Search

Objective: Descriptions of the craniofacial morphology in Saethre-Chotzen syndrome (SCS) are primarily based on case reports or visual assessments of affected families. The aim of this study was to compare cephalometric measurements of the craniofacial skeleton in a cohort of individuals with SCS and age- and sex-matched individuals without craniofacial anomalies. Design: Retrospective case series. Patients: Eight girls and 4 boys with SCS (age range, 7.0-19.2 years). Methods: Cephalometric measurements were performed using lateral and frontal cephalograms. Results: Most of the individuals with Saethre-Chotzen syndrome exhibited lower values for SNA, SNB, s-n and s-ar, while their NSL/NL, NSL/ML, NL/ML, and n-s-ba values were higher than the respective mean reference values for healthy individuals. In comparison with age- and sex-matched individuals without craniofacial anomalies, the individuals with SCS showed higher values for the maxillary and mandibular angular measurements, as well as for the menton midline angle. Conclusions: This sample of 12 unrelated individuals with SCS is the largest collected to date for cephalometric measurements. We found that the syndrome is associated with bimaxillary retrognathism, posterior maxillary and mandibular inclination, neutral sagittal relation as well as a tendency toward an open vertical skeletal relation, a short and flattened skull base, and facial asymmetry, as compared to individuals without the syndrome.

Craniosynostosis (CS), the premature closure of one or more cranial sutures, occurs both as part of a syndrome or in isolation (nonsyndromic form). Here, we have studied the prevalence and spectrum of genetic alterations associated with coronal suture closure in 100 Scandinavian patients treated at a single craniofacial unit. All patients were phenotypically assessed and analyzed with a custom-designed 63 gene NGS-panel. Most cases (78%) were syndromic forms of CS. Pathogenic and likely pathogenic variants explaining the phenotype were found in 80% of the families with syndromic CS and in 14% of those with nonsyndromic CS. Sixty-five percent of the families had mutations in the CS core genes FGFR2, TWIST1, FGFR3, TCF12, EFNB1, FGFR1, and POR. Five novel pathogenic/likely pathogenic variants in TWIST1, TCF12, and EFNB1 were identified. We also found novel variants in SPECC1L, IGF1R, and CYP26B1 with a possible modulator phenotypic effect. Our findings demonstrate that NGS targeted sequencing is a powerful tool to detect pathogenic mutations in patients with coronal CS and further emphasize the importance of thorough assessment of the patient's phenotype for reliable interpretation of the molecular findings. This is particularly important in patients with complex phenotypes and rare forms of CS.

Sagittal synostosis is the most occurring form of craniosynostosis, resulting in calvarial deformation and possible long-term neurocognitive deficits. Several surgical techniques have been developed to correct these issues. Debates as to the most optimal approach are still ongoing. Finite element method is a computational tool that’s shown to assist with the management of craniosynostosis. The aim of this study was to compare and predict the outcomes of three reconstruction methods for sagittal craniosynostosis. Here, a generic finite element model was developed based on a patient at 4 months of age and was virtually reconstructed under all three different techniques. Calvarial growth was simulated to predict the skull morphology and the impact of different reconstruction techniques on the brain growth up to 60 months of age. Predicted morphology was then compared with in vivo and literature data. Our results show a promising resemblance to morphological outcomes at follow up. Morphological characteristics between considered techniques were also captured in our predictions. Pressure outcomes across the brain highlight the potential impact that different techniques have on growth. This study lays the foundation for further investigation into additional reconstructive techniques for sagittal synostosis with the long-term vision of optimizing the management of craniosynostosis.

Background Adaptive behavior skills are important when assessing cognitive functions related to daily life; however, few studies have assessed these skills in patients treated for nonsyndromic craniosynostosis. In this study, the authors assessed the adaptive behavior skills of children treated for craniosynostosis and examined whether their outcomes are related to surgical technique. Methods The Adaptive Behavior Assessment System, 2nd Edition, parent report was used for children (age, 7 to 16 years) treated for sagittal (n = 41), metopic (n = 24), and other rare synostoses (n = 8). Background data, including intelligence quotient, were controlled for confounders. Results All evaluated children treated for craniosynostosis were estimated as lower in all aspects of adaptive behavior skills (full-scale, conceptual, social, and practical composites; effect size, 0.36 to 0.44) as compared with norms. The sagittal group showed shortcomings in social composite (effect size, 0.48) and subscales measuring self-care and self-direction, although no difference was observed between spring-assisted surgery and pi-plasty regarding outcomes of adaptive behavior skills. In addition, children treated for metopic synostosis showed results indicating shortcomings with adaptive behavior according to the full-scale, conceptual, and social composites (effect size, 0.53 to 0.61) relative to norms. Furthermore, attrition analysis revealed no significant differences between responders (rate, 80.2 percent) and nonresponders. Conclusion These results found that children treated for craniosynostosis display average adaptive behavior skills, and that the two surgical techniques used to treat sagittal synostosis did not differ in their behavioral outcomes. Clinical question/level of evidence Therapeutic, III.

Summary Background The FACE-Q Craniofacial Module is a patient-reported outcome measure designed for patients aged 8 to 29 years with conditions associated with a facial difference. In part 1, we describe the psychometric findings for the original CLEFT-Q scales tested in patients with cleft and noncleft facial conditions. The aim of this study was to examine psychometric performance of new FACE-Q Craniofacial Module scales. Methods Data were collected between December 2016 and December 2019 from patients aged 8 to 29 years with conditions associated with a visible or functional facial difference. Rasch measurement theory (RMT) analysis was used to examine psychometric properties of each scale. Scores were transformed from 0 (worst) to 100 (best) for tests of construct validity. Results 1495 participants were recruited with a broad range of conditions (e.g., birthmarks, facial paralysis, craniosynostosis, craniofacial microsomia, etc.) RMT analysis resulted in the refinement of 7 appearance scales (Birthmark, Cheeks, Chin, Eyes, Forehead, Head Shape, Smile), two function scales (Breathing, Facial), and an Appearance Distress scale. Person separation index and Cronbach alpha values met criteria. Three checklists were also formed (Eye Function, and Eye and Face Adverse Effects). Significantly lower scores on eight of nine scales were reported by participants whose appearance or functional difference was rated as a major rather than minor or no difference. Higher appearance distress correlated with lower appearance scale scores. Conclusion The FACE-Q Craniofacial Module scales can be used to collect and compare patient reported outcomes data in children and young adults with a facial condition.

Background ERF-related craniosynostosis are a rare, complex, premature trisutural fusion associated with a broad spectrum of clinical features and heterogeneous aetiology. Here we describe two cases with the same pathogenic variant and a detailed description of their clinical course. Case presentation Two subjects; a boy with a BLSS requiring repeated skull expansions and his mother who had been operated once for sagittal synostosis. Both developed intracranial hypertension at some point during the course, which was for both verified by formal invasive intracranial pressure monitoring. Exome sequencing revealed a pathogenic truncating frame shift variant in the ERF gene. Conclusions Here we describe a boy and his mother with different craniosynostosis patterns, but both with verified intracranial hypertension and heterozygosity for a truncating variant of ERF c.1201_1202delAA (p.Lys401Glufs*10). Our work provides supplementary evidence in support of previous phenotypic descriptions of ERF-related craniosynostosis, particularly late presentation, an evolving synostotic pattern and variable expressivity even among affected family members.

INTRODUCTION Spring-assisted cranioplasty to correct sagittal synostosis is based on midline craniotomy through the closed sagittal suture, over the superior sagittal sinus (SSS). The aim of the present study was to evaluate the perioperative safety of this technique. MATERIALS AND METHODS This is a retrospective study of all patients operated with median craniotomy and springs from 1998 to the end of 2015. For comparison, all Pi-plasties performed during the same time interval were also evaluated. The safety measures were evaluated based on incidence of damage to SSS, incidence of dural tears, perioperative blood loss, operative time, and hospital stay. RESULTS In the group that had undergone midline craniotomy combined with springs (n = 225), 4 perioperative damages to SSS and 1 dural tear were seen. The perioperative blood loss was 62.8 ± 65.3 mL (mean ± standard deviation). The operative time was 67.9 ± 21.5 minutes and the hospital stay was 4.8 ± 1.1 days. In the group that had undergone pi-plasty (n = 105), no damages to SSS but 3 dural tears were seen. The perioperative blood loss was 352.8 ± 174.4 mL. The operative time was 126.0 ± 31.7 minutes and the hospital stay was 7.1 ± 1.4 days. CONCLUSION Craniotomy SSS in sagittal synostosis is a safe procedure with low morbidity in terms of damage to the SSS. Midline craniotomy combined with springs has significantly lower preoperative blood loss, operative time, and hospital stay (P

Attention problems are common in patients with craniosynostosis. Craniosynostosis is a rare condition, studies face challenges of selection bias, small sample sizes, and wide age ranges. The aim of the study was to assess the sustained attention and vigilance of children treated for sagittal and metopic craniosynostosis. To reduce selection bias, we included children that had previously undergone surgery for craniosynostosis, were between 8 and 16 years, and lived close to the craniofacial centre. The Connors Continuous Performance Test (3

BACKGROUND Long-term neuropsychological and cognitive outcomes in patients with nonsyndromic craniosynostosis have proven difficult to evaluate objectively because of methodologic problems with published studies based on their small and biased samples of patients, wide age ranges, and testing with unacceptable psychometric properties. This study evaluated the Full-Scale Intelligence Quotient and its subscales in a cohort with a small selection bias. METHODS Patients aged 7 to 16 years, born with nonsyndromic craniosynostosis and surgically treated, were tested using the Wechsler Intelligence Scale for Children, Fourth Edition. Ninety-one patients were invited, and 73 patients were tested. RESULTS There was no difference in Full-Scale Intelligence Quotient score between patients who had undergone operations for sagittal synostosis or metopic synostosis and norms provided by the test. Patients operated on for sagittal synostosis showed a significantly higher perceptual reasoning intelligence quotient, but also significantly lower working-memory intelligence quotient and processing-speed intelligence quotient compared with the norms. Patients operated on for metopic synostosis showed no differences in any intelligence quotient index compared with the norm. In addition, attrition analysis showed no differences in background factors between responders and nonresponders. CONCLUSIONS These results derived from a group of patients with uniform age range, and tested using an established tool, revealed that nonsyndromic children having undergone surgery for craniosynostosis exhibited average intellectual ability. However, the analysis indicated possible issues with working memory and processing speed in patients operated on for sagittal synostosis, highlighting impairments potentially associated with neuropsychological problems and that might contribute to learning disabilities.

Spring-assisted cranioplasty (SAC) was recently introduced in Moscow. This study provides a detailed analysis of the results of the first 14 SAC cases in Russia. The patients underwent a computed tomography scan before surgery and prior to spring removal 3 months later. Fourteen cases (10 males and 4 females) were operated on, with a mean surgery time of 56 ± 14 min. All operations were uneventful, with a mean hospital stay of 4.2 days. Detailed craniometry of the 10 male patients and their matched controls revealed that SAC induced changes in the shape of the entire skull. The cranial index of the male patients increased from 68.2 to 72.3, whereas it remained stable at ∼80 for the controls. The anterior and middle skull heights were significantly larger in cases as compared with controls but shifted toward normal levels following SAC. Additionally, SAC increased parietal bone curvature, and principal component analysis showed that post-SAC morphological changes in patients were comparable to normal growth changes in the skull morphology of the controls. However, several months after the operation, patients continued to display a clearly distinct cranial morphology as compared with that of controls. These results indicated that SAC is a safe technique that showed good surgical results immediately after introduction.

Brooke-Spiegler syndrome (BSS; a.k.a. tuban tumor syndrome) is an autosomal dominant inherited skin disorder caused by germline mutations in the CYLD tumor suppressor gene. BSS is characterized by multiple skin adnexal tumors, mainly cylindromas and spiradenomas on the head and neck. The tumors are often severely disfiguring and require repeated surgical interventions. Here, we describe a four-generation BSS-family with a novel germline c.1613_1614delGC CYLD mutation that introduces a premature STOP codon predicted to result in a truncated, inactivated CYLD protein. In addition, we present a pilot study describing establishment of the first patient-derived xenografts (PDXs) from cutaneous CYLD-defective cylindromas. Fresh tumor tissues from cylindromas were transplanted into immunocompromised mice to generate PDXs. One xenograft showed progressive tumor growth after 3 months whereas the others remained unchanged in size during the 6 months study period. Histopathological and immunohistochemical analyses of the PDXs revealed that they recapitulate the histological and molecular features of their respective primary tumors, including expression of NTRK3 and the oncogenic driver MYB. In summary, we present the first preclinical BSS-model that morphologically and genetically recapitulates human CYLD-defective cylindromas. This model will be useful for preclinical therapeutic drug testing and for further studies of the molecular pathogenesis of inherited cylindromas.

INTRODUCTION Craniosynostosis is a premature closure of a cranial suture. Cranioplasty is indicated to correct skull deformity, relieve increased intracranial pressure, and promote homogenous cranial growth. Different techniques have been adopted to achieve optimal outcomes. Although surgical benefits are widely accepted, this intervention might also affect cranial skeletal growth. METHODS The authors conducted a retrospective case-control study including patients operated for isolated metopic or sagittal synostosis. These patients had undergone a computed tomography (CT) scan before surgery and/or at 3 years of age postoperatively. These were operated between 2002 and 2012. Intracranial volume was measured using a MATLAB application. The control group was age and sex-matched individuals who had CT scans for trauma or neurological indications. All results with P value

Background The aim of the current study was to determine the intracranial volume (ICV) and cephalic index (CI) in patients operated for sagittal synostosis, and to compare the outcome of 2 different surgical techniques: craniotomy combined with springs and modified pi-plasty. Methods The authors studied all patients who had been operated for isolated sagittal synostosis and registered in the Gothenburg Craniofacial Registry until the end of 2012 and who had undergone a preoperative and/or postoperative (at 3 years of age) computed tomography examination. Sex- and age-matched controls were identified from children who had undergone computed tomography for other reasons. Results Craniotomy combined with springs increased the ICV and CI from 802 ± 127 mL (mean ± SD) and 70.1 ± 4.0 to 1300 ± 158 mL and 73.1 ± 3.3, respectively. The corresponding values for controls were 796 ± 136 mL and 83.6 ± 7.3 preoperatively and 1334 ± 136 mL and 80.0 ± 4.5 at 3 years of age. Pi-plasty increased the ICV and CI from 1014 ± 115 mL and 69.7 ± 3.3 to 1286 ± 122 mL and 74.1 ± 2.6, respectively. Corresponding values for controls were 1043 ± 153 mL and 83.4 ± 7.0 preoperatively and 1362 ± 122 mL and 79.6 ± 3.9 at 3 years of age. Conclusions There was no significant difference between craniotomy combined with springs in children younger than 6 months and pi-plasty in older children regarding the efficacy of improving ICV and CI. Neither of the techniques fully normalized the head shape.

Metopic synostosis results in a keel-shaped forehead, reduced frontal intracranial volume (ICV), and lower frontal to total volume ratio. The ratio improves with cranioplasty, but at 3 years of age, the ratio is still not normalized when compared to that in normal children. The aim of the present study was to investigate whether a low frontal to total ICV ratio at 3 years of age was due to relapse or insufficient correction.All children surgically treated for metopic synostosis in combination with a spring at Sahlgrenska University Hospital with subsequent spring extraction between 2002 and 2008 (n = 20) were included. A MATLAB program was used to measure frontal and total ICV.Preoperatively, the frontal to total ICV ratio was 9.8 ± 1.3% (mean ± standard deviation). At spring removal, 6 months after cranioplasty, the ratio had increased to 11.8 ± 2.4%. At 3 years of age, the ratio was 11.6 ± 1.9%. In age-matched normal children, the ratio was 14.4 ± 1.9% preoperatively, 15.3 ± 2.2% at time of spring extraction, and 13.4 ± 1.4% at 3 years of age.Cranioplasty thus improved the frontal to total ICV ratio, but did not normalize it. The ratio did not change from 6 months after the cranioplasty to 3 years of age. These results indicate that a more pronounced frontal volume correction during cranioplasty is necessary to achieve a normalized distribution of ICV in metopic synostosis.

Multisutural nonsyndromic craniosynostosis is a rare group of malformations, whose frequency has been reported between 3% and 7% of all craniosynostosis. The clinical diagnosis can be difficult and computed tomography is usually required. Surgical treatment is challenging and staged procedures are performed in up to 80% of patients. The aim of the present study was to determine the reoperation rate and to evaluate the surgical outcomes by measuring intracranial volume (ICV) preoperatively and at follow-up, and comparing it to a control group. Perioperative variables and reoperation rate were recorded. Fifty-one patients presented with a complex pattern of synostosis without a recognizable syndrome (5% of cases of total patients evaluated). Fifteen patients have been treated with spring-assisted surgery, either alone or in combination with a foreheadplasty. The mean follow-up was 6.2 years. The mean preoperative ICV of the patients was smaller, but not significantly, than in the normal population (P = 0.13). Postoperatively, the mean ICV was similar to that of the control group at 1 year (P = 0.92), while at 3 years it was appreciably smaller, although not significantly different (P = 0.06). Five patients (33%) went through a secondary skull expansion for either raised intracranial pressure or cosmetic reasons. Spring-assisted surgery seems to temporarily expand ICV in children with complex synostosis and lower the reoperation rate, thus reducing the need for a second procedure. A longer follow-up would be necessary to further investigate the effects of springs over time.

Purpose Craniosynostosis may lead to hampered fetal head molding and birth complications. To study the interaction between single suture craniosynostosis and delivery complications, an international, multicentre, retrospective cohort study was performed. Materials and methods All infants born between 2006 and 2012 in the Netherlands and Sweden with sagittal or metopic suture synostosis were included. All births were included as a reference population. The primary outcome measure was rate of medically assisted labor. The secondary outcomes included method of conception, term of birth and fetal position. Results We included 152 trigonocephaly patients, 272 scaphocephaly patients and 1.954.141 controls. A higher rate of assisted reproductive technology (ART) was found in patients with trigonocephaly (13%) and scaphocephaly (7%) compared to controls (3%, p < 0.001). Scaphocephaly resulted in more postterm births (8% vs 4%, p < 0.001). Trigonocephaly patients showed more preterm births (11% vs 6%, p < 0.001), breech position was more frequent (10% vs 4%, p = 0.003) and labor was more often induced. Rate of assisted delivery, including cesarean section, was significantly higher in both patient groups. Conclusions Scaphocephaly leads to more postterm births and an increased rate of cesarean sections. Trigonocephaly is related to ART, and in addition higher rates of breech position and cesarean section are found. Prenatal detection of single suture craniosynostosis could improve perinatal care.

Introduction No surgical technique is reported to be the best option for gender-affirmation surgery (GAS) of the genitalia in transmen. Although patients’ preferences are central when choosing a surgical technique, no studies have evaluated this factor. Aim To investigate transmen’s priorities and preferences regarding GAS of the genitalia. Methods From November 2015 to March 2016, 54 transmen with the diagnosis of gender dysphoria who were referred to Sahlgrenska University Hospital for discussion of therapeutic steps (surgery and hormonal treatments) were asked to complete a questionnaire on different attributes achievable with GAS, such as sexual and urinary function and appearance. Forty-seven patients (87%) completed the questionnaire. Age ranged from 18 to 52 years (mean = 26 years, SD = 7.4 years). At the time of interview, no patient had undergone GAS of the genitalia. Main Outcome Measures Answers to completed questionnaires. Results Seventy-six percent of patients identified themselves as male, and 24% wrote other terms such as “mostly male,” “inter-gender” and “non-binary.” Gender identity had a significant impact on patients’ preferences for two questions: the importance of vaginal removal and the importance of having a penis that would be passable in places such as male dressing rooms. These items were more important to patients identifying themselves as male. The most important attributes requested were preserved orgasm ability and tactile sensation. The least important attribute was removal of the vagina, followed by having a penis of human material, minimal scarring, and size. The ability to urinate while standing was considered a high priority by some and a low priority by others. All answers ranged from “unimportant” to “imperative.” Conclusion This series of patients demonstrates a considerable heterogeneity among transmen in their gender identity and preferences regarding GAS of the genitalia, which supports the need for several techniques. Patients must be accurately informed on the different techniques and their specific benefits and limitations to make an informed choice.

Craniosynostosis has rarely been described in patients with Kabuki syndrome. We report here a boy with facial asymmetry due to combined premature synostosis of the right coronal and sagittal sutures as well as several symptoms reminiscent of Kabuki syndrome (KS). Our case supports previous observations and suggests that craniosynostosis is a part of the KS phenotype. The uniqueness of our case is the sporadic co-occurrence of two genetic disorders, that is, a de novo frameshift variant in the KMT2D gene and a de novo 3.2 Mbp 10q22.3q23.1 deletion. Our findings emphasize the importance of the initial clinical assessment of children with craniosynostosis and that genomic and monogenic disorders, such as Kabuki syndrome, should be considered among the differential diagnoses of syndromic forms of craniosynostosis.

The subcutaneous mastectomy is an important step in the treatment of female-to-male transsexual patients. At the Sahlgrenska University Hospital, a two-step procedure was used for mastectomies through 2002-2011. With this procedure, all patients were operated on with a concentric circular incision in the first session of surgery, followed by a second session 7-12 months later. From July 2011, a new approach was adopted, which consists of treating patients according to the algorithm and methods described by Monstrey et al. The aim of this study is to evaluate these two different approaches and determine if similar results, possibly with fewer surgeries and overall lower complication rate, can be achieved by using multiple techniques and a decision-making algorithm as compared to the two-step approach where only a concentric circular technique was used. All female-to-male transsexuals who had mastectomy at Sahlgrenska between 2002-2012 were included in the study. These were divided in two groups: those who were treated according to the single-step, algorithm based, approach (16 patients, 32 mastectomies), and those who were treated with the two-step, concentric circular approach (14 patients, 28 mastectomies). Within the single-step, algorithm based, group the following techniques were used: 6% transareolar technique, 6% semicircular, 13% free nipple graft, 31% extended concentric circular, and 44% concentric circular. Data including type of surgical technique used, complications, and number of surgeries were collected and compared. Complications (e.g., haematoma, nipple necrosis, seroma, wound dehiscence, and infection) occurred in 50% of the patients following the first surgery in the two-step, concentric-circular approach group, for a total of 71.43% of patients with complications following either the first- or the second-step surgery; complications occurred only in 25% of the patients in the one-step, algorithm-based group. The mean number of surgeries per breast was 2.5 for the two-step concentric circular approach, and 1.25 for the single step, algorithm-based approach; particularly, when the concentric circular technique was chosen for the single step, algorithm-based approach, only two of the patients required revision surgery to improve the cosmetic outcome. This study shows that the number of complications and the total number of surgeries performed to satisfy patients were lower after Monstrey's algorithm for mastectomies was implemented as routine practice at the Sahlgrenska University Hospital.

Crouzon syndrome presents with craniosynostosis, maxillary hypoplasia, exophtalmus, and sometimes hampered neuropsychological development. The aim of the present study was to evaluate the quality of life for adult patients with Crouzon syndrome. Forty patients with Crouzon syndrome born before 1990 could be identified. A questionnaire addressing education, employment, social relations, and quality-of-life was used. A matched control group was created for comparison. Logistic regression, correcting for the influence of age and sex, was used to compare patients and controls. Thirty-one patients and 285 controls answered the questionnaire. The level of education was lower in patients than in controls (p < 0.015). Patients were less often married or had a partner (p = 0.059), had fewer children of their own (p = 0.004), and had less experience of a sexual relationship (p < 0.001). The difference in housing was not significant, and only one patient lived in a care centre and three patients required a personal assistant to manage activities of daily living. The patients' estimation of their somatic health was equal to that of the controls, but the patients more often used anti-epileptic medication (p = 0.003). Periods of depressive mood were more common in patients (p = 0.001), but there was no difference between the groups regarding a general positive attitude to life. In conclusion, patients with Crouzon syndrome often have intellectual and social shortcomings that negatively affect their lives. However, the range of abilities is wide in this group.

Patients with unicoronal synostosis (UCS) present with ipsilateral forehead flattening, contralateral frontal bossing, and rotation of the facial midline. Uni- or bilateral fronto-orbital advancement (FOA) techniques are the most common surgical approaches for correction of UCS. The purpose of this study was to objectively evaluate the surgical outcome in patients for UCS, using a new MATLAB computer tool programmed to measure the symmetry of the two halves of the forehead.Files were reviewed from a consecutive series of patients treated for UCS at the unit, from 1979-2008. The patients were grouped according to the method of operation used. The computer tool evaluated preoperative and postoperative cephalograms and CT scans. Eighty-eight patients were included. The male-to-female ratio was 1:2.4. Forty-six patients had been operated on with FOA and 42 with forehead remodelling using a calvarial bone graft. Forehead symmetry was significantly improved by both techniques (p < 0.001 for both), but the postoperative forehead symmetry was significantly better after forehead remodelling (p = 0.025). The reoperation rate was much lower for the second group (6.5 vs 37.2%, p < 0.001). It is concluded that forehead remodelling with a calvarial bone graft creates a more symmetrical forehead than FOA and may, therefore, be a better alternative for treatment of unicoronal synostosis.

Premature craniosynostosis is a congenital disorder causing a skull deformity. For both functional and cosmetic reasons, the deformity is surgically treated with a cranioplasty before the age of 1 year. Temporal hollowing is a common and undesirable remaining deformity after cranioplasty for metopic synostosis. The most common method to determine the degree of temporal hollowing is subjective judgement of the temporal region. The aim of the present project was to develop a quantitative semi-automatic computer tool for objective measurement of bony temporal hollowing.Using MATLAB, a tool was developed to segment computed tomography images, defining the outermost contour. The images were dorsally limited to the widest point of the head. In each case, a sex- and age-matched control was identified and the contours compared. The bony temporal hollowing of the cases was calculated.The intra-user coefficient of variation (CV) was 5.0% (95% CI = 4.2%-6.2%) and the inter-user CV was 3.0% (95% CI = 2.1%-8.6%). For clinical testing purposes, the tool was used in 14 patients, seven of whom had been operated on with a spring-assisted cranioplasty and seven with a cranioplasty using a bone graft.In summary, this study presents a new tool for objective measurement of the surgical result after cranioplasty for metopic synostosis.

The aim of this project was to develop a tool for systematic evaluation of volumetric changes after surgery for craniosynostosis. A computer program using MATLAB was developed to measure total intracranial volume and frontal volume, anterior to the coronary sutures, by multiplying the area with slice thickness of each slice from just above foramen magnum to just beneath the vertex in CT examinations. The ratio between frontal volume and total volume was used for evaluation of the clinical result in 12 patients operated on for metopic synostosis. In 0.625 and 5 millimetre slices the coefficients of variation were 0.00049 and 0.00058, respectively, for measurements of total volume. The highest coefficient of variation was found in postoperative measurements of the frontal volume and was 0.014 in 0.625 millimetre slices. Measurements in 5 millimetre slices resulted in 3.8% ± 1.5% (mean ± SD) lower total volumes and 5.8% ± 5.3% lower frontal volumes than measurements in 0.625 millimetre slices. In patients operated on for metopic synostosis the ratio between frontal volume and total volume increased 25% ± 16% for patients operated on with cranioplasty in combination with a spring (n = 6) and 20% ± 13% for patients operated on with cranioplasty in combination with a bone transplant (n = 6). In summary, this study has developed a tool that can determine frontal and total intracranial volume with little variation. This tool can be used for systematic evaluation of the result of the operation for metopic synostosis.

BACKGROUND Apert syndrome (acrocephalosyndactyly type 1) includes craniofacial deformities, malformations of the extremities and the central nervous system, and often mental retardation. The aim of this study was to investigate the life situation of adult patients with Apert syndrome. METHODS Thirty-three patients with Apert syndrome born before 1990 were identified in the Goteborg craniofacial registry. The authors used a questionnaire mainly dealing with education, employment, social relations, and quality of life. A matched control group was created for comparison. RESULTS Five of the patients had died. Twenty-four of the remaining patients answered the questionnaire. The level of education was lower in patients than in controls (p = 0.007), but there was no significant difference in the extent of employment between the two groups. The difference in housing was significant (p < 0.001) and the majority of patients lived with their parents. Patients were less often married (p < 0.001), had fewer friends (p < 0.001), and had less experience with sexual relationships (p < 0.001). The somatic health was lower in patients [e.g., they had more hearing problems (p < 0.001) and more epilepsy (p = 0.005)]. Depressive mood periods were more common in patients (p < 0.001), but there was no difference between the groups regarding a generally positive attitude toward life. CONCLUSIONS This study shows that patients with Apert syndrome manage relatively well in adulthood. The discrepancy in social relations between the Apert patients and the healthy control group indicates that further improvement of the treatment is desirable.

Neuroendocrine (NE) tumours are characterized by their capacity to synthesize, store and release hormonal products. These substances are stored in neurosecretory vesicles together with chromogranin A (CgA). The concentration of plasma CgA in patients with NE tumours is thought to reflect the degree of NE differentiation, total tumour burden and effect of medical treatment. The aim of this study was to analyse the correlation between tumour weight and plasma CgA levels as well as the influence of treatment with a long-acting somatostatin analogue (octreotide) using nude mice with xenografted human ileal carcinoid tumours. There was a correlation between tumour weight and plasma CgA levels in all animals (p0.00001). In octreotide-treated mice, plasma CgA levels were significantly reduced versus untreated animals (p = 0.037). In conclusion, this study demonstrates that plasma CgA levels are closely correlated to tumour burden, and that plasma CgA is well suited for monitoring the clinical course and outcome of treatment in patients with NE tumours.

The radio-iodinated noradrenaline analogue meta-iodobenzylguanidine (MIBG) can be used for scintigraphy and radiation therapy of neuroendocrine (NE). The aim of the present study was to study the importance of vesicular monoamine transporters (VMATs) for the uptake of (123)I-MIBG in NE tumours. In nude mice, bearing the human transplantable midgut carcinoid GOT1, all organs and xenografted tumours accumulated (123)I after i.v. injection of (123)I-MIBG. A high concentration of (123)I was maintained in GOT1 tumours and adrenals, which expressed VMATs, but rapidly decreased in all other tissues. In the VMAT-expressing NE tumour cell lines GOT1 and BON and in VMAT-expressing primary NE tumour cell cultures (carcinoids, n=4 and pheochromocytomas, n=4), reserpine significantly reduced the uptake of (123)I-MIBG. The membrane pump inhibitor clomipramine had no effect on the uptake of (123)I-MIBG in GOT1 and BON cells, but inhibited the uptake in one out of four primary carcinoid cell cultures and three out of four primary pheochromocytoma cell cultures. In conclusion, VMATs and secretory granules are of importance for the uptake and retention of (123)I-MIBG in NE tumours. Information about the type and degree of expression of VMATs in NE tumours may be helpful in future to select patients suitable for radiation therapy with radio-iodinated MIBG.

In this study the biodistribution of a somatostatin analogue, (177)Lu-[DOTA(0),Tyr(3)]octreotate, was investigated in an animal model, as a possible therapeutic radiopharmaceutical.(177)Lu-[DOTA(0),Tyr(3)]octreotate was injected i.v. into nude mice bearing somatostatin receptor-positive tumors of the human small cell lung cancer (SCLC) cell line NCI-H69. In addition, nontumor bearing mice were injected i.v. with (177)LuCl(3). The activity concentration in tumor and normal tissues was measured and dosimetric estimations for tumor tissue were made.The tumor had higher activity concentration of (177)Lu-[DOTA(0),Tyr(3)]octreotate compared to all measured normal tissues at all time points. The activity concentration in the tumor tissue was 3.7 %IA/g, 2.1 %IA/g, and 1.2 %IA/g after 24 h, 3 days and 7 days, respectively. The mean absorbed dose to a 1 g tumor was 0.3 Gy/MBq. The highest activity concentration of (177)LuCl(3) was observed in the bone marrow and increased with time.This study shows that (177)Lu-labeled [DOTA(0),Tyr(3)]octreotate has therapeutic potential for SCLC. The study also points out the importance of optimal labeling efficiency since the high bone marrow uptake of free lutetium ions can be controlled by a high peptide-bound fraction.

Neuroendocrine secretory protein 55, NESP55, is an acidic protein belonging to the chromogranin family. The distribution of NESP55 in human tumours is not known. The aim of the present study was to study the expression of NESP55 in human gastrointestinal, pancreatic and adrenal tumours. A total of 118 human endocrine and nonendocrine tumours were examined by immunocytochemistry, and compared to the expression of chromogranin A (CgA) in the same tumours. Pancreatic endocrine tumours (14 out of 25), pheochromocytomas (19 out of 19), and neuroblastomas (seven out of 14) expressed NESP55, with the same strong labelling pattern in both benign and malignant tumours. Expression of NESP55 in pancreatic endocrine tumours and pheochromocytomas was confirmed by Western and Northern blot analysis. Immunocytochemical analysis demonstrated no labelling in ileal carcinoids (zero out of 15), and adrenocortical adenomas (zero out of 15). The majority of gastrointestinal and pancreatic carcinomas were negative for NESP55, with focal staining observed in two out of 30 tumours. In contrast, CgA was present in all neuroendocrine tumours examined (25 out of 25 pancreatic endocrine tumours, 19 out of 19 pheochromocytomas, 14 out of 14 neuroblastomas and 15 out of 15 ileal carcinoids). Thus, the expression of NESP55 in endocrine tumours of the gastrointestinal tract, pancreas and adrenals differs from that of CgA. Neuroendocrine secretory protein 55 is found in a subset of neuroendocrine tumours showing differentiation towards adrenal chromaffin cells and pancreatic islets cells.

In nude mice carrying the human carcionoid GOT1 different amounts of (111)In-DTPA-Phe(1)-octreotide and routes of administration were studied in relation to uptake in tumor and normal organs. The relative organ uptake varied with given amount; highest in tumor after 0.1 and 1 microg and lowest in muscle, heart and blood after 0.1 microg. The uptake decreased in lungs and spleen with higher amounts of (111)In-DTPA-Phe(1)-octreotide. In all organs studied the tumor-to-normal-tissue activity concentration ratio was maximal at 0.1 and 1 microg, but route of administration influenced the uptake only little.

Premature sagittal synostosis results in an elongated, narrow skull shape, scaphocephaly. It has been unclear whether the intracranial volume (ICV) of these children is different from that of normal children. The aim of the present study was to precisely determine the ICV in a large cohort of children with premature sagittal synostosis and to compare it to the ICV of a sex- and age-matched control group. All patients (n = 143) with isolated sagittal synostosis registered in the Göteborg Craniofacial Registry until the end of 2012 with a preoperative CT examination were identified. For each case, a sex- and age- (±30 days) matched control was identified from children who had undergone CT for post-traumatic or neurological reasons. The ICV was measured in a semi-automatic MATLAB program with functions such as region growing, watershed, and thresholding in axial CT slices. The ICV was calculated using the Cavalieri principle. The mean (± SEM) values of ICV for children with sagittal synostosis and for corresponding controls were 866 ± 13 ml and 870 ± 15 ml, respectively. The mean ages of these groups were 173 ± 8 days and 172 ± 8 days, respectively. Subgroup analysis of sex and age at CT (≤180 days and180 days) did not reveal any differences in ICV between cases and controls. Precise determination of ICV in addition to the use of adequate controls has made it possible to conclude that children with premature isolated sagittal synostosis have a normal ICV.

Metopic synostosis results in a keel-shaped forehead, hypotelorism, and an increased interparietal width. This study aimed to measure the frontal and total intracranial volume in patients with metopic synostosis before and after surgery and to compare the effect of 2 different operation methods. All patients operated for isolated metopic synostosis between 2002 and 2008 at Sahlgrenska University Hospital who had undergone preoperative and/or postoperative computed tomographic examination (at 3 y of age) were included. The patients were grouped according to operation method: (1) forehead remodeling in combination with a bone graft or (2) forehead remodeling in combination with a spring. Sex- and age-matched controls were identified. A previously developed MATLAB computer program was used to measure the frontal and total intracranial volumes. Sixty patients and 198 controls were included. Preoperatively, the patients with metopic synostosis had significantly lower frontal volumes than those of the controls (P < 0.001) but equal total intracranial volumes. The operations redistributed the intracranial volume and resulted in an improved, frontal-total intracranial volume ratio. However, at 3 years of age, the frontal volume (P < 0.001), total intracranial volume (P ≤ 0.002), and ratio between the 2 (P < 0.001) were significantly lower in the patients than in the controls. The 2 operation methods were equally efficient in creating an improved frontal-total ratio. Surgery for metopic synostosis improves the distribution of the intracranial volume but does not result in normal total intracranial volume or frontal volume at 3 years of age.

A human midgut carcinoid tumor was successfully transplanted into nude mice and propagated for five consecutive generations (30 months) with well-preserved phenotype. Tumor cells in nude mice expressed identical neuroendocrine markers as the original tumor, including somatostatin receptors (somatostatin receptors 1 to 5) and vesicular monoamine transporters (VMAT1 and VMAT2). Because of the expression of somatostatin receptors and VMAT1 and VMAT2 the grafted tumors could be visualized scintigraphically using the somatostatin analogue 111 In-octreotide and the catecholamine analogue 123 I-metaiodobenzylguanidine. The biokinetics of the somatostatin analogue 111 In-octreotide in the tumors was studied and showed a high retention 7 days after administration. Cell cultures were re-established from transplanted tumors. Immunocytochemical and ultrastructural studies confirmed the neuroendocrine differentiation. The human origin of transplanted tumor cells was confirmed by cytogenetic and fluorescence it situ hybridization analyses. Spontaneous secretion of serotonin and its metabolite, 5-hydroxyindole acetic acid, from tumor cells was demonstrated. The tumor cells increased their [Ca 2+ ] i in response to β-adrenoceptor stimulation (isoproterenol) and K + -depolarization. All somatostatin receptor subtypes could be demonstrated in cultured cells. This human transplantable carcinoid tumor, designated GOT1, grafted to nude mice, will give unique possibilities for studies of somatostatin receptor- and VMAT-mediated radionuclide uptake as well as for studies of secretory mechanisms.

The long time biokinetics of the radiolabeled somatostatin analogues 111 In-DTPA-D-Phe 1 -octreotide was studied in nude mice transplanted with the human carcinoid tumor, GOT1. The results were compared with those from the patient with the original tumor. This patient has been diagnosed and later treated with 111 In-DTPA-D-Phe 1 -octreotide. The animals received about 2 MBq 111 In-DTPA-D-Phe 1 -octreotide (0.1 μg) by injection into a tail vein. The animals were killed 0.5 h-14 d after injection of the radiopharmaceutical. Tumor tissue and normal tissues were collected and weighed and measured for 111 In activity. The 111 In uptake in the tumor was higher than in all normal tissues except the kidneys. The tumor-to-normal-tissue activity concentration, TNC, increased with time for all normal tissues studied. These data were similar to those observed for the original tumor in the patient. The similar biokinetics for 111 In-DTPA-D-Phe 1 -octreotide in the tumor-bearing mice and the patient makes this animal model suitable as a model for evaluation of therapy of somatostatin receptor ( sstr ) expressing tumors with radiolabeled somatostatin analogues. Furthermore, the increase with time of TNC both in mice and the patient indicates that long-lived radionuclides are preferred for therapy with radiolabeled somatostatin analogues.

Objective: To characterise the cholecystokinin (CCK) receptor subtypes in medullary thyroid cancer by measuring the expression of CCK-A and CCK-B/gastrin receptor mRNA. Design: Open study. Setting: Teaching hospital, Sweden. Subjects: 6 patients with medullary thyroid cancer. Intervention: Pentagastrin stimulation test and measurement of calcitonin concentration. Biopsy specimens were analysed using reverse transcription polymerase chain reaction (RT-PCR). Main outcome measure: Presence of CCK-A and CCK-B/gastrin receptors. Results: All 6 patients with medullary thyroid cancer had positive pentagastrin tests preoperatively. CCK-B/gastrin receptors but not CCK-A receptors were detected by RT-PCR in all six biopsy specimens. By contrast, no CCK receptors were found in normal thyroid tissues or in other thyroid tumours (follicular adenoma, papillary carcinoma, or anaplastic carcinoma). Conclusion: The presence of CCK-B/gastrin receptors in medullary thyroid tumours may have important clinical implications.

Ten consecutive patients with Hurthle cell lesions of the thyroid (nodule/adenoma/carcinoma) were studied by 111In-DTPA-D-Phe1-octreotide scintigraphy. Octreotide scintigraphy localized the primary Hurthle cell tumour in eight patients as distinct areas of increased uptake of radionuclide. Two patients with Hurthle cell carcinoma, previously thyroidectomized, had their metastases visualized by octreotide scintigraphy. Northern analyses showed expression of multiple somatostain receptor subtypes. Visualization of the Hurthle cell tumour may be due to a higher expression of somatostatin receptors in the lesions than in surrounding normal thyroid tissue. The tissue/blood 111In concentration ratios for tumour samples from five patients showed clearly higher values than observed for normal connective tissue, muscle or lymph nodes. A relatively high uptake of 111In was also observed in goiter tissue, which may lead to misinterpretations. The main indication for octreotide scintigraphy in patients with Hurthle cell carcinoma is suspicion of metastatic disease. © 1999 Cancer Research Campaign

Several types of neuroendocrine tumor express high numbers of somatostatin receptors (sstr). We have compared the expression of sstr subtypes with the outcome of octreotide scintigraphy in patients with carcinoids and medullary thyroid carcinoma (MTC) in comparison with Hürthle cell tumors. The effect of sstr activation (octreotide treatment) on tumor markers was also studied in patients with disseminated carcinoid tumors. Six patients with carcinoid tumors (four midgut and two foregut), and three patients with thyroid tumors (one MTC, one Hürthle cell carcinoma, and one Hürthle cell adenoma) were studied. Octreotide scintigraphy visualized tumor sites in all nine patients. Macroscopic tumor was verified at these sites at subsequent surgical exploration. Using Northern blotting and subtype-specific riboprobes, sstr could be detected in all tumors examined. All five sstr subtypes were detected in most of the carcinoid tumors. All six carcinoids expressed sstr2. This was in contrast to the findings for the thyroid tumors analyzed, which also expressed several sstr subtypes but in some cases lacked expression of sstr2. This was also the case for normal thyroid tissue. Clinically, octreotide treatment of the patients with midgut carcinoid tumors resulted in palliation of hormonal symptoms accompanied by a significant reduction of urinary 5-HIAA levels (28-71%). These results indicate that carcinoid tumors frequently express all five sstr subtypes. The thyroid tumors also expressed multiple sstr but could lack expression of sstr2. Nevertheless, these tumors were visualized by octreotide scintigraphy, indicating that sstr2 expression is not a prerequisite for tumor imaging.

We have compared the expression of somatostatin receptor (sstr) subtypes with the outcome of somatostatin receptor scintigraphy and the effect of somatostatin receptor activation in patients with disseminated carcinoid tumours. Tumour tissues from nine patients with midgut carcinoids (ileal) and three patients with foregut carcinoids (gastric, thymic) were analysed using Northern blotting. Expression of somatostatin receptors was demonstrated in all tumours (12 out of 12), with all five receptor subtypes present in 9 out of 12 tumours. Somatostatin receptor scintigraphy using [111In]DTPA-D-Phe1-octreotide visualized tumours in all patients (12 out of 12). The 111In activity concentrations in tumour tissue (T) and blood (B) were determined in three tumours 1-7 days after injection of the radionuclide. The T/B 111In activity concentration ratios ranged between 32 and 651. Clinically, treatment with the long-acting somatostatin analogue octreotide resulted in marked symptom relief accompanied by a significant reduction in tumour markers, for example urinary-5-HIAA levels (28-71% reduction). Incubation of midgut carcinoid tumours in primary culture with octreotide (10 microM) resulted in a reduction in spontaneously secreted serotonin (45-71% reduction) and 5-HIAA (41-94% reduction). The results demonstrate that carcinoid tumours possess multiple somatostatin receptor subtypes and that somatostatin analogues such as octreotide, which preferentially bind to somatostatin receptor subtype 2 and 5, can be used in the diagnosis and medical treatment of these tumours. In the future, novel somatostatin analogues with subtype specific receptor profiles may prove to be of value for individualizing the treatment of disseminated carcinoid tumour disease. Images Figure 1

Surgical correction of trigonocephaly is performed by fronto-orbital reshaping and advancement. Some authors supplement the frontoorbital remodelling with direct surgical correction of the hypotelorism, but the role of this step of the procedure has been questioned. At Sahlgrenska University Hospital, hypotelorism in metopic synostosis is treated with spring-assisted surgery (S) in children below 6 months of age and with fronto-orbital advancement with the interposition of a bone graft (BG) in the fronto-orbital region at higher age. The aim of the present study was to evaluate the anterior bony interorbital distance (BIOD) preoperatively and at follow-up in patients operated on with the two techniques and to compare the results with adequate control groups. Preoperatively, the patients affected by metopic synostosis had a significantly reduced BIOD compared to their respective controls (S group: 13.8± 1.6 (mean± SD) mm vs 18.6± 1.4 mm,p < 0.001, BG group: 14.7± 1.0 mm vs 18.8± 1.4 mm, p < 0.001). At 3 years follow-up, BIOD was improved in both groups, but only in the S group the mean BIOD did not differ from the control group (19.7 ± 2.9 mm vs 20.2 mm ± 1.3 mm, p = 0.3). In the BG group the BIOD was still significantly different between patients and controls (17.6 ± 1.8 vs 20.0 ± 1.1 mm, p < 0.001). Spring-assisted surgery performed before 6 months of age can normalise hypotelorism in metopic synostosis. Full correction in a large series of patients has now been achieved for the first time.

Histamine is an important stimulator of gastric acid secretion. In experimental animals, inhibition of acid secretion by long term histamine2 receptor blockade causes hypergastrinemia, proliferation of enterochromaffin-like (ECL) cells, and formation of histamine-producing gastric carcinoids. The aim of this study was to examine the role of gastrin in histamine synthesis and metabolism of the oxyntic mucosa of normal, hyperplastic, and carcinoid-bearing Mastomys natalensis. Administration of exogenous gastrin to normal animals increased histidine decarboxylase (HDC) messenger RNA (mRNA) expression in the oxyntic mucosa within 30 min, indicating that gastrin stimulates histamine synthesis by regulating HDC mRNA abundance. Endogenous hypergastrinemia, induced by short term histamine2 receptor blockade (loxtidine) for 3-29 days, did not induce tumors, but enhanced the expression of HDC mRNA (2- to 4-fold elevated) and histamine contents (2-fold elevated) in the oxyntic mucosa. Long term histamine2 receptor blockade (7-21 months) resulted in sustained hypergastrinemia and ECL tumor formation. Tumor-bearing animals had a 4-fold increase in HDC mRNA expression and histamine contents of the oxyntic mucosa. Urinary excretion of the histamine metabolite methyl-imidazole-acetic acid was 2-fold elevated. Tumor-bearing animals recovering from histamine2 receptor blockade were normogastrinemic and had normal levels of HDC mRNA and histamine in the oxyntic mucosa as well as normal excretion of methyl-imidazole-acetic acid. The results indicate that ECL cell carcinoids developing during hypergastrinemia are well differentiated tumors that respond to high gastrin levels with increased histamine synthesis and secretion.

BACKGROUND Numerous surgical techniques for cranial reconstruction of patients with bicoronal synostosis have been suggested. The outcome is, however, still often suboptimal. METHODS Since 2005, we have, at the Craniofacial Unit, Sahlgrenska University Hospital, Gothenburg, used a standardized surgical technique with advancement and remodeling of the forehead combined with spring distraction of the occipital area. The aim of the current study was to evaluate this operative technique. Eighteen consecutive patients (9 boys and 9 girls) with bicoronal synostosis operated on using this technique were identified. Sixteen patients had syndromic bicoronal synostosis, and 2 had nonsyndromic bicoronal synostosis. Cephalic index was obtained from three-dimensional computed tomography scans, and photographs were analyzed for aesthetic evaluation. RESULTS The preoperative calvarial shape was hyperbrachycephalic in all subjects. Postoperatively, the calvarial shape was, in general, much closer to the norm. The reduction in the mean cephalic index from the preoperative stage (94) to the 3-year follow-up (82) was statistically significant (P < 0.0001). The mean duration of surgery was 155 (SD, 32) minutes, with a mean perioperative bleeding of 237 (SD, 95) mL. The mean hospital stay was 6.3 (SD, 1.5) days, of which the mean intensive care unit stay was 1.6 (SD, 1.2) days. In 2 patients, one of the springs had to be reinserted because of postoperative dislocation. No other major complications were observed. CONCLUSIONS Spring-assisted cranioplasty for bicoronal synostosis is a safe technique, is less invasive than many other cranioplasties, and results in marked improvement in the calvarial shape.

Impaired psychological development in children with single suture craniosynostosis is often described in the literature. The authors' own experience was that these children appeared to have normal psychological development during their first years of life. The aim of the present study was, therefore, to evaluate if parental estimation would reveal any shortcomings in psychological development. All consecutive patients operated on for non-syndromal single suture synostosis between October 2002 and June 2006 were included (n = 66). A questionnaire was filled out by the parents when the child was 3 years old. The questions concerned development of speech, motor control, personal abilities, and emotional development. The results were compared with randomly selected controls of the same age (n = 180) whose parents answered the same questionnaire. The results showed that children operated on for single suture synostosis did not show any signs of lasting disadvantages due to craniofacial surgery. The children did not in any respect suffer from a hampered psychological development up to 3 years of age. In summary the psychological development of patients operated on for single suture synostosis seems to be normal up to 3 years of age as far as parental estimation can reveal.

Four types of gastric carcinoids have been identified: (1) multiple small body-fundus carcinoids associated with chronic atrophic gastritis type A (A-CAG); (2) sporadic solitary lesions without specific pathogenetic background (non-A-CAG); (3) carcinoidosis associated with Zollinger-Ellison/MEN 1 syndrome, and (4) rare tumors, e.g. gastrin cell tumors, neuroendocrine carcinomas and mixed endocrine-exocrine tumors. In a retrospective study of 15 patients with gastric carcinoids (11 A-CAG, 3 non-A-CAG and 1 gastrin cell tumor) over a 10-year period, the histopathological and clinical features were assessed. The A-CAG-type carcinoids were clinically silent with lymph node metastases in 2/11 cases but no hepatic metastases. The non-A-CAG-type carcinoids were malignant with disseminated disease, hormonal symptoms and increased urinary excretion of the main histamine metabolite, MeImAA. Five patients with A-CAG tumors were subjected to antrectomy to remove hypergastrinemia, which is thought to be of pathogenetic importance for these tumors. During the observation period (1.5-8 years) 1 patient developed recurrent tumors, while the other 4 showed persistent argyrophil cell hyperplasia. A prospective treatment protocol of these tumors is suggested with endoscopic removal of less numerous, small lesions as first-step therapy, followed by antrectomy at recurrence. Larger lesions should be excised in combination with antrectomy. Gastrectomy is reserved for the rare cases of invasive tumors with lymph node metastases. As evident from the outcome of patients with non-A-CAG tumors radical surgery should be performed whenever practicable.

Peptide receptor radiation therapy (PRRT) using [(177)Lu-DOTA(0)-Tyr(3)]-octreotate is a new, promising option for treatment of disseminated gastroenteropancreatic neuroendocrine tumors (GEPNETs).During 2006-2008, 26 patients with disseminated GEPNETs were treated with (177)Lu-octreotate. Radiologic response (RECIST), biochemical response [plasma chromogranin-A (P-CgA)], hematologic toxicity [Common Toxicity Criteria (CTC)], absorbed dose to the kidneys (conjugate view method), and glomerular filtration rate (GFR) were analyzed.(177)Lu-octreotate (8 GBq) was given one to five times (median = 3) with a 6-week interval between each. Sixteen of the 26 patients were evaluated radiologically; 6 (38%) had partial response (PR), 8 (50%) had stable disease (SD), and 2 (13%) had progressive disease (PD). Seventeen of the 26 patients were evaluated biochemically; 6 (35%) showed aor=30% decrease, 8 (47%) showed aor=20% increase, and 3 (18%) showed neither aor=30% decrease nor aor=20% increase. The mean absorbed dose to the kidneys was 24 Gy. With a dose limit of 27 Gy to the kidneys, 10 patients did not receive the planned four treatments, while four patients had the potential to receive additional treatment. A significant reduction (p = 0.0013) of GFR was observed at follow-up. Three patients experienced CTC grade 3 hematologic toxicity.By using the absorbed dose to the kidneys as a limiting factor, treatment with (177)Lu-octreotate can be individualized, e.g., overtreatment can be avoided and patients with the potential to receive additional treatment can be identified. Further studies are needed to define tolerance doses to the kidneys so that treatment can be optimized.

Background Hepatic artery embolization (HAE) is a palliative treatment for patients with liver metastases from neuroendocrine tumours. HAE reduces hormonal symptoms, but its impact on survival has been questioned. Methods Biochemical responses and survival in consecutive patients with disseminated liver metastases from midgut carcinoid tumours were studied after HAE. Repeat HAE was performed in selected patients with radiological and biochemical signs of progression. Results Of 107 patients who had HAE, the median survival from the first procedure was 56 (range 1–204) months. Prolonged survival showed a strong correlation with reduction of urinary 5-hydroxyindoleacetic acid (P = 0·003) and plasma chromogranin A (P = 0·001) levels. The biochemical response to repeat HAE was similar to that for the first procedure (P = 0·002). The complication rate was low (7·5 per cent), as was the mortality rate (1·9 per cent) within 1 month of HAE. Conclusion HAE is safe, provides good control of hormonal symptoms, and prolongs survival in biochemically responsive patients. It is a valuable palliative option for patients with midgut carcinoid syndrome due to liver metastases and can be repeated in patients with a favourable response to the first procedure.

Hereditary medullary thyroid carcinoma (MTC) is caused by germline mutations in the RET proto-oncogene, resulting in constitutive activation of the RET tyrosine kinase. A substantial proportion of sporadic MTCs also have RET mutations, making the RET tyrosine kinase a potential therapeutic target in MTC. We have established a transplantable MTC in nude mice from a sporadic human MTC carrying a RET C634R mutation. Transplanted tumors had an exponential growth rate with an approximate doubling time of about 3 weeks, and expressed a neuroendocrine phenotype characteristic of MTC, e.g., expression of calcitonin, chromogranin A (CgA), synaptophysin, synaptic vesicle protein 2 (SV2), vesicular monoamine transporter-1 and -2, carcinoembryonic antigen, cytokeratin 8/18, epithelial cadherin, and neural cell adhesion molecule. Plasma calcitonin and CgA levels were elevated in tumor-bearing mice and correlated with tumor size. Cytogenetic analysis, including spectral karyotyping, confirmed the human origin of the xenografted tumors and demonstrated an abnormal, near triploid karyotype. Treatment of tumor-bearing nude mice with the tyrosine kinase inhibitor ZD6474, which specifically inhibits RET, epidermal growth factor receptor (EGFR), and vascular endothelium growth factor receptor (VEGFR) tyrosine kinases, resulted in a dose-dependent inhibition of tumor growth. Oral ZD6474 given once daily (250 mg/kg, 5 days/week) reduced tumor volume to 11% when compared with controls after 4 weeks. Our results show that this transplantable MTC, designated GOT2, represents a novel and useful model for studies of MTC and RET tyrosine kinase-dependent tumor growth.

The risk for bilateral tumors and long-term outcome after conservative cortical-sparing adrenal surgery was studied in a consecutive single-center series. One hundred fifty-four patients were operated on (1950-2004) for pheochromocytoma (PC=137), or abdominal paraganglioma (PG=17). Twenty had MEN 2 (16 MEN 2A; 4 MEN 2B), 15 von Recklinghausen's disease (VRD), and 1 von Hippel-Lindau (VHL) disease. Twelve patients had, or developed, bilateral adrenal medullary tumors; four with MEN 2A, four with MEN 2B, three with VRD, and one with probably hereditary PC associated with brain tumors/meningioma. Two patients with MEN 2B and one with MEN 2A with had bilateral adrenalectomy (adx). Three VRD patients, two MEN 2B and one MEN 2A patients had cortical-sparing surgery. Two patients were operated on unilaterally, but developed small contralateral tumors; one of these (MEN 2A) had a second asymptomatic PC diagnosed at an older age, so surgery was withheld; the other patient (hereditary PC syndrome) had a small contralateral PC diagnosed at autopsy 9 years later. Only three of nine patients with bilateral operations needed corticosteroid replacement after surgery. Four of six patients died of associated tumors (MTC and meningioma). The mean follow-up was 13 (1-25) years. Twelve MEN 2A patients with unilateral adx have been followed up for 20 (4-36) years without developing a second PC. Cortical-sparing adrenal surgery can safely be performed in the majority of patients with bilateral PC. On the basis of our long-term experience of MEN 2A we perform contralateral adrenal resection only if a second PC is confirmed. Five patients underwent adrenal exploration because of clinical and biochemical findings compatible with PC. Four had asymmetrical positive MIBG scans. They all underwent unilateral adx and diffuse medullary hyperplasia was confirmed (medullary weight estimated morphometrically to 1.0-3.4 g vs. normal weight 0.3-0.5 g in matched controls). These patients have been followed for 19 (5-27) years with normal clinical and biochemical findings. In this rare condition removal of the largest adrenal seems adequate.

Small cell lung cancer (SCLC) is a tumor of neuroendocrine (NE) origin with very low survival rate. Somatostatin receptor scintigraphy using 111In-DTPA-octreotide (DTPA is diethylenetriaminepentaacetic acid) is a well-established method for the visualization of somatostatin receptor-expressing NE tumors. Recently, new combinations of radionuclides and somatostatin analogs have been investigated for therapeutic purposes. In this study, the somatostatin analog DOTA-Tyr3-octreotate (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid), labeled with the medium-energy electron emitter 177Lu (maximal electron energy = 498 keV, half-life = 6.6 d), was used for radiation therapy of human SCLC in an animal model.Nude mice, bearing tumors from the human SCLC cell line NCI-H69, were injected intravenously with 177Lu-DOTA-Tyr3-octreotate. Groups of animals (n = 5 or 6) were injected with 45-, 60-, and 120-MBq fractions and two 45-MBq fractions 48 h apart. Furthermore, 1 control group was treated with unlabeled DOTA-Tyr3-octreotate and another control group was not treated.In both control groups, the tumor volumes were increased 2-fold in approximately 5 d. Treatment with 177Lu-DOTA-Tyr3-octreotate resulted in marked tumor regression with statistically significant tumor volume reduction after 1 wk (P0.001). The tumor growth delay time was dependent on the amount of injected activity for the groups with single injections, 26 d for 60 MBq and 40 d for 120 MBq. The best therapeutic effect was obtained in mice injected with 2 fractions of 45 MBq. The relative tumor volume after 1 mo was 0.004 +/- 0.004.Radiation therapy with 177Lu-DOTA-Tyr3-octreotate on SCLC-bearing mice was successful. Since the experiments were performed on a human SCLC cell line xenografted to nude mice, the results may be clinically relevant and treatment with 177Lu-DOTA-Tyr3-octreotate could be a treatment alternative in this tumor disease that normally has a dismal prognosis.

BackgroundMidgut carcinoid tumours often present with widespread disease making curative surgery impossible. Medical treatment therefore plays a major role in the treatment of these patients.MethodsIn this prospective randomized study, the effect of interferon (IFN) α on survival and risk of tumour progression was evaluated in 68 patients with midgut carcinoid tumours metastatic to the liver. All patients had undergone primary surgical treatment and hepatic arterial embolization of liver metastases before randomization. Patients were randomized to treatment with either octreotide alone (n = 35) or octreotide in combination with IFN-α (n = 33).ResultsForty-one of the 68 patients died during a follow-up period of 33–120 months, equivalent to a 5-year survival rate of 46·5 per cent. There was no significant difference in survival between patients treated with octreotide alone (5-year survival rate 36·6 per cent) and those given octreotide in combination with IFN-α (56·8 per cent). However, patients treated with IFN-α had a significantly reduced risk of tumour progression during follow-up (P = 0·008).ConclusionAddition of IFN-α to octreotide may retard tumour growth in patients with midgut carcinoid tumours.

In this report we present the results of a combined cytogenetic and multicolor spectral karyotype (SKY) analysis of a transplantable human ileal carcinoid (GOT1). By using SKY it was possible to identify the origin and organization of all clonal marker chromosomes and to identify cryptic translocations not detectable by conventional chromosome banding. The stemline karyotype of low passage GOT1 cells was interpreted as 43,XX, der(1)del(1)(?), inv(2)(p25q13), del(3)(p21), del(5)(q13q31), del(6)(q13), -9, -13, -15, del(16) (q22). Analysis of the GOT1 cells after about 2.5 years of propagation in nude mice allowed us to follow the in vivo progression of this tumor. Relatively few additional rearrangements had occurred during this period, indicating that the GOT1 cells are genetically stable. Most of the abnormalities detected result in loss of whole or parts of chromosomes, suggesting that loss of multiple chromosomal regions, presumably containing tumor suppressor genes, might be important genetic events in ileal carcinoids.

Transforming growth-factor-alpha (TGF-alpha) is a 50-amino-acid polypeptide that binds to the epidermal growth factor (EGF) receptor and stimulates cell growth. It has been suggested that enhanced production of TGF-alpha and EGF receptors by tumour cells promote tumour-cell growth by autocrine mechanisms. In the present study we have investigated the expression of TGF-alpha and EGF receptors in human neuroendocrine tumours, including midgut carcinoid tumours, phaeochromocytomas and medullary thyroid carcinomas. TGF-alpha expression was demonstrated in biopsies of all tumours examined (n = 30) and EGF receptors in a majority of tumours by Northern analysis and/or immunocytochemistry. Expression of TGF-alpha and EGF receptors was also demonstrated in primary cultures of tumour cells. Carcinoid tumours and phaeochromocytomas in culture secreted detectable amounts of TGF-alpha into the culture medium (400-700 pM). The amount of secreted TGF-alpha could be suppressed by octreotide treatment in individual tumours. Administration of exogenous TGF-alpha stimulated carcinoid tumour growth in vitro as determined by the DNA contents of cell cultures. The growth-stimulatory effect of TGF-alpha could be partially blocked by the use of neutralizing anti-EGF receptor monoclonal antibodies (MAbs). In conclusion, several human neuroendocrine tumours express both TGF-alpha and EGF receptors in in vivo and in vitro, suggesting that TGF-alpha may regulate tumour-cell growth by autocrine mechanisms.