[Safety and Effectiveness of Zykadia® in Patients with ALK-Positive Non-Small Cell Lung Cancer-A Report of Post- Marketing Surveillance].

We conducted a post-marketing surveillance of Zykadia® in patients with ALK-positive unresectable, advanced or recurrent non-small cell lung cancer. There were 573 patients included in the safety analysis, of which 54.62% were female, and their mean age was 59.9 years. Overall, 473 patients(82.55%)experienced side effects, which were mainly diarrhea in 43.46%, nausea in 34.38%, vomiting in 18.67%, and hepatic dysfunction in 16.40%. Side effects led to treatment discontinuation in 24.78%. Among 455 patients included in the efficacy analysis, the response rate was 30.99%. The median progression- free survival was approximately 4 months. The safety and efficacy were similar to those of previous reports, and this study confirmed that there are no problems requiring additional precautions in clinical use of Zykadia®.

Elasmobranch genome sequencing reveals evolutionary trends of vertebrate karyotype organization.

Genomic studies of vertebrate chromosome evolution have long been hindered by the scarcity of chromosome-scale DNA sequences of some key taxa. One of those limiting taxa has been the elasmobranchs (sharks and rays), which harbor species often with numerous chromosomes and enlarged genomes. Here, we report the chromosome-scale genome assembly for the zebra shark Stegostoma tigrinum, an endangered species that has a relatively small genome among sharks (3.71 Gb), as well as for the whale shark Rhincodon typus Our analysis using a male-female comparison identified an X Chromosome, the first genomically characterized shark sex chromosome. The X Chromosome harbors the Hox C cluster whose intact linkage has not been shown for an elasmobranch fish. The sequenced shark genomes show a gradualism of chromosome length with remarkable length-dependent characteristics-shorter chromosomes tend to have higher GC content, gene density, synonymous substitution rate, and simple tandem repeat content as well as smaller gene length and lower interspersed repeat content. We challenge the traditional binary classification of karyotypes as with and without so-called microchromosomes. Even without microchromosomes, the length-dependent characteristics persist widely in nonmammalian vertebrates. Our investigation of elasmobranch karyotypes underpins their unique characteristics and provides clues for understanding how vertebrate karyotypes accommodate intragenomic heterogeneity to realize a complex readout. It also paves the way to dissecting more genomes with variable sizes to be sequenced at high quality.

Whale shark rhodopsin adapted to deep-sea lifestyle by a substitution associated with human disease.

Spectral tuning of visual pigments often facilitates adaptation to new environments, and it is intriguing to study the visual ecology of pelagic sharks with secondarily expanded habitats. The whale shark, which dives into the deep sea of nearly 2,000 meters besides near-surface filter feeding, was previously shown to possess the 'blue-shifted' rhodopsin (RHO), which is a signature of deep-sea adaptation. In this study, our spectroscopy of recombinant whale shark RHO mutants revealed that this blue shift is caused dominantly by an unprecedented spectral tuning site 94. In humans, the mutation at the site causes congenital stationary night blindness (CSNB) by reducing the thermal stability of RHO. Similarly, the RHO of deep-diving whale shark has reduced thermal stability, which was experimentally shown to be achieved by site 178 and 94. RHOs having the natural substitution at site 94 are also found in some Antarctic fishes, suggesting that the blue shift by the substitution at the CSNB site associated with the reduction in thermal stability might be allowed in cold-water deep-sea habitats.

Squalomix: shark and ray genome analysis consortium and its data sharing platform.

The taxon Elasmobranchii (sharks and rays) contains one of the long-established evolutionary lineages of vertebrates with a tantalizing collection of species occupying critical aquatic habitats. To overcome the current limitation in molecular resources, we launched the Squalomix Consortium in 2020 to promote a genome-wide array of molecular approaches, specifically targeting shark and ray species. Among the various bottlenecks in working with elasmobranchs are their elusiveness and low fecundity as well as the large and highly repetitive genomes. Their peculiar body fluid composition has also hindered the establishment of methods to perform routine cell culturing required for their karyotyping. In the Squalomix consortium, these obstacles are expected to be solved through a combination of in-house cytological techniques including karyotyping of cultured cells, chromatin preparation for Hi-C data acquisition, and high fidelity long-read sequencing. The resources and products obtained in this consortium, including genome and transcriptome sequences, a genome browser powered by JBrowse2 to visualize sequence alignments, and comprehensive matrices of gene expression profiles for selected species are accessible through https://github.com/Squalomix/info.

Technical considerations in Hi-C scaffolding and evaluation of chromosome-scale genome assemblies.

The recent development of ecological studies has been fueled by the introduction of massive information based on chromosome-scale genome sequences, even for species for which genetic linkage is not accessible. This was enabled mainly by the application of Hi-C, a method for genome-wide chromosome conformation capture that was originally developed for investigating the long-range interaction of chromatins. Performing genomic scaffolding using Hi-C data is highly resource-demanding and employs elaborate laboratory steps for sample preparation. It starts with building a primary genome sequence assembly as an input, which is followed by computation for genome scaffolding using Hi-C data, requiring careful validation. This article presents technical considerations for obtaining optimal Hi-C scaffolding results and provides a test case of its application to a reptile species, the Madagascar ground gecko (Paroedura picta). Among the metrics that are frequently used for evaluating scaffolding results, we investigate the validity of the completeness assessment of chromosome-scale genome assemblies using single-copy reference orthologues.

Visual and nonvisual opsin genes of sharks and other nonosteichthyan vertebrates: Genomic exploration of underwater photoreception.

Vision of sharks embraces various biological and ecological themes ranging from predation and adaptation to deep-sea life. However, behavioural and genetic studies have been limited by their elusive lifestyles, repeatedly reported declines of wild populations, and their unique life-history traits including low fecundity and enhanced longevity. Sharks have also not been actively studied on the cellular and molecular levels, because of additional difficulties in cell culture, tissue collection and genome sequencing. A recent study circumvented some of these obstacles by means of genome informatics thereby portrayed the variation of visual opsin gene repertoires among elasmobranchs (sharks and rays) and spectral shifts of the rhodopsin pigment. Comprehensive surveys in whole-genome sequences are also revealing the repertoires of nonvisual opsins with unknown functions. This review is aimed to summarize existing studies on shark opsins with an emphasis on genomic investigation of gene repertoires and to provide insights into the better understanding of underwater ecology of marine megafauna with in vitro experimentation.

Early vertebrate origin of CTCFL, a CTCF paralog, revealed by proximity-guided shark genome scaffolding.

The nuclear protein CCCTC-binding factor (CTCF) contributes as an insulator to chromatin organization in diverse animals. The gene encoding this protein has a paralog which was first identified to be expressed exclusively in the testis in mammals and designated as CTCFL (also called BORIS). CTCFL orthologs were reported only among amniotes, and thus CTCFL was once thought to have arisen in the amniote lineage. In this study, we identified elasmobranch CTCFL orthologs, and investigated its origin with the aid of a shark genome assembly improved by proximity-guided scaffolding. Our analysis employing evolutionary interpretation of syntenic gene location suggested an earlier timing of the gene duplication between CTCF and CTCFL than previously thought, that is, around the common ancestor of extant vertebrates. Also, our transcriptomic sequencing revealed a biased expression of the catshark CTCFL in the testis, suggesting the origin of the tissue-specific localization in mammals more than 400 million years ago. To understand the historical process of the functional consolidation of the long-standing chromatin regulator CTCF, its additional paralogs remaining in some of the descendant lineages for spatially restricted transcript distribution should be taken into consideration.

Fat Grafting in Patients With Extensive Unilateral Facial Deficiency: Three-Dimensional Computer-Assisted Planning, Implementation, and Outcome Assessment.

PURPOSE: Autologous fat injection is a widely used, simple, and less invasive technique to correct volume deficiency. This study developed a treatment method by using a 3-dimensional (3D) simulation to plan and implement fat injection in patients with an extensive facial deficiency and then validated the accuracy of the method and treatment outcomes. METHODS: Seven patients with a large unilateral facial deficiency receiving autologous fat grafts between 2015 and 2017 were recruited. One patient received repeated treatment. Furthermore, 3D surgical simulation was used to measure the difference between the mirrored image and lesion side. An extra 20% to 30% of fat graft was added. A color map was provided, and contour lines 2 mm deep marked the location of the fat injection. Outcome assessments were then performed, and a 3D symmetry index was defined using the contour lines on the facial surface. RESULTS: No significant difference was noted between the predicted volume and postoperative fat graft retention (35.7 ± 7.4 and 31.6 ± 9.7 mL, respectively; P = 0.176). A comparison of preoperative (79.5% ± 4.3%) and postoperative (89.0% ± 3.3%) 3D symmetry indexes indicated significantly improved facial symmetry (P = 0.018). Patient-reported outcomes of satisfaction on FACE-Q questionnaires yielded an average score of 62.73, higher than the control score (59.83). CONCLUSIONS: By using the proposed method, we could predict the required fat graft volume; moreover, the contoured map aided accurate surgical implementation. Thus, this method is useful for planning and guiding fat grafting treatment in patients with major unilateral facial deficiency.

Unique structure (construction and configuration) and evolution of the array of small serum protein genes of Protobothrops flavoviridis snake.

The nucleotide sequence of Protobothrops flavoviridis (Pf) 30534 bp genome segment which contains genes encoding small serum proteins (SSPs) was deciphered. The genome segment contained five SSP genes (PfSSPs), PfSSP-4, PfSSP-5, PfSSP-1, PfSSP-2, and PfSSP-3 in this order and had characteristic configuration and constructions of the particular nucleotide sequences inserted. Comparison between the configurations of the inserted chicken repeat-1 (CR1) fragments of P. flavoviridis and Ophiophagus hannah (Oh) showed that the nucleotide segment encompassing from PfSSP-1 to PfSSP-2 was inverted. The inactive form of PfSSP-1, named PfSSP-1δ(Ψ), found in the intergenic region (I-Reg) between PfSSP-5 and PfSSP-1 had also been destroyed by insertions of the plural long interspersed nuclear elements (LINEs) and DNA transposons. The L2 LINE inserted into the third intron or the particular repetitive sequences inserted into the second intron structurally divided five PfSSPs into two subgroups, the Long SSP subgroup of PfSSP-1, PfSSP-2 and PfSSP-5 or the Short SSP subgroup of PfSSP-3 and PfSSP-4 The mathematical analysis also showed that PfSSPs of the Long SSP subgroup evolved alternately in an accelerated and neutral manner, whereas those of the Short SSP subgroup evolved in an accelerated manner. Moreover, the ortholog analysis of SSPs of various snakes showed that the evolutionary emerging order of SSPs was as follows: SSP-5, SSP-4, SSP-2, SSP-1, and SSP-3 The unique interpretation about accelerated evolution and the novel idea that the transposable elements such as LINEs and DNA transposons are involved in maintaining the host genome besides its own transposition natures were proposed.

Shark genomes provide insights into elasmobranch evolution and the origin of vertebrates.

Modern cartilaginous fishes are divided into elasmobranchs (sharks, rays and skates) and chimaeras, and the lack of established whole-genome sequences for the former has prevented our understanding of early vertebrate evolution and the unique phenotypes of elasmobranchs. Here we present de novo whole-genome assemblies of brownbanded bamboo shark and cloudy catshark and an improved assembly of the whale shark genome. These relatively large genomes (3.8-6.7 Gbp) contain sparse distributions of coding genes and regulatory elements and exhibit reduced molecular evolutionary rates. Our thorough genome annotation revealed Hox C genes previously hypothesized to have been lost, as well as distinct gene repertories of opsins and olfactory receptors that would be associated with adaptation to unique underwater niches. We also show the early establishment of the genetic machinery governing mammalian homoeostasis and reproduction at the jawed vertebrate ancestor. This study, supported by genomic, transcriptomic and epigenomic resources, provides a foundation for the comprehensive, molecular exploration of phenotypes unique to sharks and insights into the evolutionary origins of vertebrates.

The habu genome reveals accelerated evolution of venom protein genes.

Evolution of novel traits is a challenging subject in biological research. Several snake lineages developed elaborate venom systems to deliver complex protein mixtures for prey capture. To understand mechanisms involved in snake venom evolution, we decoded here the ~1.4-Gb genome of a habu, Protobothrops flavoviridis. We identified 60 snake venom protein genes (SV) and 224 non-venom paralogs (NV), belonging to 18 gene families. Molecular phylogeny reveals early divergence of SV and NV genes, suggesting that one of the four copies generated through two rounds of whole-genome duplication was modified for use as a toxin. Among them, both SV and NV genes in four major components were extensively duplicated after their diversification, but accelerated evolution is evident exclusively in the SV genes. Both venom-related SV and NV genes are significantly enriched in microchromosomes. The present study thus provides a genetic background for evolution of snake venom composition.

Nasal Duplication Combined with Cleft Lip and Palate: Surgical Correction and Long-Term Follow-Up.

BACKGROUND: Diprosopus dirrhinus, or nasal duplication, is a rare entity of partial craniofacial duplication. METHODS: The case we present is the first report of diprosopus dirrhinus associated with complete cleft lip and palate. The baby was born in Cambodia at full term by normal vaginal delivery with no significant perinatal and family history. Physical examination revealed significant facial deformity due to the duplicated nose and the left complete cleft lip/palate on the right subset. RESULTS: There were 4 nostrils; both medial apertures including the cleft site were found to be 10-15 mm deep cul-de-sac structures without communication to the nasopharynx. The upper third of the face was notable for hypertelorism with a duplication of the soft-tissue nasion and glabella. Between the 2 nasal dorsums, there was a small cutaneous depression with a lacrimal fistula in the midline. Surgical treatment included the first stage of primary lip and nose repair and the second stage of palatoplasty. CONCLUSIONS: The patient was followed up at the age of 10 years showing satisfactory results for both aesthetic and functional aspects. Further management in the future will be required for the hypertelorism and nasal deformity.

Reinforcing the Mucoperiosteal Pocket with the Scarpa Fascia Graft in Secondary Alveolar Bone Grafting: A Retrospective Controlled Outcome Study.

BACKGROUND: Secondary alveolar bone grafting is the gold standard for the treatment of alveolar clefts in cleft lip and palate patients. The authors present a modified method using a Scarpa fascia graft that is placed deep into the mucoperiosteal pocket for watertight sealing of the bone graft chamber and limiting the graft position to the alveolar region for bony stability and tooth support. The outcome was assessed for clinical success in terms of bone graft stability and infection rate. METHODS: Seventy-four unilateral complete cleft lip and palate patients were enrolled in this retrospective study consisting of equal-size Scarpa fascia and control groups of consecutive unilateral complete cleft lip and palate patients undergoing secondary alveolar bone grafting. Occlusal radiographs of the alveolar cleft taken at least 1 year postoperatively were evaluated for Spearman correlated Bergland and Witherow scales. Statistical evaluation was conducted using t test, chi-square test, and odds ratio. RESULTS: The clinical success rate (Bergland types I and II) of the Scarpa fascia procedure was significantly higher (67.6 versus 94.6 percent, respectively), with a significantly lower infection rate (16.2 versus 2.7 percent, respectively) and a high correlation of Bergland and Witherow scales (0.964; p < 0.001). There was no wound dehiscence, fistula, bone graft exposure, or additional donor-site morbidity in the Scarpa fascia group. CONCLUSION: The authors' new method of alveolar bone grafting with the Scarpa fascia graft is safe and effective, and has one of the highest documented success rates. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

An integrated surgical protocol for adult patients with hemifacial microsomia: Methods and outcome.

BACKGROUND: Hemifacial microsomia (HFM) features hypoplasia and asymmetry in skeletal as well as soft tissue, and correction of the deformity is difficult in terms of aesthetic outcome. The purpose of this study is to examine the validity of an integrated treatment protocol for correction of this facial deformity. PATIENTS AND METHODS: A retrospective study was performed on adult HFM patients who received two-jaw orthognathic surgery combined with facial contouring procedures in the first stage, and fat injection for the residual facial deficiency in the second stage. Inclusion criteria were patients treated by the same surgeon and follow-up at least 6 months. The demographic, perioperative, and follow-up data were collected. We defined a facial surface area discrepancy index (FDI) for objective assessment of the symmetry between the affected and non-affected side, and utilized visual analogue scale (VAS) for subjective evaluation of facial asymmetry before and after surgical treatment. RESULTS: A total of 14 patients were included. The mean age at orthognathic surgery was 21.7 years. Four patients were categorized as Pruzansky-Kaban type I, while the remaining 10 patients were type II (7 patients type IIA, 3 patients type IIB). Fat injection as a secondary procedure was performed in eleven cases (79%). The mean pre- and postoperative FDI was 87.6±6.3 and 95.4±5.2 with a significant advance for symmetry (p < 0.001). The pre- and postoperative VAS for asymmetry was 7.2±1.7 and 3.8±2.4 respectively, with a significant improvement (p = 0.002). CONCLUSION: Our integrated approach using orthognathic surgery, facial contouring surgery and subsequent fat injection is satisfactory and obtain significant improvement of the facial deformity considering the complexity of HFM.

A Modified Technique of Mandibular Ramus Sagittal Split Osteotomy for Prevention of Inferior Alveolar Nerve Injury: A Prospective Cohort Study and Outcome Assessment.

BACKGROUND: Postoperative functional impairment of the inferior alveolar nerve (IAN) has been a common and well-recognized complication. Our study introduced a modified Obwegeser-Dal Pont bilateral sagittal split osteotomy (BSSO) technique and evaluated the subsequent incidence of postoperative neurosensory disturbance of IAN. METHODS: In this prospective cohort study, 57 patients receiving our modified BSSO during orthognathic surgery were enrolled. The technique contained opening the 2 ramus cortices and inserting the osteotome bypassing the IAN to avoid nerve injury. A 5-point scale self-assessment questionnaire was used to evaluate IAN neurosensory disturbance one week, six months and 12 months postoperatively. Differences between groups were analyzed using χ test for categorical and Wilcoxon signed-rank test for pairwise categorical data. RESULTS: Complete ramus splitting could be achieved in 109 (95.6%) sides. Lower lip or chin neurosensory disturbances presented in 72 (63.2%) sides 1 week postoperatively and gradually reduced to 9 (7.9%), and 4 (3.5%) at postoperative months 6 and 12, respectively. CONCLUSIONS: This BSSO technique could be safely performed with low rates of IAN exposure and injury and a low incidence of persistent neurosensory disturbance in 3.5% of patients 12 months postoperatively.

Correction of Facial Deformity in Sturge-Weber Syndrome.

BACKGROUND: Although previous studies have reported soft-tissue management in surgical treatment of Sturge-Weber syndrome (SWS), there are few reports describing facial bone surgery in this patient group. The purpose of this study is to examine the validity of our multidisciplinary algorithm for correcting facial deformities associated with SWS. To the best of our knowledge, this is the first study on orthognathic surgery for SWS patients. METHODS: A retrospective chart review included 2 SWS patients who completed the surgical treatment algorithm. Radiographic and clinical data were recorded, and a treatment algorithm was derived. RESULTS: According to the Roach classification, the first patient was classified as type I presenting with both facial and leptomeningeal vascular anomalies without glaucoma and the second patient as type II presenting only with a hemifacial capillary malformation. Considering positive findings in seizure history and intracranial vascular anomalies in the first case, the anesthetic management was modified to omit hypotensive anesthesia because of the potential risk of intracranial pressure elevation. Primarily, both patients underwent 2-jaw orthognathic surgery and facial bone contouring including genioplasty, zygomatic reduction, buccal fat pad removal, and masseter reduction without major complications. In the second step, the volume and distribution of facial soft tissues were altered by surgical resection and reposition. Both patients were satisfied with the surgical result. CONCLUSIONS: Our multidisciplinary algorithm can systematically detect potential risk factors. Correction of the asymmetric face by successive bone and soft-tissue surgery enables the patients to reduce their psychosocial burden and increase their quality of life.

A Treatment Protocol for Velopharyngeal Insufficiency and the Outcome.

BACKGROUND: A simple algorithm is applied to treat velopharyngeal insufficiency. The purpose of this study was to assess its success rate and complications. METHODS: The diagnosis includes speech perceptual assessment and nasopharyngoscopy, focusing on velopharyngeal closure ratio. The treatment is composed of a double-opposing Z-plasty for marginal velopharyngeal insufficiency or a pharyngeal flap for moderate to severe velopharyngeal insufficiency. A retrospective chart review was conducted for 84 consecutive nonsyndromic postpalatoplasty patients undergoing velopharyngeal insufficiency surgery from August of 2007 to December of 2014. The demographic, perioperative, and follow-up data were collected. Statistical analyses were performed. RESULTS: Mean age at velopharyngeal insufficiency surgery was 7.0 years. The overall improvement rate for patients was 86.9 percent. Nine patients in the double-opposing Z-plasty group and two patients in the pharyngeal flap group were refractory to velopharyngeal insufficiency surgery. The improvement rates for each surgical group were 80.4 percent for the double-opposing Z-plasty group and 94.7 percent for the pharyngeal flap group. There were no significant differences in postoperative velopharyngeal function between the coronal and noncoronal groups. Airway-associated complications were observed in nine patients (10.7 percent). The complications in the double-opposing Z-plasty group were observed in two patients (4.3 percent), and none of the patients presented obstructive sleep apnea. Seven patients (18.4 percent) in the pharyngeal flap group showed postoperative snoring, and one (2.6 percent) of them presented with obstructive sleep apnea. CONCLUSION: The authors' algorithm is a simple patient- and surgeon-friendly strategy to obtain satisfactory improvement of velopharyngeal function for velopharyngeal insufficiency patients, with a low risk of airway complications. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Modified Furlow Palatoplasty Using Small Double-Opposing Z-Plasty: Surgical Technique and Outcome.

BACKGROUND: A smaller Z-plasty is applied in a modified Furlow palatoplasty. The purpose of this study was to assess its surgical and functional outcome. METHODS: The surgical technique included mucoperiosteal flap elevation in the hard palate, complete pedicle dissection and release, double-opposing Z-plasty using 5-mm limbs and muscle dissection in the soft palate, and the buccal fat pad covering lateral relaxing wounds. A retrospective chart review was conducted for 231 consecutive nonsyndromic patients undergoing modified palatoplasty from May of 2007 to December of 2014. The demographic, postoperative, and follow-up data were collected. Statistical analyses were performed. RESULTS: Average age at palatoplasty was 8.3 months. The overall oronasal fistula rate was 0.4 percent; oronasal fistula occurred in only one case with bilateral cleft. Other complications included postoperative bleeding in two cases (0.8 percent), postoperative airway obstruction in one case (0.4 percent), obstructive sleep apnea in one case (0.4 percent), stitch abscess in one case (0.4 percent), and distal uvula dehiscence in two cases (0.8 percent). One hundred twenty-seven patients had full speech evaluation, and seven (5.5 percent) were diagnosed with velopharyngeal insufficiency requiring surgical correction. CONCLUSION: This modified palatoplasty using a small double-opposing Z-plasty provided adequate cleft palate closure, with a low fistula rate and satisfactory speech outcome. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Computer-Assisted Orthognathic Surgery for Patients with Cleft Lip/Palate: From Traditional Planning to Three-Dimensional Surgical Simulation.

BACKGROUND: Although conventional two-dimensional (2D) methods for orthognathic surgery planning are still popular, the use of three-dimensional (3D) simulation is steadily increasing. In facial asymmetry cases such as in cleft lip/palate patients, the additional information can dramatically improve planning accuracy and outcome. The purpose of this study is to investigate which parameters are changed most frequently in transferring a traditional 2D plan to 3D simulation, and what planning parameters can be better adjusted by this method. PATIENTS AND METHODS: This prospective study enrolled 30 consecutive patients with cleft lip and/or cleft palate (mean age 18.6±2.9 years, range 15 to 32 years). All patients received two-jaw single-splint orthognathic surgery. 2D orthodontic surgery plans were transferred into a 3D setting. Severe bony collisions in the ramus area after 2D plan transfer were noted. The position of the maxillo-mandibular complex was evaluated and eventually adjusted. Position changes of roll, midline, pitch, yaw, genioplasty and their frequency within the patient group were recorded as an alternation of the initial 2D plan. Patients were divided in groups of no change from the original 2D plan and changes in one, two, three and four of the aforementioned parameters as well as subgroups of unilateral, bilateral cleft lip/palate and isolated cleft palate cases. Postoperative OQLQ scores were obtained for 20 patients who finished orthodontic treatment. RESULTS: 83.3% of 2D plans were modified, mostly concerning yaw (63.3%) and midline (36.7%) adjustments. Yaw adjustments had the highest mean values in total and in all subgroups. Severe bony collisions as a result of 2D planning were seen in 46.7% of patients. Possible asymmetry was regularly foreseen and corrected in the 3D simulation. CONCLUSION: Based on our findings, 3D simulation renders important information for accurate planning in complex cleft lip/palate cases involving facial asymmetry that is regularly missed in conventional 2D planning.