Survival and disease progression in UK patients with lymphangioleiomyomatosis

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare and progressive disease of young women with no effective treatment. Previous estimates of 10 year survival, based mostly on case series or patients from tertiary centres, have ranged from 40% to 79%; no data are available on the progression of respiratory disability. In order to provide data for patients and for planning intervention studies, we have looked at the time course of LAM using a national cohort. METHODS: Time to death, time to MRC dyspnoea grades 2-5, and need for oxygen in patients on the UK LAM database were analysed using Kaplan-Meier analysis and Cox regression. RESULTS: Fifty seven of 72 patients responded with a median duration of follow up of 12.6 years (range 2.3-37) from the onset of symptoms. Ten year survival was 91% from onset of symptoms but varied widely with 11 patients alive after 20 years. Median time to MRC grade 3 dyspnoea (breathless walking on the flat) was 9.3 years (95% CI 5.1 to 13.4) from onset of symptoms. CONCLUSIONS: Survival from LAM appears to be better than that reported in early studies. These data should be helpful for patients and for planning clinical trials.     

Pregnancy and lymphangioleiomyomatosis: anaesthetic management

Lymphangioleiomyomatosis is a rare, progressive cystic pulmonary disease related to tuberous sclerosis complex, affecting almost exclusively females of childbearing age. Progression of the disease is variable but may lead to terminal respiratory failure. As the disease may be oestrogen-dependent, it can arise de novo in pregnancy or established disease may undergo exacerbation. We report on the successful labour and delivery of such a patient and present the results of an internet survey of 30 pregnancies in 15 patients worldwide with lymphangioleiomyomatosis conducted by our patient before delivery.     

Clinical experience of lymphangioleiomyomatosis in the UK

BACKGROUND: Lymphangioleiomyomatosis is a rare lung disease that affects only women. No controlled trials of management have been performed and, until such data are available, management must be based on clinical experience. This study provides data on the natural history of lymphangioleiomyomatosis in the UK and compares this with experience from other centres. METHODS: We tried to identify all cases of lymphangioleiomyomatosis in the UK over a five year period by contacting all chest physicians. Cases were confirmed by lung biopsy or history and high resolution computed tomographic (CT) scanning. Details of disease and management were obtained from hospital notes. RESULTS: The 50 patients who fitted the diagnostic criteria for lymphangioleiomyomatosis had a median age at onset of 35 years (range 22-50). Five presented when postmenopausal (four taking hormone replacement therapy). Pneumothorax and dyspnoea were the most common presenting features. Extrapulmonary presentations included renal angiomyolipomas (3) and lymphangiomyomas (2). Only half the patients were assessed for renal angiomyolipoma and six were identified. Thirty patients had had one or more pneumothoraces, of which two thirds recurred if treated conservatively. Chylous effusions occurred in 11 patients, five requiring surgery. Pregnancy was uncommon once the diagnosis was made (n=7), but was associated with an increase in complications. Half the patients were taking a beta agonist and many showed a bronchodilator response in the laboratory. Thirty six patients had received hormone treatment. CONCLUSIONS: Our UK five year period prevalence was one per 1.1 million population. Since prophylactic interventions are sometimes indicated for renal angiomyolipoma, these data suggest that screening for angiomyolipoma, ideally by CT scanning, may be underused. Patients need to be aware of the increase in complications associated with pregnancy. Recurrence rate of pneumothorax was high in those not treated surgically. Hormone treatment was used variably and controlled trials are needed to determine their role and the optimum duration and dose.     

Pulmonary lymphangioleiomyomatosis in Korea

BACKGROUND: Pulmonary lymphangioleiomyomatosis (LAM) is a rare disease occurring in women of reproductive age and leading to progressive respiratory failure in spite of treatment. In Korea the first case was reported in 1984 and by 1997 a total of 23 cases had been reported. The clinical findings of these Korean cases are reviewed. METHODS: The details of 10 cases of LAM on file at Seoul National University Hospital were reviewed together with those of 13 cases previously reported from other Korean institutes. Two, including the only one to be reported in a man, were excluded after reviewing the clinical, radiological, and pathological findings, leaving a total of 21 cases in the present study. RESULTS: All 21 patients were women and in all cases the disease was proven pathologically. The mean (SD) age at onset of symptoms was 32 (8.6) years. The most common symptoms were dyspnoea and pneumothorax which were seen in 19 (90%) and 13 (76%) patients, respectively. Pulmonary function tests showed decreased transfer factor (TLCO) (100%) and airflow limitation (67%). All the cases had characteristic cysts on high resolution computed tomographic (HRCT) scanning. The overall severity score based on HRCT scans correlated with the percentage predicted TLCO/VA (p = 0.03) and FEV1/FVC (p = 0.02). The patients were all treated with medroxyprogesterone and/or tamoxifen. Follow up was possible in 10 cases. Two of these patients appeared to stabilise with no appreciable change clinically or in lung function on medroxyprogesterone and/or tamoxifen, but the remaining patients all deteriorated with two dying of respiratory insufficiency and one of infection following lung transplantation. CONCLUSIONS: As in other countries, in Korea LAM occurs exclusively in women and progresses despite hormonal treatment.     

Lymphangiogenesis in tissue-engineered small intestine

BACKGROUND: Lymphangiogenesis, the formation of lymphatic vessels, has not been reported in engineered tissue. The purpose of this study was to characterize lymphangiogenesis in tissue-engineered small intestine. METHODS: Biodegradable polymer scaffolds seeded with intestinal organoid units were implanted into syngenic recipient rats. Twenty-three neointestinal grafts were harvested from adult rat recipients 1 to 8 weeks postimplantation. Cells expressing the lymphatic endothelial marker vascular endothelial growth factor receptor (VEGFR)-3 were detected immunohistochemically. The lymphangiogenic growth factor VEGF-C was quantified by enzyme-linked immunoadsorbent assay. RESULTS: Between the first and eighth weeks, neointestinal cysts increased in volume and mass. Muscular and mucosal layers increased in thickness and developed to resemble normal intestine histologically. The proportion of neointestinal VEGFR-3-positive cells increased and ultimately, tubular structures developed that resembled lymphatics architecturally, were distinct from CD34-positive blood vessels, and lacked luminal erythrocytes. CONCLUSION: Lymphangiogenesis occurs in tissue-engineered small intestine. This is the first demonstration of lymphatic vessels in an engineered tissue.     

Antiphospholipid syndrome; its implication in cardiovascular diseases: a review

Antiphospholipid syndrome (APLS) is a rare syndrome mainly characterized by several hyper-coagulable complications and therefore, implicated in the operated cardiac surgery patient. APLS comprises clinical features such as arterial or venous thromboses, valve disease, coronary artery disease, intracardiac thrombus formation, pulmonary hypertension and dilated cardiomyopathy. The most commonly affected valve is the mitral, followed by the aortic and tricuspid valve. For APLS diagnosis essential is the detection of so-called antiphospholipid antibodies (aPL) as anticardiolipin antibodies (aCL) or lupus anticoagulant (LA). Minor alterations in the anticoagulation, infection, and surgical stress may trigger widespread thrombosis. The incidence of thrombosis is highest during the following perioperative periods: preoperatively during the withdrawal of warfarin, postoperatively during the period of hypercoagulability despite warfarin or heparin therapy, or postoperatively before adequate anticoagulation achievement. Cardiac valvular pathology includes irregular thickening of the valve leaflets due to deposition of immune complexes that may lead to vegetations and valve dysfunction; a significant risk factor for stroke. Patients with APLS are at increased risk for thrombosis and adequate anticoagulation is of vital importance during cardiopulmonary bypass (CPB). A successful outcome requires multidisciplinary management in order to prevent thrombotic or bleeding complications and to manage perioperative anticoagulation. More work and reporting on anticoagulation management and adjuvant therapy in patients with APLS during extracorporeal circulation are necessary.     

Uric acid and chronic renal disease: possible implication of hyperuricemia on progression of renal disease

Although hyperuricemia has long been associated with renal disease, uric acid has not been considered as a true mediator of progression of renal disease. The observation that hyperuricemia commonly is associated with other risk factors of cardiovascular and renal disease, especially hypertension, has made it difficult to dissect the effect of uric acid itself. However, recent epidemiologic evidence suggests a significant and independent association between the level of serum uric acid and renal disease progression with beneficial effect of decreasing uric acid levels. Furthermore, our experimental data using hyperuricemic animals and cultured cells have provided robust evidence regarding the role of uric acid on progression of renal disease. Hyperuricemia increased systemic blood pressure, proteinuria, renal dysfunction, vascular disease, and progressive renal scarring in rats. Recent data also suggest hyperuricemia may be one of the key and previously unknown mechanisms for the activation of the renin-angiotensin and cyclooxygenase-2 (COX-2) systems in progressive renal disease. Although we must be cautious in the interpretation of animal models to human disease, these studies provide a mechanism to explain epidemiologic data that show uric acid is an independent risk factor for renal progression. Although there is no concrete evidence yet that uric acid bears a causal or reversible relationship to progressive renal disease in humans, it is time to reevaluate the implication of hyperuricemia as an important player for progression of renal disease and to try to find safe and reasonable therapeutic modalities in individual patients based on their clinical data, medication history, and the presence of cardiovascular complications.     

Sulf2促进淋巴管生成的实验研究

目的 研究硫酸酯酶2(Heparan sulfate 2,Sulf2)在淋巴管生成中的作用。方法 根据Sulf2 cDNA序列,设计并构建pCDH-Flag-Sulf2真核表达载体,慢病毒转染293FT细胞,获得合成纯化的rSulf2。通过流式分析、成管试验、裸鼠耳部淋巴管生成模型等实验,研究rSulf2对于淋巴管内皮细胞(Lymphatic endothelial cells,LECs)细胞周期、凋亡、成管能力和淋巴管生成的影响。结果 构建的pCDH-Flag-Sulf2真核表达载体,经酶切和测序证明构建完全正确。Western blot检测证明293FT细胞转染pCDH-Flag-Sulf2真核表达载体后,rSulf2表达增高。合成纯化的rSulf2可以减少无血清培养液诱导的LECs细胞的凋亡,增加活细胞的比例,但对细胞周期无显著影响,rSulf2还可以增加淋巴管内皮细胞的体外成管能力及增加裸鼠耳部淋巴管的数量。结论 Sulf2可以抑制LECs细胞的凋亡,对淋巴管生成起到促进作用。     

Oestrogen metabolism in lymphangioleiomyomatosis: catechol-O-methyltransferase pathway is not involved

BACKGROUND: Lymphangioleiomyomatosis (LAM) is an uncommon lung disease for which no effective method of treatment has been found. The predilection of LAM for premenopausal women has led to the assumption that hormonal factors play an important role in the pathogenesis of this disease. The aim of this study was to determine if women with LAM manifest alterations in the catechol-O-methyltransferase (COMT) pathway which is essential for preventing the generation of oestrogen derived reactive oxygen species (ROS). METHODS: Blood samples were collected from 15 women with LAM and compared with appropriate controls. The distribution of high and low activity alleles of COMT was determined with a PCR based RFLP assay. The enzymatic activity of COMT was measured in each sample and the potential presence of a circulating inhibitor of COMT was determined. Since an alteration in the COMT pathway could increase the oxidative stress, the plasma concentration of malondialdehyde (MDA), a secondary product generated from lipid peroxidation, has been used as an internal marker. RESULTS: The distribution of high and low activity alleles of COMT (named COMT(HH), COMT(LL), and COMT(HL)) was similar in the two groups with proportions of 40%, 7%, and 53%, respectively, in the women with LAM and 38%, 6%, and 56% in the control subjects. The mean (SD) COMT activity was 24.2 (12.3) pmol/min/mg protein in women with LAM and 24.1 (6.3) pmol/min/mg protein in the control group. Incubation of plasma from women in the two groups with a preparation of commercial COMT showed that no detectable COMT inhibitor was present. The plasma concentration of MDA in the women with LAM was also not significantly different from control subjects. CONCLUSIONS: This study shows that there are no significant alterations in the COMT pathway of women with LAM. It is therefore unlikely that alterations in oestrogen mediated cell signalling pathways are mediated by oxidants derived from an excess of catecholoestrogens in LAM.     

Emerging clinical picture of lymphangioleiomyomatosis

OBJECTIVE: To provide a comprehensive update of the clinical picture of lymphangioleiomyomatosis (LAM) using two large patient registries. METHODS: A cross sectional questionnaire survey which included questions on 14 LAM symptoms, pneumothorax, tuberous sclerosis complex (TSC), date of diagnosis, and pulmonary function tests (PFTs). RESULTS: The response rate was 70.5% (n = 328). The mean age at the time of the survey was 46.7 years. The mean age at diagnosis was 42.7 years for women diagnosed 1 year before the survey and 35.8 years for women diagnosed 10 years previously. The main symptoms were dyspnoea (74%), fatigue (72%), cough (47%) and chest pain (44%); younger patients (<40 years) were less likely to report dyspnoea (p = 0.02). Patients with TSC (n = 51) were less likely to report dyspnoea (p = 0.05) and 76.5% reported angiomyolipoma (p < 0.0001) compared with patients with sporadic LAM. Patients with pneumothorax (63.0%) were less likely to report dyspnoea or fatigue (p < or = 0.05) than patients without pneumothorax. PFT results showed that low forced expiratory volume in 1 second and carbon monoxide transfer factor were highly associated with dyspnoea (p < 0.0001), but not with fatigue or history of pneumothorax. CONCLUSION: Previously considered a condition of women of childbearing age, more older women (50% without pneumothorax) are now being diagnosed with LAM. LAM should be considered in women over 40 with unexplained dyspnoea. LAM patients with pneumothorax have less fatigue and less dyspnoea than those without pneumothorax. Fatigue has been overlooked as a symptom of LAM and appears across the spectrum of pulmonary function.     

郑州市紫外线强度及其皮肤病学意义

目的：研究郑州市紫外线强度特征,为该市居民,包括正常人、光敏性皮肤病和紫外线相关性皮肤癌患者提供科学防晒依据。方法：测量该地一年中、长波紫外线强度,并分别统计其不同季节、不同日间时间点强度差异。结果：春夏秋冬长波紫外线平均强度分别为（1542．06±94．27）μW／cm2、（1828±92．95）μW／cm2、（1017．98±97．09）μW／cm2、（534．94±94．27）μW／cm2;中波紫外线平均强度分别为（109．04±7．12）μW／cm2、（136．32±7．02）μW／cm2、（76．91±7．33）μW／cm2、（34．56±7．12）μW／cm2。春夏长波紫外线强度无差异（P春vs夏=0．195）,其余季节两两比较均有差异（P春vs秋=0．001,P秋vs冬=0．003,其余所有只〈0．001）。春夏、春秋中波紫外线强度无差异（P春vs夏=O．043、P春vs秋=O．012）,其余季节均有差异（所有Ps〈0．001）。一年内在8：00、10：00、12：00、14：00、16：00长波紫外线平均强度分别为（590．29±38．28）μW／cm2、（1332．02±53．91）μW／cm2、（1894．82±75．88）μW／cm2、（1584．04±67．73）μW／cm2、（752．80±36．85）μW／cm2;中波紫外线平均强度分别为（41．18±2．95）μW／cm2、（100．10±3．96）μW／cm2、（142．76±5．67）μW／cm2、（111．64±5．04）μW／cm2,（50．36±2．67）μW／cm2。五个测量时间点长波紫外线强度两两比较均有差异（所有R〈0．001）。8：00和16：00中波紫外线强度无差异（P8：00vs16：00=0．030）,其余测量时间点均有差异（P110：00vs14：00=0．014,其余所有Ps〈0．001）。结论：郑州市四季和日间紫外线强度可有差异,但任何季节均需根据当时紫外线强度、个人敏感紫外线种类及其最小红斑量采取防晒措施。     

Tumor size of renal cell carcinoma: its clinical implication.

We studied the clinical implication of tumor size in renal cell carcinoma, by revealing its relation with the other histopathological and clinical features. The tumor size was well correlated with histopathological findings and metastatic status of the carcinoma. Smaller carcinomas (usually less than 60 mm) generally had a higher disease-specific survival than those of 60 mm or greater. The results indicated that the size reflected the biological character of the carcinoma. However, 10% of patients with the smaller carcinoma had lymph node metastasis or distant metastasis at the time of diagnosis, each of which contributed to a renal cell carcinoma-related death in the early follow-up period.     

Growth patterns of craniopharyngioma in children: role of the diaphragm sellae and its surgical implication

BACKGROUND: Most craniopharyngiomas can be classified as either "prechiasmatic" or "retrochiasmatic" according to their growth patterns. The purpose of our study was to investigate the factors determining these growth patterns. METHODS: The radiological, operative, and pathological findings of 25 consecutive cases were reviewed. RESULTS: In cases with prechiasmatic growth (n = 14), most tumors were easily separated from the undersurface of the third ventricular floor with the exception of a small area at the top of the tumor where tumor-glial interfaces occurred. Pathological examination of the tough tumor surface demonstrated well-organized collagen tissue, which is compatible with diaphragm sellae. All tumors of this type had intrasellar components, suggesting a subdiaphragmatic origin for this tumor type. On the other hand, tumors with retrochiasmatic growth (n = 11) demonstrated a prefixed chiasm, and most of the surface excluding areas exposed to ventricular cerebrospinal fluid showed tumor-glial interfaces. With the exception of three, all tumors of this type lacked intrasellar components, and the diaphragm sellae was depressed and free of tumor, suggestive of a supradiaphragmatic infundibular origin of the tumor. CONCLUSION: Growth pattern is closely correlated to the origin of the tumor, whether it is above or below the diaphragm sellae. In craniopharyngiomas with prechiasmatic growth, the major portion of the tumor could be resected by traction. These tumors are candidates for the transsphenoidal approach if the sphenoid sinus is pneumatized. Tumors with retrochiasmatic growth, which are not covered by diaphragm sellae and contact brain tissue directly, are easily torn by traction and the tumor-glial interface should be carefully dissected under direct vision.     

Air travel in women with lymphangioleiomyomatosis

BACKGROUND AND OBJECTIVE: The safety of air travel in patients with pneumothorax-prone pulmonary diseases, such as lymphangioleiomyomatosis (LAM), has not been studied to any great extent. A questionnaire-based evaluation of air travel in patients with LAM was conducted to determine experiences aboard commercial aircraft. METHODS: A survey was sent to women listed in the US LAM Foundation registry (n = 389) and the UK LAM Action registry (n = 59) to assess air travel, including problems occurring during flight. Women reporting a pneumothorax in flight were followed up to ascertain further details about the incident. RESULTS: 327 (73%) women completed the survey. 308 women answered the travel section, of whom 276 (90%) had "ever" travelled by aeroplane for a total of 454 flights. 95 (35%) women had been advised by their doctor to avoid air travel. Adverse events reported included shortness of breath (14%), pneumothorax (2%, 8/10 confirmed by chest radiograph), nausea or dizziness (8%), chest pain (12%), unusual fatigue (11%), oxygen desaturation (8%), headache (9%), blue hands (2%), haemoptysis (0.4%) and anxiety (22%). 5 of 10 patients with pneumothorax had symptoms that began before the flight: 2 occurred during cruising altitude, 2 soon after landing and 1 not known. The main symptoms were severe chest pain and shortness of breath. DISCUSSION AND CONCLUSION: Adverse effects occurred during air travel in patients with LAM, particularly dyspnoea and chest pain. Hypoxaemia and pneumothorax were reported. The decision to travel should be individualised; patients with unexplained shortness of breath or chest pain before scheduled flights should not board. Patients with borderline oxygen saturations on the ground should be evaluated for supplemental oxygen therapy during flight. Although many women had been advised not to travel by air, most travelled without the occurrence of serious adverse effects.     

Lymphangiogenesis does not occur in breast cancer

Breast cancer metastasis predominantly occurs via lymphatic vessels. However, the study of lymphatic vessels and lymphangiogenesis has been hampered by lack of specific markers. Recently, antibodies directed against M2A (D2-40), Podoplanin, and Prox-1 that specifically mark lymphatic vessels in paraffin-embedded sections have become available. These were used to study lymphangiogenesis in archival paraffin sections of normal breast (n = 23), fibrocystic disease (n = 7), ductal carcinoma in situ (n = 32), invasive ductal carcinoma (n = 50), and invasive lobular carcinoma (n = 5). In addition, endothelial proliferation in lymphatic vessels was analyzed by dual-color immunohistochemistry with D2-40 and proliferating cell nuclear antigen (PCNA). Expression of D2-40, Prox-1, and Podoplanin was seen in lymphatic vessels but not in blood vessels. Lymphatic vessels were seen in the peritumoral area and as "entrapped" intratumoral vessels adjacent to preexisting normal lobules and ducts. Unlike angiogenesis, there was no increase of lymphatic vessel density in association with neoplastic transformation. On the contrary, a marked reduction in intratumoral lymphatic vessel density was seen in comparison to normal breast tissue, fibrocystic disease, and ductal carcinoma in situ (P = 0.0001). There was an increase in peritumoral lymphatic vessel density as compared with normal breast (P = 0.0001). However, the endothelial cells in the "entrapped" or the peritumoral lymphatic vessels did not show any expression of PCNA indicating minimal or no proliferative activity. This was in contrast to the strong expression seen in adjacent tumor cells and blood vessel endothelial cells. Thus, lymphangiogenesis was not evident when studied by lymphatic vessel density or by lymph vessel endothelial proliferation.     

胰腺癌中雌激素受体表达与其生物学特性的研究

探讨胰腺癌中雌激素受体（ＥＲ）的表达及与其生物学特性的关系。方法观察２４例胰腺癌切除标本的ＥＲ表达（Ｓ－Ｐ免疫组化染色法）与肿瘤大小、有无血管浸润、淋巴转移关系,并以正常胰腺组织标本作为对照。结果２４例胰腺癌病人ＥＲ阳性１４例（５８．３％）,１２例正常胰腺中仅有１例为ＥＲ阳性（８３％）。胰腺癌的ＥＲ表达明显高于正常胰腺组织（Ｐ＜０．０１）。其中肿瘤越大其阳性表达越低,＞５ｃｍ者ＥＲ阳性率明显低于≤５ｃｍ者（Ｐ＜０．０５）。高分化胰腺癌中ＥＲ阳性率明显高于低分化者,两者之比为８３．３３％：３３．３％,Ｐ＜０．０５。ＥＲ阳性者的血管侵犯率明显低于ＥＲ阴性者（Ｐ＜０．０５）。ＥＲ阳性的胰腺癌转移率低于ＥＲ阴性者,但两者差异无显著意义（Ｐ＞０．０５）。结论胰腺癌组织中ＥＲ有较高的表达率（５３．３％）。ＥＲ的表达与肿瘤的大小、细胞分化程度、血管浸润等生物学特性相关,ＥＲ阳性者多有较好的生物学特性。     

Demonstration of live lymphatic circulation in the deep fascia and its implication

It is well known that vascular arcades and lymphatic networks co-exist all over the body with distinct physiological functions complimentary to each other. We visualized lymphatics in the deep fascia under electron microscope using 4000 magnification. Encouraged by our previous research with demonstration of live microcirculation in the deep fascia, we successfully explored the possibility of demonstrating live lymphatic circulation. The fascial extension of inferiorly based fasciocutaneous flaps were dissected in five patients with distal leg defects. The fascial extension was mounted on a glass slide and examined under microscope using 600 magnification (×40 lens). We witnessed live microcirculation as well as live lymphatic circulation in the same field of observation with specific characteristics. A video recording was made to document these important features which to the best of our knowledge is not mentioned in the literature. The theme of this study is to explain, how by incorporating the deep fascia in the flap, besides vascularity, other physiological functions are augmented.