of orthodontic registrations and speech registrations at age 5 years was 92 and 97.5% respectively. CONCLUSION: In order to achieve valid and reliable data in a healthcare quality registry, the degree of coverage and reporting needs to be high, the variables included should be limited and checked for reliability, and the professionals must calibrate themselves regularly. The Swedish CLP registry fulfils these requirements.

The pan-ErbB receptor tyrosine kinase inhibitor canertinib promotes apoptosis of malignant melanoma in vitro and displays anti-tumor activity in vivo.

The ErbB receptor family has been suggested to constitute a therapeutic target for tumor-specific treatment of malignant melanoma. Here we investigate the effect of the pan-ErbB tyrosine kinase inhibitor canertinib on cell growth and survival in human melanoma cells in vitro and in vivo. Canertinib significantly inhibited growth of cultured melanoma cells, RaH3 and RaH5, in a dose-dependent manner as determined by cell counting. Half-maximum growth inhibitory dose (IC(50)) was approximately 0.8 µM and by 5 µM both cell lines were completely growth-arrested within 72 h of treatment. Incubation of exponentially growing RaH3 and RaH5 with 1 µM canertinib accumulated the cells in the G(1)-phase of the cell cycle within 24h of treatment without induction of apoptosis as determined by flow cytometry. Immunoblot analysis showed that 1 µM canertinib inhibited ErbB1-3 receptor phosphorylation with a concomitant decrease of Akt-, Erk1/2- and Stat3 activity in both cell lines. In contrast to the cytostatic effect observed at doses ≤ 5µM canertinib, higher concentrations induced apoptosis as demonstrated by the Annexin V method and Western blot analysis of PARP cleavage. Furthermore, canertinib significantly inhibited growth of RaH3 and RaH5 melanoma xenografts in nude mice. Pharmacological targeting of the ErbB receptors may prove successful in the treatment of patients with metastatic melanoma.

The cleft lip evaluation profile (CLEP): a new approach for postoperative nasolabial assessment in patients with unilateral cleft lip and palate.

To assess the postoperative results after primary or secondary operation on unilateral cleft lip and nose, various methods have been published, in which qualitative methods are often based on the opinions of an expert panel and the quantitative methods are based on measurements of different landmarks of the lip and nose. Common problems with the present methods are the associated costs, based on the need for advanced techniques and expertise. Our cleft team now present a simplified, inexpensive, and reproducible protocol to evaluate the cosmetic and functional outcome after operations on the cleft lip and nose, together with the patients. Our protocol has been developed as a guideline to evaluate and score six variables of the lip and seven variables of the nose, including scars, projections of the lips and nose, volumes of the lip, and the alae and septum. The protocol contains series of three photographs of each of the variables that present a good postoperative result, an acceptable result, and finally a result with a clearly visible disfigurement. We also tested the reproducibility and validity of the protocol. Plastic surgeons with no knowledge of the index were approached twice and asked to assess a version with photographs in random order. The evaluation protocol is a simple and cost-effective tool for evaluation of the lip or nose, or both, among patients with repaired unilateral complete cleft lip.

ErbB receptor tyrosine kinases contribute to proliferation of malignant melanoma cells: inhibition by gefitinib (ZD1839).

Members of the epidermal growth factor (EGF) family of structurally related tyrosine kinase receptors, known as the ErbB receptors (EGFR/ErbB1/HER1, ErbB2/HER2/neu, ErbB3/HER3 and ErbB4/HER4) and their respective ligands, have been suggested to be involved in the development and progression of malignant melanoma. Here we investigate the effects of the ErbB1 tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) on human malignant melanoma cells (RaH3 and RaH5) in vitro. ZD1839 inhibited proliferation of exponentially growing RaH3 and RaH5 cells in a dose-dependent manner with a half-maximally effective dose of 3.5 and 2.0 micromol/l, respectively. Cell growth was inhibited at 0.1 micromol/l ZD1839 in both cell lines. Maximal inhibition was accomplished at 10 micromol/l ZD1839; however, the effect was not complete as both cell lines showed a continuous slow growth during the treatment period. Flow cytometry analysis of cell-cycle distribution showed that ZD1839 treatment caused accumulation of RaH3 and RaH5 cells in the G1 phase. The growth arrest induced by ZD1839 coincided with upregulation of the cyclin-dependent kinase inhibitor p27 KIP 1. There was no increase in apoptosis as determined by analysis of plasma phosphatidyl serine redistribution. Western blot analysis revealed that ZD1839 substantially reduced tyrosine phosphorylation of ErbB1 as well as ErbB2 and ErbB3. This was accompanied by a concomitant decrease in Akt-phosphorylation, Erk1/2-phosphorylation, and Stat3-phosphorylation. Our results show that ZD1839 interferes with the growth of human malignant melanoma cells by cytostatic effects. These findings indicate the possible use of ErbB receptor kinase inhibitors as a novel treatment strategy in malignant melanoma.

The nasal alar elevator: a new device that may reduce the need for primary operation of the nose in patients with cleft lip.

To improve the shape of the cleft lip nose preoperatively, we have developed the nasal alar elevator. This has been used routinely since 1996 on all our cleft lip patients who have an asymmetrical nose, from the first week after birth until the date of primary lip surgery. We present our 11-year-long experience of using the device on patients born with complete, unilateral cleft lip. In this study 56 children, born between 1996 and 2006 inclusive, with complete unilateral cleft lip, had preoperative treatment with the elevator. During this 11-year period, continuous evaluation during the preoperative period, and its effects on the cleft lip nose, were evaluated, both preoperatively and postoperatively. Our results show that the preoperative use of the device has led to less need for primary nasal surgery. Instead of having to have a primary rhinoplasty (McComb) together with a lip plasty, as a routine, now only about 30% of the patients need primary surgical correction of the nose. If nasal correction is needed, a rather limited undermining of skin over the ala on the cleft side will often be sufficient. The use of a nasal elevator reduces both the length and the extent of the primary intervention, without compromising the final result.

Sentinel node biopsy in malignant melanoma: Swedish experiences 1997-2005.

The sentinel node biopsy (SNB) procedure is a multidisciplinary technique, invented to gain prognostic information in different malignant tumors. The aim of the present study was to study the cohort of patients with malignant melanoma, operated with SNB, from the introduction of the technique in Sweden, concerning the prognostic information retrieved and the outcome of the procedures. In Sweden all patients with malignant melanoma are registered at regional Oncological Centers. From these databases ten centers were identified, treating malignant melanoma and performing sentinel node biopsy. Consecutive data concerning tumor characteristics, outcome of the procedure and disease related events during the follow-up time were collected from these ten centers. All cases from the very first in each centre were included. The SNB procedure was performed in 422 patients with a sentinel node (SN) detection rate of 97%, the mean Breslow thickness of the primary tumors was 3.2 mm (median 2.4 mm) and the proportion of ulcerated melanomas 38%. Metastasis in the SN was found in 19% of the patients but there was a wide range in the proportion of SN metastases between the different centers (5-52%). After a follow-up of median 12 months of 361 patients, SN negative patients had better disease-free survival than SN positive (p<0.0001). A false negative rate of 14% was found during the follow-up time. In this study the surgical technique seemed acceptable, but the non-centralized pathology work-up sub-optimal. However, SNB was still found to be a significant prognostic indicator, concerning disease free survival.

Serotonin kinetics in patients with burn injuries: a comparison between the local and systemic responses measured by microdialysis-a pilot study.

OBJECTIVES: To investigate serotonin (5HT) locally in burned and uninjured skin (intracutaneous) by microdialysis, and simultaneously record urinary and blood values in the same subjects. For comparison, serotonin values were also measured in skin of healthy controls. DESIGN AND SETTING: An experimental study in burned patients with of more than 25% TBSA (total burn surface area) % in an 8-bed tertiary burns unit, serving about 3.5 million persons. PATIENTS AND METHODS: Six subjects with a median TBSA% of 59% (range 33.5-90), and five healthy controls were examined by intracutaneous microdialysis of the skin. RESULTS: 5HT was increased in burned patients, compared with controls. This increase was tenfold in skin and was noted both in uninjured and burned skin. The highest values were recorded on day 1 (median 16.1nmol in uninjured and 9.5nmol in burned skin) and day 2 (15.6nmol in uninjured and 13.4nmol in burned skin). A rapid reduction was noted on day 3 (4.9nmol in uninjured and 3.8nmol in burned skin). The corresponding value for control subjects was 1.3nmol. The 5HT in blood was twice normal on day 2, and gradually reduced on days 3 and 4 (3189, 3035 and 2573nmol, respectively). Urinary 5HT concentrations were increased only on day 2 at 1755nmol and thereafter returned to the normal range on days 3 and 4 (1248 and 1344nmol, respectively). CONCLUSIONS: We showed that microdialysis may be used in the critical care of burns, and local skin serotonin concentrations examined continuously for several days. The findings of significantly raised tissue serotonin concentrations, compared to that in blood and urine, suggests that serotonin may be important in local vascular control and formation of oedema.

Autocrine production of biologically active hepatocyte growth factor (HGF) by injured human skin.

BACKGROUND: Hepatocyte growth factor (HGF) is a potent regenerative factor involved in wound healing. Previous studies have shown that mesenchymal cells produce HGF, stimulating epithelial cells in a paracrine fashion. OBJECTIVE: To examine whether autocrine HGF production by keratinocytes can occur upon skin injury. METHODS: A 31-year-old male patient sustained a burn affecting 80% of his total body surface area. Biopsies were taken from intact skin near the injured area, and skin keratinocytes were separated and cultured. Conditioned medium from keratinocytes was analyzed for HGF by ELISA, surface plasmon resonance (SPR), and dot blotting. Binding of HGF from conditioned medium to its receptor, c-Met, was compared with recombinant HGF by SPR. Finally, we examined the motogenic effect on mouse transformed skin epithelial cells (CCL-53.1) of HGF from conditioned medium. RESULTS: HGF was detected in the cultured keratinocyte medium. Similar to recombinant HGF, HGF from conditioned medium had a high affinity for dextran sulfate and albumin, and the same epitopes were engaged by the interaction of HGF with the c-Met receptor. The conditioned medium from keratinocytes obtained from the burn patient, but not medium from keratinocytes obtained from healthy volunteers, accelerated the motogenesis of CCL-53.1 cells. Unexpectedly, anti-HGF antibodies did not prevent this effect. However, anti-c-Met antibodies completely inhibited the motogenic effect. CONCLUSION: Upon injury, human skin keratinocytes might produce biologically active HGF in an autocrine fashion. This HGF might have different structural and/or biological properties from HGF produced by mesenchymal cells.

Bcl-2 expression in metastatic malignant melanoma. Importance for the therapeutic efficacy of biochemotherapy.

For the majority of patients with metastatic malignant melanoma the prognosis is poor. Immunotherapy and biochemotherapy have shown promise with a subset of durable responses, but there is still a great need for a better understanding of the mechanisms of action during treatment to optimize future treatment schedules. In the present study Bcl-2 expression was studied in biopsies from ten patients with metastatic malignant melanoma (five with regional disease and five with systemic disease) treated with biochemotherapy (cisplatinum 30 mg/m2 days 1-3, DTIC 250 mg/m2 days 1-3 i.v. and Interferon-alpha2b 10 MIU s.c. 3 days a week, on a 28-day cycle). The expression of Bcl-2 by the tumour cells was separately recorded in areas of histopathological regressive changes and in areas of unaffected tumour growth. Comparisons were made with biopsies from 14 untreated patients. In 10 of 10 treated patients a high expression of Bcl-2 by the tumour cells was found in areas of unaffected tumour growth. In contrast, only in 5 of 13 untreated patients was a high expression of Bcl-2 by the tumour cells found in these areas ( P=0.008). A significant difference was also found in the expression of Bcl-2 by the tumour cells between areas of unaffected tumour growth and areas of histopathological regressive changes ( P=0.03). The significantly higher expression of Bcl-2 by the tumour cells in areas of unaffected tumour growth in treated patients compared to untreated patients indicates that clones with a high expression of Bcl-2 may be present after therapy, preventing apoptosis and eventually in many patients resulting in progressive disease. Supporting this concept, a difference was also found between the expression of Bcl-2 in areas of unaffected tumour growth, i.e. in areas of treatment failure, and the expression in areas of histopathological regressive changes. Thus immunohistochemical analysis of tumour biopsies shortly after therapy seems to be a good surrogate endpoint that allows a detailed analysis of Bcl-2 expression. The high expression of Bcl-2 shown in unaffected tumour areas after therapy suggests the need for additional treatment, e.g. Bcl-2 antisense therapy.