Follow-up of Thalidomide treatment in patients with Hereditary Haemorrhagic Telangiectasia.

BACKGROUND: Patients with a hereditary vascular disorder called Rendu-Osler-Weber syndrome (Hereditary Haemorrhagic Telangiectasia, HHT) haemorrhage easily due to weak-walled vessels. Haemorrhage in lungs or brain can be fatal but patients suffer most from chronic and prolonged nosebleeds (epistaxis), the frequency and intensity of which increases with age. Several years ago, it was discovered serendipitously that the drug Thalidomide had beneficial effects on the disease symptoms in several of a small group of HHT patients: epistaxis and the incidence of anaemia were reduced and patients required fewer blood transfusions. In addition, they reported a better quality of life. However, Thalidomide has significant negative side effects, including neuropathy and fatigue. METHODS: We followed up all HHT patients in the Netherlands who had been taking Thalidomide at the time the original study was completed to find out (i) how many had continued taking Thalidomide and for how long (ii) the nature and severity of any side-effects and (iii) whether side-effects had influenced their decision to continue taking Thalidomide. RESULTS: Only a minority of patients had continued taking the drug despite its beneficial effects on their symptoms and that the side effects were the primary reason to stop. CONCLUSION: Despite symptom reduction, alternative treatments are still necessary for epistaxis in HHT patients and a large-scale clinical trial is not justified although incidental use in the most severely affected patients can be considered.

International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia.

BACKGROUND: HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults. OBJECTIVE: The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease. METHODS: The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches. RESULTS: The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations.

The effect of N-acetylcysteine on epistaxis and quality of life in patients with HHT: a pilot study.

BACKGROUND: Free O2- radicals may cause precapillary sphincter abnormalities, resulting in epistaxis in hemizygous knockout mice for Endoglin. The objective of this study was to test if antioxidants, like N-acetylcysteine (NAC), are have a role in the treatment of epistaxis in hereditary hemorrhagic telangiectasia (HHT). METHODS: Forty-three patients participated in this study taking NAC 600 mg t.i.d for 12 weeks. Patients registered frequency, severity and duration of epistaxis and private and work-related quality of life (QOL), using a diary for two 6 weeks periods. The first period was prior to starting treatment and the second started after 6 weeks using NAC. RESULTS: There was a decrease infrequency (p < 0.01) and severity (p < 0.01) of epistaxis during the day. The improvement was most remarkable in male patients and patients with an ENDOGLIN mutation. In women and patients with an ALK-1 mutation, only a trend for improvement was found. Nocturnal epistaxis did not improve. The effect of epistaxis on the ability to work (p = 0.02) was reduced. CONCLUSION: This pilot study was conducted to investigate whether animal experiments can be translated to humans with HHT regarding epistaxis. The positive results with NAC are promising and justify a randomised clinical trial.

Screening for pulmonary arteriovenous malformations using transthoracic contrast echocardiography: a prospective study.

Pulmonary arteriovenous malformations (PAVMs) are associated with severe neurological complications in patients with hereditary haemorrhagic telangiectasia (HHT). The objective of the present study was to prospectively establish the diagnostic value of transthoracic contrast echocardiography (TTCE) as a screening technique for PAVM using chest high-resolution computed tomography (HRCT) as the gold standard for PAVMs. All consecutive adult patients referred for HHT screening underwent a chest HRCT (n = 299), TTCE (n = 281), arterial blood gas analysis (n = 291), shunt fraction measurement (n = 111) and chest radiography (n = 296). TTCE was positive in 87 (58.8%), 12 (16.7%) and four (6.7%) patients, and chest HRCT was positive in 54 (36.5%), three (4.2%) and zero (0%) patients with a definite, possible and negative clinical diagnosis of HHT, respectively. Two patients with a negative TTCE were diagnosed with PAVMs after computed tomography; in both cases the PAVMs were too small to be treated by embolotherapy. The sensitivity of TTCE was 97% (95% confidence interval (CI) 93.6-98.3) and negative predictive value 99% (95% CI 96.9-99.8). The other diagnostic tests showed a considerable lower diagnostic value. The present prospective study shows that transthoracic contrast echocardiography has an excellent diagnostic value and can be used as an initial screening procedure for pulmonary arteriovenous malformations. The high false-positive rate of transthoracic contrast echocardiography possibly represents microscopic pulmonary arteriovenous malformations.

SMAD4 mutations found in unselected HHT patients.

BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disease exhibiting multifocal vascular telangiectases and arteriovenous malformations. The majority of cases are caused by mutations in either the endoglin (ENG) or activin receptor-like kinase 1 (ALK1, ACVRL1) genes; both members of the transforming growth factor (TGF)-beta pathway. Mutations in SMAD4, another TGF-beta pathway member, are seen in patients with the combined syndrome of juvenile polyposis (JP) and HHT (JP-HHT). METHODS: We sought to determine if HHT patients without any apparent history of JP, who were undergoing routine diagnostic testing, would have mutations in SMAD4. We tested 30 unrelated HHT patients, all of whom had been referred for DNA based testing for HHT and were found to be negative for mutations in ENG and ALK1. RESULTS: Three of these people harboured mutations in SMAD4, a rate of 10% (3/30). The SMAD4 mutations were similar to those found in other patients with the JP-HHT syndrome. CONCLUSIONS: The identification of SMAD4 mutations in HHT patients without prior diagnosis of JP has significant and immediate clinical implications, as these people are likely to be at risk of having JP-HHT with the associated increased risk of gastrointestinal cancer. We propose that routine DNA based testing for HHT should include SMAD4 for samples in which mutations in neither ENG nor ALK1 are identified. HHT patients with SMAD4 mutations should be screened for colonic and gastric polyps associated with JP.

Untreated idiopathic aneurysm of the pulmonary artery; long-term follow-up.

A 57-year-old man with an idiopathic aneurysm of the left pulmonary artery is presented. The aneurysm was stable over many decades. No such long-term follow-up of an idiopathic pulmonary aneurysm has been described previously. After 39 years there is no evidence of heart failure or pulmonary hypertension. Because corrective surgery has a variable outcome, and prognosis is suggested to be good in the idiopathic form of pulmonary aneurysm, no surgical correction was proposed.

Bleeding risk of cerebrovascular malformations in hereditary hemorrhagic telangiectasia.

OBJECT: Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal-dominant vascular dysplasia with a high prevalence of cerebrovascular malformations (CVMs), mostly manifested as arteriovenous malformations (AVMs). The natural history and bleeding risk of these CVMs is unknown. The authors investigated the risk of bleeding in conjunction with clinical and radiological features in patients with HHT and proven CVMs. METHODS: Intravenous digital subtraction (DS) angiography was used to screen 196 patients with HHT for the presence of CVMs. Patients with abnormal results on DS angiography were asked to undergo a conventional cerebral angiographic study. All patients with a proven CVM were assessed by a neurologist. The bleeding risk was retrospectively and prospectively calculated for patients with AVMs only, as well as for the whole cohort of patients with CVMs. Twenty-four patients (12.2%; 16 female and eight male), aged 14 to 66 years (mean 35.4 years) with one or more CVMs were identified. Fifteen patients (62.5%) had a CVM and a pulmonary AVM. Eleven patients (45.8%) exhibited no neurological signs of their CVM; six (25%) had headache or migraine; four (16.7%) had seizures; and three (12.5%) had an intracranial hemorrhage. Twenty-two patients had at least one AVM (with a total of 28 AVMs), whereas two patients only had telangiectases. Twenty-seven AVMs were small (96%), 36% were located in eloquent areas of the brain, and 82% had superficial venous drainage. One third of the patients had multiple CVMs. The bleeding risk for patients with at least one AVM ranged from 0.41 to 0.72% per year, and for the whole cohort the range was 0.38 to 0.69% per year. Calculation of the bleeding risk as determined by lesion-years ranged from 0.36 to 0.56% per year for patients with AVMs and from 0.27 to 0.46% per year for all patients with CVMs. CONCLUSIONS: Patients with HHT have a high risk of harboring a CVM, especially in the presence of a pulmonary AVM. These CVMs are mostly low-grade AVMs (Spetzler-Martin Grade I or II), are frequently multiple, and have a lower risk of bleeding than that associated with sporadic AVMs. Female patients are more often affected than male patients. The inherent low sensitivity of DS angiography screening for CVMs may yield false negative results.

Effects of formoterol in apparently poorly reversible chronic obstructive pulmonary disease.

This randomized, double-blind, placebo-controlled, crossover study was designed to investigate the effects of the long-acting beta2-adrenoreceptor agonist formoterol fumarate in 12 current or exsmokers having chronic obstructive pulmonary disease, with a mean forced expiratory volume in one second (FEV1) 47% of predicted, poorly reversible (5.1% pred) after terbutaline sulphate inhalation. After inhaling a single dose of formoterol (6 or 24 microg), or placebo via Turbuhaler, FEV1 and pulmonary function parameters measured during quiet breathing (work of breathing (WoB) and airway resistance (Raw)) were recorded over 12 h on three test days. Immediate changes in FEV1 were modest, although each dose of formoterol caused a response >12% pred within 10 min in one subject. Compared to placebo, both doses of formoterol induced a clinically and statistically relevant improvement in WoB (>25%) and Raw (>20%), which occurred within 10 min and lasted over a period of 12 h (p < or = 0.02, analysis of variance). Thus, inhaled formoterol causes long-lasting lung functional improvements in apparently poorly reversible chronic obstructive pulmonary disease. Additional lung function measurements during quiet breathing after forced expiration tests may be useful in such patients to assess beneficial effects of bronchodilators.

Mutation and expression analysis of the endoglin gene in hereditary hemorrhagic telangiectasia reveals null alleles.

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by multisystemic vascular dysplasia and recurrent hemorrhage from the sites of vascular lesions. Two genes have been identified for HHT. Endoglin, a TGF-beta binding protein which maps to chromosome 9q3, is the gene for HHT1. The type and location of most of the previously described mutations in the endoglin (ENG) gene suggested a dominant-negative model of receptor-complex dysfunction for the molecular basis of this disorder. In this article we describe 11 novel ENG mutations in HHT kindreds, which include missense and splice-site mutations. Two identical missense mutations in unrelated families disrupt the start codon of the gene. In addition, some frameshift and nonsense mutations lead to very low or undetectable levels of transcript from the mutant allele. These combined data suggest that the nature of most ENG mutations is to create a null (nonfunctional) allele, and that there is no requirement for the synthesis of a truncated endoglin protein in the pathogenesis of HHT.

Results of resection of T3 non-small cell lung cancer invading the mediastinum or main bronchus.

BACKGROUND: T3 tumors can be divided into several subgroups. Surgical treatment of T3 tumors with chest wall invasion results in good survival. This study shows the results of resection of T3 non-small cell tumors located in the main bronchus or with invasion of mediastinal structures. METHODS: From 1977 through 1993, 108 patients underwent resection for primary non-small cell carcinomas located in the main bronchus or with invasion of mediastinal structures. A complete resection was performed in 70 patients (64.8%). Actuarial survival time was estimated and risk factors for late death were identified. RESULTS: Overall hospital mortality was 8.3%. All deaths followed pneumonectomy. Mean 5-year survival was 29% for all hospital survivors, 35% for patients with complete resection, and 18% for patients with incomplete resection (p = 0.03). In patients with complete resection, mean 5-year survival was 45% for N0 patients and 37% for N1 patients. There were no 5-year survivors in the group of N2 patients. The mean 5-year survival was greater (but not statistically significantly greater) in patients with tumors located in the main bronchus (40%) than in patients with tumors with invasion of mediastinal structures (25%) (p > 0.05). Histology, tumor spill, age, sex, and type of operative procedure were not significant prognostic factors. CONCLUSIONS: Patients with tumors located in the main bronchus have a better survival than patients with invasion of the mediastinal structures. Pneumonectomy increases hospital mortality. Incompleteness of resection and mediastinal lymph node involvement influence survival significantly.

Epistaxis in hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) is characterized by easily bleeding telangiectases of the skin and mucosa. Epistaxis is the most common symptom of HHT. Larger arteriovenous malformations (AVM) occur in the lungs (in up to 33% of the patients), brain (in up to 11% of patients), and liver. These may cause severe complications which can be prevented by early therapy. To gain insight in the characteristics of epistaxis in HHT, 171 persons were investigated, who either had HHT or participated in a screening programme for relatives of HHT patients. Of these, 58 persons had HHT. Epistaxis without signs of HHT was present in 12 persons, whereas 10% of HHT patients did not have epistaxis. Seventeen HHT patients with epistaxis had visited an otorhinolaryngologist before, without a correct diagnosis of HHT being made. Telangiectases were most common on lips, tongue, the nasal septum, and the turbinates. In view of the prevalence of visceral AVM and the associated complications, HHT patients presenting to an otorhinolaryngologist should be encouraged to engage in a screening programme for these AVM.

Surgical treatment of 125 patients with non-small cell lung cancer and chest wall involvement.

BACKGROUND: The optimum operative procedure for lung cancer with chest wall invasion (T3) remains controversial. In this study results of en bloc resection and extrapleural dissection are reviewed to determine survival characteristics. METHODS: Between 1977 and 1993 125 patients underwent surgery for primary non-small cell lung cancer with chest wall invasion. Patients with superior sulcus tumours, metastatic carcinomas, synchronous tumours, or recurrences were excluded. Extrapleural dissection was performed in 73 patients and en bloc resection (range 1-4 ribs) in 52. Resection was regarded as complete in 86 and incomplete in 39 patients. Actuarial survival time was estimated and risk factors for late death were identified. RESULTS: Hospital mortality was 3.2%. (n = 4). Estimated mean five year survival was 24% for all hospital survivors (n = 121), 11% for patients with incomplete resection, and 29% for patients having a complete resection. In patients who underwent complete resection mediastinal lymph node involvement and intrapleural tumour spill worsened the prognosis. Patients with adenocarcinoma had a better chance of long term survival. No relationship was found between survival and age, type of operative procedure, depth of chest wall invasion, and postoperative radiotherapy. CONCLUSIONS: Both operative procedures show reasonable survival results. Incomplete resection, mediastinal lymph node involvement, and intrapleural tumour spill adversely influence survival.

Is resection of bronchiectasis beneficial in patients with primary ciliary dyskinesia?

A retrospective study of 21 patients with primary ciliary dyskinesia (PCD) was done. Thirteen had prior resection of bronchiectasis and eight had not. Information about present complaints was obtained by a questionnaire. The prevalence of present respiratory symptoms was the same in both groups. The surgical patients had more severe disease and 85% of them considered the operation beneficial. Selected patients with PCD may have improved conditions with resection of bronchiectasis.

Screening family members of patients with hereditary hemorrhagic telangiectasia.

PURPOSE: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disorder which may give rise to arteriovenous malformations in lungs and brain. When left untreated, these may cause serious complications. We screened family members of HHT patients for presence of the disease and associated pulmonary or cerebral arteriovenous malformations. PATIENTS AND METHODS: We investigated 98 family members of HHT patients on an outpatient basis. A stepped screening protocol was used based on prevalence of different manifestations of HHT. RESULTS: Thirty-six cases of HHT were found in the 98 persons screened. Pulmonary arteriovenous malformations were found in 12 of the 36 patients (33%), and cerebral arteriovenous malformations in 4 (11%). Therapy was recommended in 9 patients with pulmonary arteriovenous malformations and in 2 with cerebral arteriovenous malformations. CONCLUSIONS: Family members of known HHT patients should be encouraged to engage in a screening program, since the prevalence of potentially serious localizations is higher than previously thought.

Pulmonary resection after pneumonectomy in patients with bronchogenic carcinoma.

Eight patients with a previous pneumonectomy for bronchogenic carcinoma underwent an additional resection because of a second primary carcinoma in the remaining lung. One patient died of pulmonary embolism in the postoperative period. The postoperative course was otherwise uneventful except for prolonged air leak. Two patients died after 3 months (bone metastasis) and 5 months (recurrent small-cell carcinoma). Two patients were alive at the time this article was written but had evidence of recurrence after 18 months (distant metastasis) and 21 months (local recurrence at the site of positive resection margins). Three patients were alive and doing well without evidence of disease after 16, 17, and 40 months. After careful selection, even patients with a previous pneumonectomy may be good candidates for additional resection of a second primary bronchogenic carcinoma.

A twenty-five-year follow-up of ninety-three resected typical carcinoid tumors of the lung.

From 1965 to 1990, 93 patients (57 women and 36 men) with typical bronchopulmonary carcinoids were operated upon. Patient ages ranged from 17 to 78 years, the mean age being 45.5 years. Central carcinoids were symptomatic in 80% of the patients. A correct preoperative diagnosis was made in 54 of 64 (84%) patients. Peripheral carcinoids were usually asymptomatic and a correct diagnosis was established in 4 of 29 patients (14%). The prognosis in the group of patients with bronchopulmonary carcinoids treated surgically was excellent. Seven patients died from nonrelated causes. The 5-, 10-, and 15-year survival rates for the remaining 86 patients are 100%. Only one patient died as a result of the tumor after 17 years and another patient is known to have had distant metastasis 9 years after resection. There was no hospital mortality. In the last decade a lung parenchyma-preserving attitude was adopted. Whenever possible, bronchoplastic surgery was applied for central carcinoids and resection of one segment or less was used for peripheral carcinoids. This approach was possible in 30 of 50 patients (60%). Nine patients were treated with preoperative endobronchial neodymium:yttrium-aluminum-garnet laser resection to facilitate a lung-preserving surgical resection. The prognosis of patients for whom a lung-preserving approach was adopted was as good as that of those with conventional resections. Involvement of regional lymph nodes (nine patients, 9.7%) or positive resection margins (two patients, 2.1%) had no influence on prognosis. We conclude that lung-preserving resections are often facilitated by preoperative neodymium:yttrium-aluminum-garnet laser treatment in central obstructing carcinoids.

[Late manifestation of a right-sided diaphragmatic rupture]. / Late manifestatie van een rechtszijdige diafragmaruptuur.

Diaphragmatic rupture is commonly of traumatic origin and can complicate thoracoabdominal injuries. Some cases are diagnosed after a delay of years. We present three patients with a rupture of the right hemi-diaphragm with herniation of liver fragments, and discuss the diagnostic and therapeutic challenge.

Postpneumonectomy syndrome in adulthood. Surgical correction using an expandable prosthesis.

The postpneumonectomy syndrome is a rare complication occurring after right pneumonectomy and is seen mainly after pneumonectomy in childhood. The presenting symptoms are dyspnea, stridor, and recurrent pulmonary infections. The syndrome is caused by the shifting and rotation of the heart and mediastinum into the right hemithorax, and anterior herniation of the left lung. This causes tortuosity and stretching of the trachea and compression of the left main bronchus and left lower lobe bronchus, eventually resulting in secondary tracheobronchomalacia. This report reviews two cases of postpneumonectomy syndrome following pneumonectomy in adulthood. After implantation of an expandable prosthesis, an anatomic correction of the shifted mediastinum was achieved, which in both cases resulted in instantaneous and sustained relief.