Transformation-specific matrix metalloproteinases (MMP)-7 and MMP-13 are expressed by tumour cells in epidermolysis bullosa-associated squamous cell carcinomas.

BACKGROUND: Patients with recessive dystrophic epidermolysis bullosa (RDEB) have an increased risk of developing rapidly progressive and metastatic cutaneous squamous cell carcinomas (SCC). It is unclear why these SCC behave more aggressively than sporadic SCC. Matrix metalloproteinases (MMP) are a family of endopeptidases that contribute to growth, invasion and metastasis of SCC. The role of MMP in RDEB-associated SCC is not known. OBJECTIVES: To investigate the expression of MMP-7, MMP-13 and MMP-9 in RDEB-associated SCC in comparison with sporadic SCC and Bowen's disease. METHODS: Immunohistochemical analysis of 25 RDEB-associated SCC, 61 sporadic SCC and 28 sporadic lesions of Bowen's disease was carried out using monoclonal antibodies for MMP-7, MMP-9, MMP-13 and E-cadherin and syndecan-1. RESULTS: MMP-7 was detected in all RDEB-associated SCC, in tumour cells within the invasive edge, where E-cadherin and syndecan-1 were markedly diminished or absent. MMP-7 expression was also observed in 98% of sporadic SCC and in 68% of Bowen's diseases. MMP-7 staining was significantly stronger in RDEB-associated SCC than in sporadic SCC, and was most abundant in poorly differentiated tumours. MMP-13 was detected in tumour cells in 96% of RDEB-associated SCC and in all sporadic cutaneous SCC. MMP-9 was detected in the inflammatory cells in all SCC examined. CONCLUSIONS: These results identify MMP-7 and MMP-13 as tumour cell-specific markers for SCC progression and as potential therapeutic targets in RDEB-associated SCC. The pattern of immunolabelling suggests that MMP-7 may shed E-cadherin and syndecan-1 from the SCC cell surface.

Novel mutations in the ATP2C1 gene in two patients with Hailey-Hailey disease.

Benign familial chronic pemphigus (Hailey-Hailey disease, HHD) is a rare hereditary condition characterized by development of blisters at sites of friction and in the intertriginous areas. Mutations in the ATP2C1 gene, which encodes the human secretory pathway calcium ATPase 1 (hSPCA1), have been identified as possible causative mutations. Studying Hungarian patients with HHD, we found two novel, distinct, heterozygous mutations. In a 65-year-old man with a 41-year history of severe recurrent symptoms, a single nucleotide insertion, 1085insA, was detected. In a patient whose symptoms were induced by environmental contact allergens, we found a nonsense mutation, Q506X, in exon 17. Our study further illustrates the diversity of mutational events in the pathogenesis of HHD.

High frequency of the 425A-->G splice-site mutation and novel mutations of the COL7A1 gene in central Europe: significance for future mutation detection strategies in dystrophic epidermolysis bullosa.

BACKGROUND: Mutations in the type VII collagen gene (COL7A1) are responsible for dominant and recessive forms of dystrophic epidermolysis bullosa (DEB). These mutations are usually specific for individual families; only a few cases of recurring mutations have been identified. OBJECTIVES: Forty-three unrelated Hungarian and German patients with different DEB phenotypes were screened for novel and recurrent COL7A1 mutations. METHODS: All patients were classified based on clinical and genetic findings, skin immunofluorescent antigen mapping, and electron microscopic studies. Mutation analysis was performed by amplification of genomic DNA with polymerase chain reaction using COL7A1-specific primers, heteroduplex analysis, and direct nucleotide sequencing. Restriction endonuclease digestion was used for family screening and mutation verification. Results In this group of patients, the splice-site mutation 425A-->G was observed frequently, in 11 of 86 alleles (12.8%), once in homozygous form and in nine cases in heterozygous form. One of 100 control alleles from clinically unaffected individuals also carried the mutation. We also identified three novel mutations: the 976-3C-->A splice-site mutation, and the 4929delT and 8441-15del20 deletions. CONCLUSIONS: High recurrence of the splice-site mutation 425A-->G in central European patients with DEB should be taken into account when designing COL7A1 mutation detection strategies. Reporting of three novel COL7A1 mutations in this study further emphasizes the molecular heterogeneity of DEB and provides more information for studies on genotype-phenotype correlations in different DEB subtypes.

Identification of mutations in the ATP2A2 gene in patients with Darier's disease from Hungary.

Mutation analysis in the ATP2A2 gene had been performed in eight Hungarian patients with Darier's disease (DD), to get more information about phenotype-genotype relations. All patients had moderate to severe skin symptoms. Polymerase chain reaction (PCR) amplification of the entire coding region of ATP2A2 was performed. Mutation detection strategies included heteroduplex scanning by conformation-sensitive gel electrophoresis (CSGE) and direct nucleotide sequencing. We found distinct, heterozygous mutations (five missense, one nonsense, one deletion, and one insertion), six of which were novel. In a 31-year-old DD woman with learning difficulties we disclosed a previously described missense mutation (D702N) in exon 15. A 44-year-old DD woman had a novel T insertion at nucleotide 559 in exon 7 of the ATP2A2 gene, which resulted in a premature termination codon (PTC) at codon 192. A woman, whose skin symptoms developed unusually late, at the age 50, had a new T deletion (1320delT) in exon 11 resulting in a PTC at codon 448. Our most severe case had a known missense mutation N39T, resulting in a non-conservative amino acid change at the upstream stalk region. Three new missense mutations (A161D, R164S, and Q790P) affected conservative regions of the SERCA2 protein within the activation (A)-domain and the M6 transmembrane region. A further new nonsense mutation (C909X) was detected in the M8 transmembrane domain. Our data suggest that differences in DD phenotypes are probably also related to factors different from the type of causative mutation.

[Surgical treatment of acquired, benign esophago-respiratory fistulas]. / Die chirurgische Behandlung gutartiger Fisteln zwischen dem Osophagus und dem Respirationstrakt.

BACKGROUND: Acquired, benign esophago-respiratory fistula occurs as a rare complication of different disorders. STUDY DESIGN: Over a period of 30 years, 37 patients with acquired, benign esophago-respiratory fistulas were treated at the authors' institutions. 35 of the 37 patients were operated upon. Acute operation involved primary repair of the trachea and esophagus, or intubation of the gullet and/or gastrostomy. Elective operations were performed on 13 patients. RESULTS: Complications were observed in 14 patients. There were 4 cases with anastomotic leakage (all of them on the neck). Direct closure was carried out in 2 patients; the remaining 2 cases healed spontaneously. None of the 4 patients died. Seven of the 37 patients died (18.9%). This seems acceptable in view of the severity of the cases and the extension of the operations. CONCLUSIONS: 1. The causes of a majority of the esophago-respiratory fistulas in this material are connected with the complications of corrosive injury and peptic stricture of the esophagus. 2. The well-known fact that most of these fistulas occur in the right chest is confirmed. 3. Gastrostomy and/or intubation of the gullet seems to be the best solution for this lesion in the acute cases and in severely ill patients. 4. In elective cases, reconstruction is suggested, if possible in one step.

Identification of two novel nonsense mutations in the transglutaminase 1 gene in a Hungarian patient with congenital ichthyosiform erythroderma.

Congenital ichthyosiform erythroderma (CIE) belongs together with lamellar ichthyosis (LI) to the group of autosomal recessive congenital ichthyoses (ARCI). Mutations in the transglutaminase (TGase) 1 gene (TGM1) have been identified in several families with LI and in some families with CIE. We report a case of CIE with two new nonsense mutations: a C7780G transversion in exon 11 resulting in a premature stop codon at aminoacid residue Y503X and a C8533G transversion in exon 13 leading to a nonsense mutation at S669X. These mutations were also identified in a heterozygous pattern in the unaffected parents. These two termination-codons result in the translation of a truncated protein at the C-terminal end domain of the TGM 1 molecule. B.C1 monoclonal antibody failed to detect TGase 1 in the patient's skin sample, and TGase activity measured by monodansyl cadaverine-incorporation showed the reduced TGase activity at the distribution of TGase 1 in the epidermis.

Dystrophic epidermolysis bullosa complicated by cutaneous squamous cell carcinoma and pulmonary and renal amyloidosis.

A 25-year-old woman with Hallopeau-Siemens recessive dystrophic epidermolysis bullosa had generalized blistering, scarring and milia since birth. In the course of the disease, acral pseudosyndactyly developed, and the patient suffered from corneal erosions, oesophageal strictures, malabsorption, recurrent severe pneumonias and nephrotic syndrome. In addition, she had severe anaemia, sideropaenia, hypocalcaemia, heavy proteinuria and hypoalbuminaemia. A rapidly growing skin squamous cell carcinoma developed on the neck that spread to axillary and cervical lymph nodes. Recurrent hypocalcaemic tetanic convulsions and dyspnoea and a pneumonia refractory to antibiotics led to the premature demise of the patient. Autopsy revealed extensive amyloidosis of the renal, hepatic and splenic tissues. AA type amyloid deposits were detected in the renal glomeruli and in the lung, explaining the patient's unusually severe pulmonary infections. In essence, the patient had severe recessive dystrophic epidermolysis bullosa, complicated by squamous cell carcinoma, recurrent pneumonias and nephrotic syndrome due to secondary amyloidosis of the kidney and lung. The possibility of secondary pulmonary amyloidosis should be considered in severe dystrophic epidermolysis bullosa patients with recurrent pulmonary infections.

Identification of a novel mutation in 3beta-hydroxysteroid-Delta8-Delta7-isomerase in a case of Conradi-Hünermann-Happle syndrome.

The X-linked dominant Conradi-Hünermann-Happle (CDPX2, MIM 302960) syndrome belongs to the rare, heterogeneous group of diseases called chondrodysplasia punctata. The disease has been connected recently with deficiency of 3beta-hydroxysteroid-Delta8-Delta7-isomerase (also called emopamil-binding protein, EBP), catalysing an intermediate step in the conversion of lanosterol to cholesterol (1, 2). We report a case of CDPX2 with a new missense mutation (C-->G 439) in exon 4, leading to a R147G aminoacid substitution in the EBP.

Different techniques for creating oesophageal anastomoses. A historical review and personal experience.

UNLABELLED: Among the surgical techniques used to create a reliable oesophageal anastomosis, mention should be made of the handmade (in one or two layers, wire or Vicryl) and the different stapler anastomoses. 41 oesophageal anastomoses were performed by stapler technique between 4 March 1985 and 4 March 1991. The EEA stapler was used in 15, and the SPTU stapler in 26 patients. The average age was 56.8 years overall, 53.6 in the female (7 patients) and 57.4 years in the 34 male patients. Tumours in the middle and lower third of the oesophagus and on the cardia were the indications for resection in 30 instances. Total gastrectomy was performed in 9 patients and oesophageal resection for peptic stricture in 2 cases. Replacement with stomach was carried out after oesophageal resection (17 patients), and with Roux-loop in 24 cases. The EEA anastomoses were not covered by a hand-made layer of interrupted sutures as is compulsory in the case of the SPTU gun. The intraoperative complication rate was 12.2%--two severe complications with the SPTU and 3 mild ones with the EEA (2 cases) and SPTU (1 case) machines. The postoperative complication rate was 17%--the severe ones with the SPTU gun. The only fatal anastomosis insufficiency was observed in this group. 3 of the 41 patients died--a mortality rate of 7.3%--but only one of them was due to technical failure in the SPTU group: 2.4%. CONSEQUENCES: Both the intra- and postoperative complications were more severe with the SPTU technique. The early postoperative complications are closely related to the intraoperative ones. Mortality due to technical failure was only observed in the SPTU group. The EEA stapler gun is superior in every respect to the SPTU sewing-machine. The future belongs to the even more sophisticated bent and modifiable devices. These were used in our Department Between 1992 and 1997, with practically no morbidity and no mortality. Although they are the most expensive of all the possibilities, the low morbidity and mortality rates pay off from the aspects of the short hospital stay and the savings in human life.

Bypass with transdiaphragmatic Roux loop in nonresectable malignant stricture of the lower oesophagus.

Bypass with a Roux-en-Y loop is proposed for palliation of nonresectable malignant obstruction in the distal oesophagus and cardia without peritoneal dissemination. Over a 15-year period, 51 transdiaphragmatic Roux-en-Y procedures with side-to-end oesophagojejunal anastomosis were performed. The 11.8% mortality was unrelated to anastomotic leakage. Gastrostomy should be avoided because of its nutritional and psychologic disadvantages. Other methods for surgical bypass are discussed and comparison is made with intubation. Wider indications for the Roux loop bypass are mentioned.

[Development of esophageal cancers in patients following cardiomyotomy]. / Entstehung von Speiseröhrencarcinomen bei kardiomyotomierten Patienten.

During a 20 year period we observed that in six patients with carcinoma of the esophagus associated with achalasia, four patients had had a prior Heller operation. Fifty patients with achalasia of the esophagus took part in endoscopic and histologic surveillance 5-15 years after cardiomyotomy. We have found a correlation between the severity of histologic changes and the duration of symptoms before the operation. It seems reasonable to advise early therapy to avoid the development of a dilated, poorly emptying esophagus. Our results suggest that long-term regular surveillance of the patient with achalasia is essential even after surgical treatment.

Late malignant transformation of chronic corrosive oesophageal strictures.

The number of patients with scar carcinoma of the oesophagus developing on the basis of a corrosive stricture seems to have been rising in the past two decades. 36 patients of this kind were treated surgically between 1965 and 1984; this is the second largest series in the literature. The patients with scar cancer comprised 7.2% of the overall oesophageal carcinoma cases; this ratio is currently the highest of all in the literature. The interval between the caustic burn and the diagnosis of scar carcinoma was found to be 46.1 years; this is higher than the 30-35 years generally accepted so far. It was 50.9 years in those patients who drank lye before the age of 12, but 14 years less when it happened in adulthood. The long-term survival time proved to be excellent: 45.6% of the resected cases were alive after 5 years and 14.4% after 10 years. The explanation of the good prognosis lies in the fact that carcinoma developing in a lye stricture is at first surrounded by a rigid scar which allows only its intraluminal growth, and it causes early dysphagia through luminal obstruction. Early dissemination is prevented for the same reason. One-stage resection and replacement is suggested in the radically operable cases. In patients with oesophageal corrosive stricture which needs operation, both a by-pass procedure and resection can be adopted, but it should be pointed out that malignancy may develop even years after the operation in the remaining part of the gullet. Total oesophagectomy is therefore suggested instead of bypass.

Complications of oesophagoplasty with isoperistaltic transverse colon.

An analysis is presented of late results in 144 reconstructions of oesophagus with transplants (137 isoperistaltic, 7 anisoperistaltic) from transverse colon for correction of stricture, mainly after corrosive trauma. The grafts were interposed retrosternally in 126 cases and intrathoracically in 18. Delayed passage due to excessive size of the colon segment was managed in four cases by plication of the intra-abdominal part of the graft or by jejunal by-pass. 'Pseudo-diverticulum' at the proximal anastomosis occurred in five cases as a complication of the standard by-pass procedure. Correction was made by closure of the pouching oesophagus below the cervical anastomosis. Transformation to end-to-end anastomosis is also recommended. The incidence of gastrocolic reflux was low. In two of the four observed cases the cause was late pyloric stenosis. There was no case of peptic ulceration. For good late results of colo-oesophageal reconstruction, appropriate length and type of colon segment, suitable site of gastric implantation and isoperistalsis are of primary importance.

Mechanical capacity of esophagogastric anastomosis at early postoperative stage.

The tensile strength of esophagogastric anastomosis was measured in 20 dogs. In case of 32 other animals the preparations were histologically examined, too. Mechanical tolerance was found significant from the 7th postoperative day on, reaching its maximum on the 15th day with no later change. An explanation is sought in the prevalence of the elastic elements growing in direct proportion to the time elapsing after operation. This role of the elastic fibres has not yet been reported in the available literature.

Ischemic stricture of the intrathoracic roux loop used for esophagoplasty.

Three cases of stenosis of a Roux loop are presented, following the replacement of the lower third of the esophagus resected for cancer. In each case fibrotic stenosis developed 6 weeks after reconstruction, which was attributed to ischemia: in one case it was due to reduced blood flow during digitalization and in the other two cases to the vascular compression of the supplying vessels because of unsatisfactory dilatation of the hiatus.