Anti-tumor necrosis factor treatment in cherubism--clinical, radiological and histological findings in two children.

Cherubism is a rare and disfiguring genetic disorder with excessive bone resorption and multilocular lesions in the mandible and/or maxilla. The disease-causing gain-of-function mutations in the SH3-binding protein 2 (SH3BP2) gene result in increased myeloid cell responses to macrophage colony stimulating factor and RANK ligand, formation of hyperactive osteoclasts (giant cells), and hyper-reactive macrophages that produce excessive amounts of the inflammatory cytokine tumor necrosis factor α (TNF-α). Recent findings in the cherubism mouse model suggest that TNF-α plays a major role in disease pathogenesis and that removal of TNF-α prevents development of the bone phenotype. We treated two children with cherubism with the TNF-α antagonist adalimumab for approximately 2.5 years and collected extensive clinical, radiological and histological follow-up data during the treatment. Histologically the treatment resulted in a significant reduction in the number of multinucleated giant cells and TNF-α staining positivity in both patients. As evaluated by computed tomography and magnetic resonance imaging, the lesions in Patient 1 showed either moderate enlargement (mandibular symphysis) or remained stable (mandibular rami and body, the maxilla). In Patient 2, the lesions in mandibular symphysis showed enlargement during the first 8 months of treatment, and thereafter the lesions remained unchanged. Bone formation and resorption markers remained unaffected. The treatment was well tolerated. Based on our findings, TNF-α antagonist may decrease the formation of pathogenic giant cells, but does not result in lesion regression or prevent lesion expansion in active cherubism. TNF-α modulator treatment thus does not appear to provide sufficient amelioration for patients suffering from cherubism.

Investigating the etiology of multiple tooth agenesis in three sisters with severe oligodontia.

OBJECTIVES: To describe the dentofacial phenotypes of three sisters with severe non-syndromic oligodontia, to report on the mutation analysis in three genes, previously shown to cause various phenotypes of non-syndromic oligodontia and in two other suspected genes. Based on the phenotypes in the pedigree of this family, the different possible patterns of transmission are discussed. METHODS: Anamnestic data and a panoramic radiograph were taken to study the phenotype of the three sisters and their first-degree relatives. Blood samples were also taken to obtain their karyotypes and DNA samples. Mutational screening was performed for the MSX1, PAX9, AXIN2, DLX1 and DLX2 genes. RESULTS: The probands' pedigree showed evidence for a recessive or multifactorial inheritance pattern. Normal chromosomal karyotypes were found and - despite the severe oligodontia present in all three sisters - no mutation appeared to be present in the five genes studied so far in these patients. CONCLUSIONS: In the three sisters reported, their common oligodontia phenotype is not caused by mutations in the coding regions of MSX1, PAX9, AXIN2, DLX1 or DLX2 genes, but genetic factors most probably play a role as all three sisters were affected. Environmental and epigenetic factors as well as genes regulating odontogenesis need further in vivo and in vitro investigation to explain the phenotypic heterogeneity and to increase our understanding of the odontogenic processes.

[Treatment of colorectal cancer liver metastases]. / Il trattamento delle metastasi epatiche da cancro del colon-retto.

Liver is the main target for colorectal cancer (CRC) metastases. About 50% of all patients affected by CRC develop liver metastases. Surgery remains the only potentially curative strategy and indications to surgery and resectability criteria are now less restrictive than before so that a more aggressive attitude in the treatment of metastatic lesions is the rule. However surgery is not possible in the majority of patients. For non resectable patients two options are available: local treatment strategies (Radio-frequency ablation and Cryosurgery: alone or in combination with surgery) and chemotherapy. High rates of objective response achieved with Fluoropyrimidines, Oxaliplatin (OHP) and Irinotecan (CPT-11) based chemo-therapy, enable initially unresectable patients to undergo surgery, with a 5-year survival rate comparable to that observed for primary resectable patients. Therefore chemotherapy has not only a palliative aim, but becomes a fundamental moment of a combined medical and surgical treatment with curative purpose. After surgery two-thirds of patients will relapse in first two years, so that adjuvant therapy has been investigated to reduce recurrence rates, mainly testing hepatic arterial infusion (HAI) schedules. So far no randomized trials have been published on the role of systemic intravenous adjuvant chemo-therapy. Finally we report the results of our monoinstitutional experience, suggesting a possible role of systemic adjuvant chemotherapy in reducing recurrence rates after liver metastasectomy. Probably in the next years new targeted drugs and locoregional therapies will contribute to further improve prognosis of such patients, in a neoadjuvant, adjuvant and palliative setting.

Characteristics of incisor-premolar hypodontia in families.

Nonsyndromic tooth agenesis is a genetically and phenotypically heterogenous condition. It is generally assumed that different phenotypic forms are caused by different mutated genes. We analyzed inheritance and phenotype of hypodontia and dental anomalies in 214 family members in three generations of 11 probands collected for genetic linkage study on incisor-premolar hypodontia (IPH). Our analysis confirms the autosomal-dominant transmission with reduced penetrance of IPH. The prevalence of hypodontia and/or peg-shaped teeth was over 40% in first- and second-degree relatives and 18% in first cousins of the probands. Four of nine noted obligate carriers of hypodontia gene had dental anomalies, including small upper lateral incisors, ectopic canines, taurodontism, and rotated premolars. These anomalies were also observed at higher than normal frequency in relatives affected with hypodontia. We conclude that incisor-premolar hypodontia is a genetic condition with autosomal-dominant transmission and that it is associated with several other dental abnormalities.

Identification of a nonsense mutation in the PAX9 gene in molar oligodontia.

Development of dentition is controlled by numerous genes, as has been shown by experimental animal studies and mutations that have been identified by genetic studies in man. Here we report a nonsense mutation in the PAX9 gene that is associated with molar tooth agenesis in a Finnish family. The A340T transversion creates a stop codon at lysine 114, and truncates the coded PAX9 protein at the end of the DNA-binding paired-box. All the affected members of the family were heterozygous for the mutation. The tooth agenesis phenotype involves all permanent second and third molars and most of the first molars and resembles the earlier reported phenotype that was also associated with a PAX9 mutation. The phenotype is presumably a consequence of haploinsufficiency of PAX9. In another Finnish family with molar tooth agenesis, we could not find similar sequence changes in PAX9.

Impact of a 4-week treatment with prostaglandin E1 on health-related quality of life of patients with intermittent claudication.

Intermittent claudication impairs functional status and quality of life in many patients by limiting walking capacity. The aim of this study was to evaluate the effects of a 4-week treatment with prostaglandin E1 (PGE1), a drug inducing vasodilation and inhibiting platelet aggregation, on improving functional status and health-related quality of life in patients with disabling intermittent claudication. Forty-two untrained outpatients (37 men and five women, mean age 64 +/- 8 years) with intermittent claudication,and maximum walking distance (MWD) of at least 50 and no more than 200 m on treadmill test (5% slope, 3 km/hr) were randomized to 4 weeks of double-blind treatment either with 60 mcg PGE1 daily given IV in 250 mL saline over a period of 2 hours (21 patients) or placebo (250 mL saline, 21 patients). Treatment-free follow-up was completed 8 weeks after the final infusion. Pain free walking distance (PFWD), MWD, and questionnaire evaluation were determined at baseline, after the 4-week treatment period, and at the end of the 8 weeks of the treatment-free follow-up period. After 4 weeks of treatment with PGE1 PFWD and MWD increased from 72 +/- 16 m to 135 +/- 33 m (+87%, p<0.001)and from 140 +/- 30 m to 266 +/- 62 m (+90%, p<0.001), respectively. Analysis of the Walking Impairment Questionnaire responses in the PGE1 group at 4 weeks demonstrated significant improvements in the walking impairment score (+19 percentage points, p<0.001), in the distance score (+25 percentage points, p<0.001), in the speed score (+24 percentage points, p<0.001), in the stair climbing score (+20 percentage points, p<0.001). The RAND survey responses showed improvements in physical function and bodily pain scores (+14 percentage points, p<0.001, and +15 percentage points, p<0.01, respectively). After the treatment-free follow-up period of 8 weeks, increases in PFWD and MWD were maintained (113 +/- 26 m, +57%, p<0.001, and 229 +/- 55 m, +63%, p<0.001, respectively). Similarly, at the end of the treatment-free follow-up, the walking impairment score (+16 percentage points, p<0.001), the distance score (+23 percentage points, p<0.001), the speed score (+22 percentage points, p<0.001), the stair climbing score (+18 percentage points, p<0.001) as well as the RAND physical function and bodily pain scores (+10 percentage points, p<0.001, and +13 percentage points, p<0.01, respectively) were still increased compared with baseline. No change from baseline was found in all the target parameters in the placebo group after 4 weeks of treatment and at the end of the treatment-free follow-up period. These data show that a 4-week treatment with PGE1 improves functional status and quality of life as well as treadmill performance in patients with disabling intermittent claudication as compared with placebo-treated patients. The improvements are also maintained for a period of 8 weeks beyond the end of the treatment. Additional studies are needed to determine the duration of functional benefits after the end of treatment.

Treadmill exercise-induced release of endothelin-1 in patients with peripheral arterial occlusive disease at Fontaine stage IIb.

BACKGROUND: Endothelin-1 (ET-1) is an endothelial vasoconstrictor mitogenic peptide which is thought to be a marker of endothelial damage and a potential participant in the pathophysiological processes of the development of atherosclerotic lesions and disease states associated with vasoconstriction and vasospasm. METHODS: To investigate the endothelin-1 release in response to dynamic exercise in patients with peripheral arterial occlusive disease (PAOD), plasma concentrations were determined by radioimmunoassay in 16 patients (14 men, 2 women, mean age 56.2 +/- 8.1 years) with peripheral arterial occlusive disease at Fontaine stage IIb and in 10 control subjects (8 men, 2 women, mean age 58.1 +/- 7.2 years) in normal health during treadmill testing (slope 5%, speed 3 km/hr). Blood samples were collected at rest from an antecubital vein, at the onset of claudication pain, and 10 minutes after exercise. RESULTS: Mean plasma endothelin-concentrations during the stress test increased significantly in the patients with arterial disease, rising from basal values of 4.4 +/- 0.6 pmol/L to values of 8.9 +/- 0.7 pmol/L at the end of the test (p < 0.0001), whereas it did not change significantly in control subjects (rising from 2.6 +/- 0.4 pmol/L to 2.7 +/- 0.5 pmol/L). Further, plasma endothelin- in the patients with arterial disease was at all times higher than in the control subjects (p < 0.0001). CONCLUSIONS: In conclusion, this study shows that in patients with peripheral arterial occlusive disease, plasma endothelin-1 increases after treadmill exercise performed until claudication pain supervenes. Raised endothelin-1 could be a marker of ischaemic acute endothelial damage and/or could contribute to increase the vascular resistance in ischaemic limbs of these patients during dynamic exercise by promoting arterial/arteriolar vasoconstriction or vasospasm.

Effects of a 4-week treatment with prostaglandin E1 on plasma endothelin-1 release in patients with intermittent claudication.

OBJECTIVE: Endothelin-1 (ET-1) is a vasoconstrictor mitogenic peptide whose plasma concentrations are increased in patients with peripheral arterial occlusive disease (PAOD). The aim of this study was to investigate whether changes in plasma ET-1 concentrations occur after a 4-week treatment with prostaglandin (PG) E1 in patients with intermittent claudication. PATIENTS, MATERIAL AND METHODS: Twenty-four non-trained outpatients with Fontaine stage II PAOD (20 men and 4 women, mean age 63+/-7 years, age range 48-72 years) were randomized to receive over a 4-week period either PGE1 (60 microg given daily i.v. over 2 hours in 250 ml saline, n = 12) or placebo (250 ml saline, n = 12). Plasma levels of ET-1 were measured by radioimmunoassay at baseline and after treatment period. Before and after treatment pain-free walking distance (PFWD) and maximum walking distance (MWD) were evaluated by treadmill walking test as the target parameters for assessing treatment efficacy. RESULTS: At week 4, PFWD and MWD significantly increased in comparison to baseline only in PGE1 treatment group (from 136+/-38 m to 246+/-95 m, p = 0.0004, and from 238+/-54 m to 411+/-137 m, p = 0.0001, respectively). At the end of the treatment period with PGE1, ET-1 plasma concentration decreased from 4.50+/-0.8 pmol/l to 3.6+/-1.1 pmol/l (p = 0.002), whereas it remained unchanged in placebo group. A significant correlation between the decrease in ET-1 plasma levels and the increase in the PFWD and MWD (r = -0.92, p < 0.0001; r = -0.78, p = 0.002, respectively) was detected in PGE1 treatment group. CONCLUSIONS: Reduced ET-1 plasma concentrations after PGE1 treatment could be an index of improved endothelial function and/or could contribute to a reduction in vascular resistance and vessel wall growth in PAOD patients. Moreover, plasma ET-1 could be a marker of clinical improvement in these patients.

Plasma endothelin-1 levels in patients with peripheral arterial occlusive disease at different Fontaine's stages.

UNLABELLED: Endothelin-1 (ET-1) is a potent vasoconstrictor and mitogenic peptide produced and secreted by endothelial cells, which can play a potential role in the development of atherosclerosis and in the pathophysiology of extreme vasoconstriction of various diseases. METHODS: To assess plasma endothelin-1 (ET-1) concentrations in patients with peripheral arterial occlusive disease (PAOD) at different Fontaine's stages, we measured plasma ET-1 by radioimmunoassay in 14 stage II PAOD patients (12 men, 2 women; mean age 59.5 +/- 3.4 years) and in 10 stage III-IV PAOD patients (8 men, 2 women, mean age 61.2 +/- 3.3 years). Ten normal subjects (8 men, 2 women, mean age 58.1 +/- 7.2 years) were considered as controls. RESULTS: Mean (+/- SD) plasma ET-1 levels, as measured by radioimmunoassay, were significantly greater in stage II and stage III-IV PAOD patients than in control subjects (4 +/- 0.4 and 5 +/- 0.4 pmol/L vs 2.5 +/- 0.6 pmol/L, respectively, p < 0.001). Furthermore, plasma levels of ET-1 in stage III-IV patients were significantly higher than in stage II patients (p < 0.01). A significant correlation was found between plasma ET-1 levels and number of the arterial obstructive lesions in PAOD patients (r = 0.698; p < 0.0001). No significant correlation was found between plasma ET-1 concentrations and pain-free walking distance (r = -0.279, p = 0.333, in stage II patients; r = 0.137, p = 0.705, in stage III-IV patients), and between plasma ET-1 levels and ankle/arm pressor index (r = 0.032, p = 0.913, in stage II patients; r = 0.149, p = 0.681, in stage III-IV patients) in the PAOD patients. CONCLUSIONS: Raised plasma ET-1 could be a sensible marker both of endothelial damage and disease extension. It could also promote the progression of atherosclerotic plaques and enhance the microvascular resistance in these patients.

Short root anomaly in families and its association with other dental anomalies.

In the present study, we collected a family series with short root anomaly in order to analyze the inheritance pattern of the condition. Another aim was to identify in these families an association with other dental anomalies, such as tooth agenesis, peg-shaped lateral incisors, supernumeraries, ectopia, and such morphological characteristics as invaginations, taurodontism, and a tendency to root resorption. Mesiodistal dimensions of the crowns of the affected teeth were measured in order to reveal any association with reduction or increase in tooth size. The apparent genetic heterogeneity of the pedigrees did not permit definitive conclusions as to the mode of inheritance. Autosomal dominant transmission of short root anomaly was seen in 3/8 families. In 2/8 families, the condition was seen in siblings but not in parents. An association with tooth agenesis and ectopic canines was noted, the prevalences of which were 46% and 33%, respectively. We stress the importance of not misdiagnosing this anomaly as resorption.

Palatal displacement of canine is genetic and related to congenital absence of teeth.

The palatally displaced canine is a harmful complication of dental development. It appears in 1 to 2% of the Western population. According to our clinical experience, this anomaly is seen in families in which missing and peg-shaped teeth are common. It could be caused by the same genetic component that causes incisor-premolar hypodontia. We examined 106 patients who had been operated on and treated orthodontically for palatally impacted canine(s). The patients and their family members were examined for dental anomalies. One hundred and ten first- and 93 second-degree relatives were clinically and radiologically examined, and 35 pedigrees were constructed. Thirty-six percent of the patients had congenitally missing permanent teeth (hypodontia), which is 4.5 times the population prevalence. Hypodontia was noted in 19 to 20% of both the first- and second-degree relatives. This is 2.5 times the population prevalence. Frequency of missing teeth, analyzed by tooth groups, was of the same order as that shown for incisor-premolar hypodontia in the Western population. In six of the 35 pedigrees, a palatally impacted canine was noted in several generations of the same family. Prevalence of this anomaly was 4.9% in the studied group, which is 2.5 times the population prevalence. From the findings, we conclude that the palatally displaced canine belongs to the spectrum of dental abnormalities related to hypodontia.

Gene defect in hypodontia: exclusion of EGF, EGFR, and FGF-3 as candidate genes.

Hypodontia, congenital absence of one or a few permanent teeth without any systemic disorders, is regarded as an autosomally inherited dominant condition with varying expression and incomplete penetrance. Many studies have reported that the prevalence of hypodontia varies from 5% to 10% among European and Asian populations. The teeth most often missing are second premolars, upper lateral incisors, and lower central incisors. Consequently, we call this trait incisor-premolar hypodontia. Peg-shaped or strongly mesio-distally reduced upper lateral incisors demonstrate variation in the expression of the trait. The gene or genes causing incisorpremolar hypodontia are not known. We have begun the genetic mapping of hypodontia by using linkage analyses in seven Finnish three-generation families with 77 individuals, 31 affected with incisor-premolar hypodontia. As the first step, we studied the possibility of linkage between hypodontia and some candidate genes which have been suggested to have important functions during tooth development. Here we report the exclusion of EGF, EGFR, and FGF-3 loci as possible sites for gene mutation causing incisor-premolar hypodontia in our family material. Because of the close location of the FGF-3 and FGF-4 genes, the results also suggest the exclusion of the FGF-4 locus.

Gene defect in hypodontia: exclusion of MSX1 and MSX2 as candidate genes.

Hypodontia, congenital lack of one or a few teeth, is an autosomally inherited dominant trait. Homeobox genes MSX1 and MSX2 are expressed in presumptive dental tissues at the stage of initiation of tooth development. Recently, tooth development was shown to be inhibited in transgenic mice lacking a functional Msx1 gene. Here, we studied the relationship of the MSX1 and MSX2 genes to familial hypodontia in five Finnish families with a total of 20 affected individuals, by linkage analysis. The pairwise lod-scores regarding the intragenic microsatellites in the MSX1 and MSX2 genes at a recombination fraction of 0.0 were -3.1 and -3.0, respectively, thus excluding these genes as causative loci for hypodontia in these families.

Craniofacial and dental characteristics of Silver-Russell syndrome.

We found significant differences in a craniometric, cephalometric, and dental study of 19 Silver-Russell syndrome patients (13 without growth hormone treatment) with appropriate controls. Although head circumference was normal for age, head length was increased, while cranial and facial widths and facial heights were reduced. Posterior facial height, posterior cranial base length, cranial base height, and mandibular body size were significantly smaller than in healthy children of the same height. Articulatory speech disorders were common. Enamel defects pointed to an early prenatal insult. Delayed dental age and small mandibular and cranial base dimensions support the possibility of physiological growth hormone deficiency in many Silver-Russell syndrome children; however, facial soft tissue structures were strikingly different from those observed in classical growth hormone deficiency.