The Development of a European Multidisciplinary Cleft Lip and Palate Registry by the European Reference Network CRANIO: Experiences, Barriers, And Facilitators.

The European Reference Network for Rare Craniofacial Aanomalies and Ear-Nose-Throat disorders aims to improve care for patients with such afflictions, including cleft lip and palate (CL/P) across Europe. Cleft treatment remains varied throughout European centers, inhibiting meaningful comparison of treatment outcomes. To overcome these issues, a European-wide common CL/P dataset and registry was developed, facilitating standardized treatment endpoints and outcome measures for international comparison and benchmarking of CL/P centers. Questionnaires and semi-structured interviews were used to determine the set-up of the registry. Previous CL/P initiatives were analyzed to create an initial dataset, refined through consensus meetings. In total, 87 cleft specialists working in specialized CL/P centers from 16 European nations participated. Consensus on a common dataset was reached. A "Level 1" dataset, with mandatory clinical and patient-reported outcome measures, and "Level 2" dataset with additional outcome measures. Finally, 2 dashboards were developed for data dissemination. The development of the European CL/P common dataset and registry tackled challenges with resource disparities, variations in specialists within CL/P teams, regulatory differences in patient data usage, patient-reported outcome measures availability in European languages, and use of assessment tools. This study described the successful development of the European Reference Network for Rare Craniofacial Aanomalies and Ear-Nose-Throat disorders CL/P common dataset and registry. This achievement will help improve patient care and outcomes for patients with CL/P in Europe. Furthermore, this study provides useful information for initiatives with similar aims.

Patient Reported Outcome Following the Skoog Unilateral Cleft Lip Repair among Adults- a Long-Term Cohort Study and Comparison to a Non-cleft Population.

OBJECTIVE: The study primarily aimed to compare satisfaction with lip appearance among adults treated for unilateral cleft lip and palate (UCLP) with Skoog's primary lip repair procedure to those without clefts. The secondary aim was to determine whether satisfaction with lip appearance and the desire to change the lip/face appearance correlated with the number of secondary lip revisions performed. DESIGN: Long-term follow-up. PATIENTS/SETTINGS: All UCLP patients treated at the Uppsala University Hospital born between 1960- and 1987 (n = 109) were invited. At an average of 37 years following the primary lip repair, the participation rate was 76% (n = 83). A control group of adults without cleft (n = 67) completed the same study protocol for comparison. MAIN OUTCOME MEASURES: Satisfaction with appearance was measured with The Satisfaction with Appearance Questionnaire (SWA) and a modified version of the Body Cathexis -Scale was used to assess the desire to change the lip and facial appearance. RESULTS: UCLP patients were less satisfied with their lip, face, and overall appearance and reported a greater desire to change the appearance of their lips and face than non-cleft controls (p < 0.001). Dissatisfaction with lip appearance correlated to a greater willingness to change the appearance of the lip and face. No correlation was found between satisfaction with appearance and the number of the previously performed secondary lip revisions. CONCLUSION: Adults treated for UCLP are less satisfied with the appearance of their lips compared to the non-cleft population. The number of secondary revisions does not necessarily correlate to greater satisfaction with lip appearance.

Longitudinal data on speech outcomes in internationally adopted children compared with non-adopted children with cleft lip and palate.

BACKGROUND: At the beginning of the 21st century, international adoptions of children with cleft lip and/or palate increased dramatically in Sweden. Many children arrived partially or totally unoperated, despite being at an age when palatoplasty has usually been performed. To date, the speech development of internationally adopted (IA) children has been described up to age 7-8 years, but later development remains unstudied. AIMS: To investigate speech development between ages 5 and 10 years in children born with cleft lip and palate (CLP) adopted from China and to compare them with non-adopted (NA) children with CLP. A secondary aim was to compare the frequencies of secondary palatal surgery and number of visits to a speech and language pathologist (SLP) between the groups. METHODS & PROCEDURES: In a longitudinal study, 23 IA children from China were included and matched with 23 NA children born in Sweden. Experienced SLPs blindly reassessed audio recordings from routine follow-ups at ages 5 and 10 years. Velopharyngeal function (VPF) was assessed with the composite score for velopharyngeal competence (VPC-Sum) for single words and rated on a three-point scale (VPC-Rate) in sentence repetition. Target sounds in words and sentences were phonetically transcribed. Per cent correct consonants (PCC) were calculated at word and sentence levels. For in-depth analyses, articulation errors were divided into cleft speech characteristics (CSCs), developmental speech characteristics (DSCs) and s-errors. Information on secondary palatal surgery and number of visits to an SLP was collected. OUTCOMES & RESULTS: VPF differed significantly between the groups at both ages when assessed with VPC-Sum, but not with VPC-Rate. Regardless of the method for assessing VPF, a similar proportion in both groups had incompetent VPF but fewer IA than NA children had competent VPF at both ages. IA children had lower PCC at both ages at both word and sentence levels. More IA children had CSCs, DSCs and s-errors at age 5 years, and CSCs and s-errors at age 10. The development of PCC was significant in both groups between ages 5 and 10 years. The proportion of children receiving secondary palatal surgery did not differ significantly between the groups, nor did number of SLP visits. CONCLUSIONS & IMPLICATIONS: CSCs were more persistent in IA children than in NA children at age 10 years. Interventions should target both cleft and DSCs, be comprehensive and continue past the pre-school years. WHAT THIS PAPER ADDS: What is already known on this subject At the beginning of the 21st century, IA children with cleft lip and/or palate arrived in Sweden partially or totally unoperated, despite being at an age when palatoplasty has usually been performed. Studies up to age 7-8 years show that adopted children, compared with NA peers, have poorer articulation skills, demonstrate both cleft-related and developmental articulation errors, and are more likely to have velopharyngeal incompetence. Several studies also report that adopted children more often require secondary palatal surgery due to fistulas, dehiscence or velopharyngeal incompetence compared with NA peers. What this paper adds to existing knowledge This longitudinal study provides additional knowledge based on longer follow-ups than previous studies. It shows that the proportion of children assessed to have incompetent VPF was similar among IA and NA children. It was no significant difference between the groups regarding the proportion that received secondary palatal surgery. However, fewer IA children were assessed to have a competent VPF. Developmental articulation errors have ceased in most IA and all NA children at age 10 years, but significantly more adopted children than NA children still have cleft-related articulation errors. What are the potential or actual clinical implications of this work? Speech and language therapy should target both cleft-related and developmental articulation errors. When needed, treatment must be initiated early, comprehensive, and continued past the pre-school years, not least for adopted children.

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.

Greater Palatal Cleft Width Predicts an Increased Risk for Unfavorable Outcomes in Cleft Palate Repair.

OBJECTIVE: To investigate the impact of cleft width and cleft type on the need for secondary surgery and velopharyngeal competence from a longitudinal perspective. DESIGN: Retrospective, longitudinal study. SETTING: A single multidisciplinary craniofacial team at a university hospital. PATIENTS: Consecutive patients with unilateral or bilateral cleft lip and palate and cleft palate only (n = 313) born from 1984 to 2002, treated with 2-stage palatal surgery, were reviewed. A total of 213 patients were included. MAIN OUTCOME MEASURES: The impact of initial cleft width and cleft type on secondary surgery. Assessment of hypernasality, audible nasal emission, and glottal articulation from routine follow-ups from 3 to 16 years of age. The assessments were compared with reassessments of 10% of the recordings. RESULTS: Cleft width, but not cleft type, predicted the need for secondary surgery, either due to palatal dehiscence or velopharyngeal insufficiency. The distribution of cleft width between the scale steps on a 4-point scale for hypernasality and audible nasal emission differed significantly at 5 years of age but not at any other age. Presence of glottal articulation differed significantly at 3 and 5 years of age. No differences between cleft types were seen at any age for any speech variable. CONCLUSIONS: Cleft width emerged as a predictor of the need for secondary surgery as well as more deviance in speech variables related to velopharyngeal competence during the preschool years. Cleft type was not related to the need for secondary surgery nor speech outcome at any age.

Proboscis Lateralis: A Novel Surgical Technique Using Tape Elongation and One-Stage Tunneling.

ABSTRACT: Proboscis lateralis is a rare craniofacial anomaly characterized by a tubular, trunk-like appendage, often arising from the medial canthal region. It can occur in isolation or in association with a variety of other anomalies. Several treatment options have been described depending on the characteristics of the defect, but due to its infrequency, the body of knowledge is limited. Here, the authors present a case of proboscis lateralis in an 18-month-old girl, being successfully treated with a novel technique including tape elongation and a 1 stage tunneling procedure.

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.

Dr. Tillman et al. Reply.

We read with interest the commentary of Dr. Zablow1 on our publication on neurodevelopmental disorders and orofacial clefts (OFC).2.

Increased Risk for Neurodevelopmental Disorders in Children With Orofacial Clefts.

OBJECTIVE: Children with orofacial clefts (OFC) may have an increased risk of poor mental health. This study aimed to investigate the risk of psychiatric diagnoses in individuals with OFC, stratified by cleft type. METHOD: A nationwide register-based cohort of all individuals born with nonsyndromic OFC in Sweden between 1973 and 2012 (n = 7,842) was compared to a matched cohort (n = 78,409) as well as to their unaffected siblings (n = 9,637). The risk of psychiatric diagnoses, suicide attempts, and suicides was examined by crude and adjusted Cox regression models. Effect modification by sex was investigated with interaction terms in the models. RESULTS: Children with cleft lip (CL) had a significantly higher risk of any psychiatric disorder, intellectual disability, and language disorders; children with cleft lip and palate (CLP) had, in addition, an increased risk of autism spectrum disorder (ASD). Children with cleft palate only (CPO) had risk increases for the same diagnoses as children with CL and CLP, but with higher hazard ratios, and also for psychotic disorders, attention-deficit/hyperactivity disorder (ADHD), and other behavioral or emotional disorders in childhood. Sex stratification indicated higher risk increases among females in CL and CLP but not in CPO. Siblings without OFC were less likely to be diagnosed with any psychiatric disorder, intellectual disability, language disorder, ASD, or ADHD compared to their siblings with OFC. CONCLUSION: Children with nonsyndromic clefts had a significantly higher risk of neurodevelopmental disorders. This risk is unlikely to be explained by familial influences such as inherited genetic or shared environmental factors.

The Skoog Lip Repair for Unilateral Cleft Lip Deformity: The Uppsala Experience.

BACKGROUND: The Uppsala Craniofacial Center has been treating patients with unilateral cleft lip deformity using the lip repair technique described by Tord Skoog. The aim of this study was to determine complications after lip surgery and the incidence and indications for lip revisions in all patients born with unilateral cleft lip from 1960 to 2004. METHODS: All patients who were born from 1960 to 2004 with unilateral cleft lip, cleft lip and alveolus, or cleft lip and palate and underwent lip repair were studied retrospectively. The timing, indication, complications of the primary procedure, and type of secondary surgery were recorded. Kruskal-Wallis and Fisher's exact tests were used, with Bonferroni correction. RESULTS: The study included 443 patients. The total rate of early surgical complications was 6 percent (n = 26). Secondary surgery for short upper lip was performed in 3.8 percent (n = 17), 8.4 percent (n = 37) underwent reduction of excess vermillion, 8.6 percent (n = 38) underwent scar revision, 11 percent (n = 51) underwent revision for incongruent vermillion-cutaneous border, and 10 percent (n = 45) underwent revision for other indications. Altogether, 45 percent had no secondary revisions. CONCLUSION: In conclusion, the Skoog lip repair is associated with a low total revision rate, and a short-lip deformity is rare. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Secondary Alveolar Bone Grafting in Patients Born With Unilateral Cleft Lip and Palate: A 20-Year Follow-up.

OBJECTIVE: To identify factors of oral health important for the final outcome, after secondary alveolar bone grafting in patients born with unilateral cleft lip and palate and compare occlusal radiographs with cone beam computed tomography (CBCT) in assessment of alveolar bone height. DESIGN: Observational follow-up study. SETTING: Cleft Lip and Palate Team, Craniofacial Center, Uppsala University Hospital, Sweden. PATIENTS: 40 nonsyndromic, Caucasian patients with unilateral complete cleft lip and palate. INTERVENTIONS: Clinical examination, CBCT, and occlusal radiographs. MAIN OUTCOME MEASUREMENTS: Alveolar bone height was evaluated according to Bergland index at a 20-year follow-up. RESULTS: The alveolar bone height in the cleft area was significantly reduced compared to a previously reported 10-year follow-up in the same cohort by total ( P = .045) and by subgroup with dental restoration ( P = .0078). This was positively correlated with the gingival bleeding index (GBI) ( r = 0.51, P = .0008) and presence of dental restorations in the cleft area ( r = 0.45, P = .0170). There was no difference in the Bergland index generated from scoring the alveolar bone height on occlusal radiographs as with the equivalent index on CBCT. CONCLUSION: Patients rehabilitated with complex dental restoration seems to be at higher risk for progression of bone loss in the cleft area. Supportive periodontal therapy should be implemented after complex dental restorations in cleft patients. Conventional occlusal radiographs provide an adequate image for evaluating postoperative bone height in clinical follow-up.

Skoog Primary Periosteoplasty versus Secondary Alveolar Bone Grafting in Unilateral Cleft Lip and Alveolus: Long-Term Effects on Alveolar Bone Formation and Maxillary Growth.

BACKGROUND: Clefts involving the alveolus are treated using one of two strategies: primary periosteoplasty at the time of lip repair or secondary alveolar bone grafting at mixed dentition. Most teams favor secondary alveolar bone grafting because of its high success rate, and concerns have been raised that primary periosteoplasty may interfere with maxillary growth. However, primary periosteoplasty may obviate the need for future bone grafting and is still practiced in some centers. Few studies compare the long-term outcomes of these two strategies. METHODS: Fifty-seven consecutive patients born with unilateral cleft lip and alveolus were studied retrospectively. All patients underwent primary lip repair using Skoog's method; 28 patients underwent primary periosteoplasty at the time of lip repair and the remaining 29 underwent secondary alveolar bone grafting at mixed dentition. Occlusal radiographs obtained at ages 10 and 16 years were analyzed for alveolar bone height. Cephalometric analysis assessed growth at ages 5, 10, and 18 years. RESULTS: Seventeen of 28 patients treated using primary periosteoplasty required later secondary bone grafting, and the bone height at age 16 years was lower in the primary periosteoplasty group (p < 0.0001). There was a more pronounced decrease in maxillary protrusion from ages 5 to 10 years in the primary periosteoplasty group (p < 0.03). However, at age 18 there was no significant difference in maxillary growth between the two groups. CONCLUSION: Primary periosteoplasty did not seem to inhibit long-term maxillary growth but was ineffective as a method of reconstructing the alveolar cleft. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Normal Oral Keratinocytes and Head and Neck Squamous Carcinoma Cells Induce an Innate Response of Fibroblasts.

BACKGROUND: Tumor stroma is similar to the connective tissue of chronic inflammation. The extracellular matrix of tumors is formed by cancer-associated fibroblasts that also modulate the inflammatory response. MATERIALS AND METHODS: We studied the ability of oral keratinocytes (NOK) and oral squamous cell carcinoma cells (SCC) to induce an innate immune response in fibroblasts. Co-cultures with fibroblasts in collagen gels and keratinocytes in inserts were used. Pentraxin 3 (PTX3) was used as an indicator of an innate immune response. RESULTS: SCC and NOK up-regulated fibroblast mRNA expression and protein release of PTX3. mRNA levels were more pronounced in cultures with malignant cells. The induction of PTX3 was abrogated by an interleukin-1 receptor antagonist CONCLUSION: Keratinocytes have the capacity to induce an interleukin-1-dependent innate immune response by fibroblasts in vitro. This could be important for subsequent fibroblast modulation of the inflammatory reaction in non-malignant and malignant disease processes.

Correlations between initial cleft size and dental anomalies in unilateral cleft lip and palate patients after alveolar bone grafting.

Objective To determine in individuals with unilateral cleft lip and palate the correlation between initial cleft size and dental anomalies, and the outcome of alveolar bone grafting. Methods A total of 67 consecutive patients with non-syndromic unilateral complete cleft lip and palate (UCLP) were included from the cleft lip and palate-craniofacial center, Uppsala University Hospital, Sweden. All patients were operated by the same surgeon and treated according to the Uppsala protocol entailing: lip plasty at 3 months, soft palate closure at 6 months, closure of the residual cleft in the hard palate at 2 years of age, and secondary alveolar bone grafting (SABG) prior to the eruption of the permanent canine. Cleft size was measured on dental casts obtained at the time of primary lip plasty. Dental anomalies were registered on radiographs and dental casts obtained before bone grafting. Alveolar bone height was evaluated with the Modified Bergland Index (mBI) at 1 and 10-year follow-up. Results Anterior cleft width correlated positively with enamel hypoplasia and rotation of the central incisor adjacent to the cleft. There was, however, no correlation between initial cleft width and alveolar bone height at either 1 or 10 years follow-up. Conclusions Wider clefts did not seem to have an impact on the success of secondary alveolar bone grafting but appeared to be associated with a higher degree of some dental anomalies. This finding may have implications for patient counseling and treatment planning.

Differential Gene Regulation in Fibroblasts in Co-culture with Keratinocytes and Head and Neck SCC Cells.

BACKGROUND: While carcinoma-associated fibroblasts (CAFs) support tumorigenesis, normal tissue fibroblasts suppress tumor progression. Mechanisms behind conversion of fibroblasts into a CAF phenotype are largely unrevealed. MATERIALS AND METHODS: Transwell co-cultures with fibroblasts in collagen gels and squamous-cell carcinoma (SCC) cells or normal oral keratinocytes (NOKs) in inserts. Differences in fibroblast global gene expression were analyzed using Affymetrix arrays and subsequent functional annotation and cluster analysis, as well as gene set enrichment analysis were performed. RESULTS: There were 52 up-regulated and 30 down-regulated transcript IDs (>2-fold, p<0.05) in fibroblasts co-cultured with SCC compared to NOKs. Functional analysis demonstrated an enrichment of collagen-related genes. There were similarities with gene sets reflecting a non-specific, innate-type response with activation of both interferon pathways and connective tissue turnover. CONCLUSION: There were distinct differences in fibroblast gene expression between the co-culture types. Many were in genes related to an innate-type of response and to connective tissue turnover.

Optimization of dental status improves long-term outcome after alveolar bone grafting in unilateral cleft lip and palate.

Objective : To evaluate the importance of dental status for long-term outcome after alveolar bone grafting in patients with unilateral cleft lip and palate. Design : Retrospective longitudinal study. Setting : Cleft lip and palate-craniofacial center, Uppsala University Hospital, Sweden. Patients : A total of 67 consecutive patients with unilateral complete cleft lip and palate. Interventions : Secondary alveolar bone grafting, prior to the eruption of the permanent canine, was performed at the average age of 10.0 years (range, 8.5 to 12.0 years). Main Outcome Measures : Alveolar bone height was evaluated with the modified Bergland index at 1 and 10 years after surgery. Results : Of the patients, 97% had modified Bergland index grade I and the remaining 3% had modified Bergland index grade II at 1 year after surgery. At 10 years' follow-up, 43% showed modified Bergland index grade I; 55%, modified Bergland index grade II; and 2% (one patient), modified Bergland index grade III. The degree of dental anomalies in the cleft area, such as enamel hypoplasia, incisor rotation, incisor inclination, canine inclination, and oral hygiene registered preoperatively, all correlated negatively to the modified Bergland index at 10 years after surgery. Enamel hypoplasia (ρ = 0.70195, P < .0001), followed by canine inclination (ρ = 0.55429, P < .0001), showed the strongest correlation to reduced bone height in the cleft area. Conclusions : In patients with unilateral cleft lip and palate, excellent results from secondary alveolar bone grafting in terms of bone height in the alveolar cleft tend to decrease with time. This seems to be correlated with factors that might to some extent be treated preoperatively through adequate planning and execution of the orthodontic treatment.

Keratinocytes and head and neck squamous cell carcinoma cells regulate urokinase-type plasminogen activator and plasminogen activator inhibitor-1 in fibroblasts.

BACKGROUND: To investigate possible differences in the effects of soluble factors from oral squamous cell carcinoma (SCC) cells (UT-SCC-87) and normal oral keratinocytes (NOK) on fibroblast expression of genes involved in tumor stroma turnover. MATERIALS AND METHODS: Transwell co-cultures with fibroblasts in collagen gels, and SCC cells or NOK in inserts were carried out. Fibroblast gene expression was measured with real-time polymerase chain reaction (PCR). RESULTS: The expression of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) was up-regulated in co-cultures with SCC cells but not with NOK. In contrast, both SCC cells and NOK regulated matrix metalloproteinase-1 (MMP1) and -3, and tissue inhibitor of metalloproteinases-2 (TIMP2) and -3 to a similar extent, while MMP2 and TIMP1 were largely unaffected. Interleukin 1 alpha (IL1α) up-regulated both MMP1 and MMP3 and down-regulated PAI-1, TIMP2 and -3. CONCLUSION: SCC and NOK regulate fibroblast expression of genes involved in tumor stroma turnover differentially in vitro. These observations may contribute to a better understanding of the mechanisms behind extracellular matrix turnover in tumors.

Interleukin-1-mediated effects of normal oral keratinocytes and head and neck squamous carcinoma cells on extracellular matrix related gene expression in fibroblasts.

OBJECTIVES: The composition of tumor stroma and the activity of tumor associated fibroblasts are important for tumor growth. Interactions between carcinoma cells and fibroblasts regulate the turnover of extracellular matrix (ECM). Here, the in vitro effects of oral squamous cell carcinoma (SCC) cells (UT-SCC-30 and UT-SCC-87) on fibroblast expression of genes for ECM components and connective tissue growth factor (CTGF/CCN2), were compared to those of normal oral keratinocytes (NOK). MATERIALS AND METHODS: Cocultures with fibroblasts in collagen gels and keratinocytes with the two cell types separated by a semi permeable membrane were used, and relative gene expression was measured with real-time PCR. RESULTS: All investigated genes were regulated by NOK and the SCCs. The downregulation of pro-collagens α1(I) and α1(III) was more pronounced in cocultures with NOK, while the expression of CCN2 and fibronectin was downregulated by both NOK and the SCCs to a similar extent. UT-SCC-87, but not UT-SCC-30, secreted significantly more IL-1α than NOK. A recombinant interleukin-1 receptor antagonist reversed many of the observed effects on fibroblast gene expression suggesting involvement of IL-1 in cocultures with NOK as well as with SCCs. CONCLUSION: The observed differential effects on fibroblast gene expression suggest that NOK are more antifibrotic compared to UT-SCC-30 and UT-SCC-87. These findings may contribute to a better understanding of the mechanisms behind ECM turnover in tumors.

Early release of interalveolar synechiae under general anesthesia through fiberscopic nasal intubation.

This article presents a treatment strategy for early release of interalveolar synechiae, aiming to facilitate early oral feeding and prevent temporomandibular joint ankylosis.The treatment results of 2 patients with van der Woude syndrome were retrospectively studied. Both patients underwent early surgical release of interalveolar synechiae under general anesthesia through fiberscopic nasal intubation. The 2 patients were treated at the ages of 6 and 14 days, respectively. The interincisival distances increased from 5 and 6 mm preoperatively to 11 and 10 mm immediately after surgery. This was increased further to 25 and 20 mm at long-term follow-up (6 and 24 months).In conclusion, synechiae between the upper and lower jaws can be safely treated at a very early age under general anesthesia with fiberscopic nasotracheal intubation. The purpose of early intervention in these cases is to facilitate oral feeding and prevent temporomandibular joint ankylosis.

Regulation of fibroblast gene expression by keratinocytes in organotypic skin culture provides possible mechanisms for the antifibrotic effect of reepithelialization.

To investigate the mechanisms behind the antifibrotic effect associated with epidermal regeneration, the expression of 12 fibroblast genes important for the modulation of the extracellular matrix (ECM), as well as α-smooth muscle actin, was studied in a keratinocyte-fibroblast organotypic skin culture model. The study was performed over time during epidermal generation and in the presence or absence of the profibrotic factor transforming growth factor-ß. the Presence of epidermal differentiation markers in the model was essentially coherent with that of native skin. Fibroblast gene expression was analyzed with real-time polymerase chain reaction after removal of the epidermal layer. After 2 days of air-exposed culture, 11 out of the 13 genes studied were significantly regulated by keratinocytes in the absence or presence of transforming growth factor-ß. The regulation of connective tissue growth factor, collagen I and III, fibronectin, plasmin system regulators, matrix metalloproteinases and their inhibitors as well as α-smooth muscle actin was consistent with a suppression of ECM formation or contraction. Overall, the results support a view that keratinocytes regulate fibroblasts to act catabolically on the ECM in epithelialization processes. This provides possible mechanisms for the clinical observations that reepithelialization and epidermal wound coverage counteract excessive scar formation.