Lymphangioleiomyomatosis.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare disease that is characterized by proliferation of abnormal smooth muscle-like cells (LAM cells), which leads to the formation of lung cysts, fluid-filled cystic structures in the axial lymphatics, and abdominal tumors. It primarily affects women. METHODS: The authors present a review of large series, registries, and protocols to highlight the prevalence, pathology, clinical features, diagnosis, and treatment options for patients with LAM. RESULTS: LAM commonly presents with progressive breathlessness or with recurrent pneumothorax, chylothorax, or sudden abdominal hemorrhage. Computed tomography (CT) scans show numerous thin-walled cysts throughout the lungs, abdominal angiomyolipomas, and lymphangioleiomyomas. Pulmonary function tests show decreased forced expiratory volume in 1 second (FEV1) and diffusion capacity for carbon monoxide (DLCO). Exercise testing shows gas-exchange abnormalities, ventilatory limitation, and hypoxemia that may occur with near-normal lung function. CONCLUSIONS: No effective treatment currently exists for this progressive disorder. However, recent progress in cancer and smooth muscle cell biology and a better understanding of the factors regulating angiogenesis and lymphangiogenesis may provide a foundation for the development of new therapeutic strategies.     

Efficacy of hormonal manipulation in lymphangioleiomyomatosis. A 20-year-experience in 36 patients

RATIONALE: Lymphangioleiomyomatosis (LAM) is a rare disease of unknown aetiology which mainly affects women of reproductive age. A growing body of evidence suggests a relation between the disease and estrogenic hormones. In particular, pregnancy and use of estrogens favour the progression of the disease, which is in turn slowed down by menopause. These observations suggested already in the past a treatment strategy based on hormonal manipulation: discontinuation of estrogens containing medications, avoiding pregnancy, inhibition of estrogens activity and induction of menopause. OBJECTIVES: In the present study, conducted on a relatively large population for a rare disease, we sought to show the hormonal manipulation's positive effects for the survival rate. METHODS: 36 women suffering from LAM were evaluated between January 1985 and March 2005. All our patients were treated with hormonal therapy, following different schemes. The response to the treatment was evaluated in all patients with arterial blood sampling, lung function tests (total body plethysmography, DLCO), measurement of the hormones in the blood, chest and abdomen CT scan. MEASUREMENTS AND MAIN RESULTS: The survival rate since the clinical onset was 97% at the 5 year timepoint, 90% at 10 years, and 71% at 25 years. Previous studies, conducted before the introduction of the hormonal treatment showed a survival rate of 20% at 10 years. CONCLUSIONS: Our results highlight the role of the hormonal manipulation as a mainstay in the treatment of LAM, with the capability of reducing mortality and improving the quality of life as well.     

Prospective study on the dose relationship of mitomycin C-induced interstitial pneumonitis

Lung damage after mitomycin C (MMC) was first reported in 1978. Although this side effect has been frequently reported since then, there are no data on dose dependency nor on incidence. Therefore, the authors initiated a prospective study to obtain more data on this subject. Forty-four patients treated with MMC entered the study; 37 were evaluable. All patients were subjected to repeated physical examinations, chest x-rays, chest computed tomography (CT) scan and pulmonary function tests. The results were evaluated per cumulative dose level. None of the patients had clinical pulmonary toxicity develop; one patient had pulmonary changes on CT scan, the significance of which remained unclarified. The world literature on this subject was also reviewed. Based on the combined data of the present study as well as the literature review, the authors concluded that MMC-related lung toxicity is a dose-dependent side effect, occurring at cumulative dose levels of 20 mg/m2 or more. The incidence is likely to be less than 10%.     

TSC2 loss in lymphangioleiomyomatosis cells correlated with expression of CD44v6, a molecular determinant of metastasis

Lymphangioleiomyomatosis (LAM), a rare multisystem disease found primarily in women of childbearing age, is characterized by the proliferation of abnormal smooth muscle-like cells, LAM cells, that form nodules in the pulmonary interstitium. Proliferation of LAM cells results, in part, from dysfunction in tuberous sclerosis complex (TSC) genes TSC1 (hamartin) and/or TSC2 (tuberin). Identification of LAM cells in donor lungs, their isolation from blood, and their presence in urine, chylous ascites, and pleural effusions are consistent with their ability to metastasize. Here, we investigated the presence on LAM cells of the hyaluronic acid receptor CD44 and its splice variants associated with metastasis. The heterogeneous populations of cells grown from lungs of 12 LAM patients contain cells expressing mRNA for the variant CD44v6. Histologically, CD44v6 was present in LAM lung nodules, but not in normal vascular smooth muscle cells. CD44v6-positive sorted cells showed loss of heterozygosity at the TSC2 locus; binding of CD44v6 antibody resulted in loss of cell viability. Levels of CD44 were higher in cultured Eker rat (Tsc2-/-) cells than in Tsc2+/+ cells, but unlike human LAM cells, the Tsc2-/- Eker rat cells did not contain CD44v6 splice variant mRNA. CD44 splicing and signaling is regulated by osteopontin. Plasma from LAM patients contained higher concentrations of osteopontin than plasma of healthy, age-, and sex-matched volunteers (P = 0.00003) and may be a biomarker for LAM. The cell surface receptor CD44 and its splice variant CD44v6 may contribute to the metastatic potential of LAM cells.     

Characterization of an epithelial and a tumor-associated human small cell lung carcinoma glycoprotein antigen

The small cell carcinoma (SCC) antigens recognized by LAM2 and LAM8 antibody were characterized by comparison of their tissue expression and analysis of their biochemical composition. LAM2, but not LAM8 antigen could be demonstrated in lipid extracts of SCC cells. By immunohistochemical staining the SCC antigen LAM2 was shown to be an epithelial type membrane antigen. Immunoblotting experiments and competition solid phase radioimmunoassays showed LAM2 antigen to be a native conformation of a glycoprotein with major bands at Mr 100,000-120,000 and a minor band at Mr 210,000. L-Fucose was a dominant part of the epitope which appeared to be closely related to the carbohydrate epitope of the blood group antigen H(O). The tumor-associated membrane antigen LAM8 was shown to be a glycoprotein with major bands at Mr 90,000-135,000 and a minor band at Mr 200,000. Neuraminic acid was the predominant part of the carbohydrate epitope. LAM8 antibody recognized a structure in the saliva of Lea positive probands, but untreated and neuraminidase-treated SCC extracts were unreactive with anti-Lea antibody. Anti CA 19-9 (sialo-Lea antigen) and LAM2 antibodies did not compete for LAM8 binding in direct radioimmunoassays. The sialo-GP90-135 antigen recognized by LAM8 antibody therefore is likely to represent a novel tumor antigen.     

Murine monoclonal antibody LAM2 defines cell membrane determinant with preferential expression on human lung small-cell carcinoma and squamous-cell carcinomas

Murine monoclonal antibodies (MAbs) were generated against a human undifferentiated lung carcinoma cell line. The hybridoma designated LAM2 produced an IgM kappa MAb with reactivity to the cell membrane. Indirect immunofluorescence staining and radioimmunoassay showed LAM2 antibody to react preferentially with lung small-cell carcinoma (SCC) cell lines and squamous-cell carcinoma (SQC) cell lines. LAM2 antibody also stained primary cultures of normal bronchial epithelial cells, but was unreactive with human erythrocytes and nucleated marrow cells. Indirect immunofluorescent staining with LAM2 antibody was performed on frozen sections of human tumor tissues and normal tissues. LAM2 antibody stained all 8 SCC carcinomas, 4 of 5 SQC of the lung and head and neck region, and 2 or 4 lung large-cell carcinomas. No staining was seen on lung adenocarcinomas, breast carcinomas, ovarian carcinomas, renal cell carcinomas, colon carcinomas, or mesotheliomas. Staining was present on sections of normal bronchus, but not on normal lung parenchyma, liver, kidney, adrenal or skin. While LAM2 antibody was highly reactive with all SCC examined, its antigenic determinant was not expressed in other cell lines and tumors of presumed neuroectodermal origin, including neuroblastoma, melanoma, and bronchial carcinoid. Radioimmunoprecipitation showed the antigen defined by LAM2 antibody to have two major bands of approximate molecular weights of 45,000 and 125,000. The selective reactivity of LAM2 antibody with SCC and SQC, but not with most other tumor tissues and normal tissues, makes it a good candidate for use in clinical diagnosis and possibly serotherapy.     

Targeted Approaches toward Understanding and Treating Pulmonary Lymphangioleiomyomatosis (LAM)

Pulmonary lymphangioleiomyomatosis (LAM) is a rare disease found almost exclusively in women that is characterized by neoplastic growth of atypical smooth muscle-like cells in the lung, destruction of lung parenchyma, and obstruction of lymphatics. These processes lead to the formation of lung cysts, rupture of which results in spontaneous pneumothorax. Progression of LAM often results in loss of pulmonary function and death. LAM affects predominantly women of childbearing age and is exacerbated by pregnancy. The only proven treatment for LAM is lung transplantation, and even then LAM cells will often return to the transplanted lung. However, methodical and targeted approaches toward understanding LAM pathophysiology have led to the discovery of new potential therapeutic avenues. For example, the mutational inactivation of tumor suppressor complex genes tuberous sclerosis complex 1 or tuberous sclerosis complex 2 has been shown to be present in lung LAM cells. These mutations occur sporadically or in association with inherited hamartoma syndrome tuberous sclerosis (TSC). Since TSC genes function as negative regulators of the mammalian target of rapamycin, a major controller of cell growth, metabolism, and survival, rapamycin analogs have recently been used to treat LAM patients with promising results. Similarly, studies focusing on the importance of estrogen in LAM progression have suggested that anti-estrogen therapy might prove to be an alternative means of treating LAM. This minireview summarizes recent progress in understanding LAM pathophysiology, including the latest preclinical and clinical studies, and insights regarding the role of hormones in LAM.     

Congenital mesoblastic nephroma: Other magnetic resonance imaging findings

Congenital mesoblastic nephroma (CMN) is a rare renal tumour usually imaged by ultrasound and or CT. To the authors’ knowledge there have been only two previous reports concerning MR imaging of CMN in the English-speaking literature. The MRI findings in a neonate with CMN, which were not previously described, are reported here.     

Progesterone and Estradiol Synergistically Promote the Lung Metastasis of Tuberin-Deficient Cells in a Preclinical Model of Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a female-predominant lung disease that can lead to respiratory failure. LAM cells typically have inactivating tuberous sclerosis 2 (TSC2) mutations, leading to mTORC1 hyperactivation. The gender specificity of LAM suggests that female hormones contribute to disease progression. Clinical findings indicate that estradiol exacerbates LAM behaviors and symptoms. Although hormonal therapy with progesterone has been employed, the benefit in LAM improvement has not been achieved. We have previously found that estradiol promotes the survival and lung metastasis of cells lacking tuberin in a preclinical model of LAM. In this study, we hypothesize that progesterone alone or in combination with estradiol promotes metastatic behaviors of TSC2-deficient cells. In cell culture models of TSC2-deficient LAM patient-derived and rat uterine leiomyoma-derived cells, we found that progesterone treatment or progesterone plus estradiol resulted in increased phosphorylation of Protein Kinase B (Akt) and Extracellular signal-regulated kinases1/2 (ERK1/2), induced the proliferation, and enhanced the migration and invasiveness. In addition, treatment of progesterone plus estradiol synergistically decreased the levels of reactive oxygen species and enhanced cell survival under oxidative stress. In a murine model of LAM, treatment of progesterone plus estradiol promoted the growth of xenograft tumors; however, progesterone treatment did not affect the development of xenograft tumors of Tsc2-deficient cells. Importantly, treatment of progesterone plus estradiol resulted in alteration of lung morphology and significantly increased the number of lung micrometastases of Tsc2-deficient cells compared with estradiol treatment alone. Collectively, these data indicate that progesterone increases the metastatic potential of Tsc2-deficient LAM patient-derived cells in vitro and lung metastasis in vivo. Thus, targeting progesterone-mediated signaling events may have therapeutic benefit for LAM and possibly other hormonally dependent cancers.     

Case Report: Gastroepiploic Artery Pseudoaneurysm as a Cause of Abdominal Apoplexy. Role of CT Scanning

Abdominal apoplexy can be a difficult condition to diagnose prior to surgery. A case is reported where intra-abdominal bleeding resulting from a gastroepiploic artery pseudoaneurysm was diagnosed prior to operative intervention with CT Scanning including dynamic studies. The authors believe that this method of imaging does have a place in the diagnosis of suspected intra-abdominal bleeding, and the condition and the place of CT Scanning in this instance are briefly reviewed.     

Adrenal metastasis of breast cancer with involvement of the inferior vena cava

Tumour thrombosis of the inferior cava vein is usually associated with primary renal cell cancer. To our knowledge, this is the first case reported of adrenal metastasis of breast cancer extending into the inferior vena cava. There are few references in the literature documenting this extension with positron emission tomography (PET) and enhanced computed tomography (CT). The authors focus on the role of combined PET-CT imaging in the accurate detection of malignant thrombus.     

Contribution and limits of x-ray computed tomography and magnetic resonance imaging in evaluating the extent of primary cancers of the bronchi

The authors report the contribution and the limits of CT and MRI in the thoracic and extrathoracic staging of bronchogenic carcinoma. From data of a personal study and of the literature, findings and performances of CT and MRI are reported and compared for the evaluation of mediastinal and parietal extension and in the detection of nodes and metastases. Their respective places and indications are underlined.     

CD68阳性淋巴瘤相关巨噬细胞在滤泡性淋巴瘤间质中的密度及其临床意义的研究

滤泡性淋巴瘤（FL）是最常见的惰性NHL,亦是一种异质性的疾病。FL的预后指标是临床上广泛应用的滤泡淋巴瘤国际预后指标（FLIPI）,具有较高的准确性和简便性,但相同FLIPI的患者预后情况实际不尽相同,反映了FL异质性的特点,在相同的组织分类中存在遗传学和生物学特征不同的亚型。因此有必要寻找新的分子指标以期更准确地预测FL患者的预后。本研究旨在探讨淋巴瘤相关巨噬细胞（LAM）对FL预后判断的价值。方法:免疫组化二步法检测2002年2月至2006年11月间收治的48例初治FL患者组织中LAM的密度,分析其表达与患者临床特征、近期疗效及远期生存率的关系。结果:48例FL患者LAM低密度者38例（79.2％）,高密度者10例（20.8％）。LAM密度与患者年龄、PS状态、血清LDH水平、分期等临床特征无关,与FLIPI评分也无相关性。LAM低密度组化疗疗效和高密度组相近。全组48例患者未达到中位生存期（MST）,LAM低密度组MST优于高密度组（P=0.002）。多因素分析结果显示LAM与FL的预后无明显相关（P>0.05）。结论:LAM的高密度与FL的远期生存呈负相关。但由于本研究入组患者较少,随访时间短,未能达到统计学意义,值得进一步探讨。      

Impact of computed tomography screening for lung cancer on participants in a randomized controlled trial (NELSON trial)

BACKGROUND: Computed tomography (CT) screening is an important new tool for the early detection of lung cancer. In the current study, the authors assessed the discomfort associated with CT scanning and the subsequent wait for results and health-related quality of life (HRQoL) over time. METHODS: A total of 351 participants in the Dutch-Belgian randomized controlled trial for lung cancer screening in high-risk subjects (the NELSON trial) who had an appointment for a baseline CT scan were asked to complete questionnaires regarding their experienced discomfort and HRQoL before, 1 day after, and approximately 6 months after the CT scan. HRQoL was measured as generic HRQoL (12-item Short Form [SF-12] and EuroQol questionnaire [EQ-5D]), generic anxiety (State-Trait Anxiety Inventory [STAI-6]), and lung cancer-specific distress (Impact of Event Scale [IES]). Approximately 76.9% of the participants completed all 3 questionnaires. RESULTS: Approximately 87% to 99% of participants reported experiencing no discomfort related to the CT scan. The median SF-12, EQ-5D, STAI-6, and IES scores did not appear to change relevantly over time. Approximately 46.0% and 51.3%, respectively, of the participants reported discomfort in connection with having to wait for the results of the CT scan and dreading those results. These patients had relevantly higher STAI-6 and IES scores (P < .01) (unfavorable) at all 3 assessments. CONCLUSIONS: The current evaluation of the potential adverse effects of CT screening for lung cancer on HRQoL demonstrated no negative effects. However, waiting for the CT scan results was reported to be discomforting by approximately half of the participants. Minimizing the waiting time for the test results is therefore recommended.     

Low molecular weight inhibitors of matrix metalloproteinases can enhance the expression of matrix metalloproteinase-2 (gelatinase A) without inhibiting its activation

BACKGROUND: In the current study, the authors investigated the effects of synthetic low molecular weight inhibitors of matrix metalloproteinases (MMPs) on the expression and activation of MMP-2 in a three-dimensional tissue system. METHODS: Rabbit periosteal explants were cultured with or without various concentrations of the MMP inhibitors CT1166, CT1399, or CT1746, and conditioned media and tissue extracts were analyzed for the expression and activity of MMP-2. RESULTS: The data showed that blocking the activity of all MMPs with relatively high inhibitor concentrations completely prevented the conversion of pro-MMP-2 into its active form and that the level of protein was decreased. Selective inhibition of the activity of gelatinases (MMP-2 and MMP-9) by using low inhibitor concentrations, however, induced a higher level of active MMP-2 and increased its expression significantly. CONCLUSIONS: The current observations indicate that selective inhibitors of MMPs affect the expression and activity of MMP-2, thus providing clues regarding the differing effects such inhibitors appear to have when applied in vivo.     

结直肠癌组织中LAMβ1、ARPC4、Cx26的表达及#br# 对肿瘤侵袭、转移的影响#br#

目的探究结直肠癌组织中层粘连蛋白β1（LAMβ1）、肌动蛋白相关蛋白2/3复合体4（ARPC4）及间隙连接蛋白26（Cx26）的表达及与肿瘤侵袭、转移的关系。方法选取2018年6月至2019年12月如皋市人民医院病理科收集的100例结直肠癌手术切除的肿瘤组织及相应的癌旁正常组织,应用实时荧光定量PCR检测肿瘤组织及癌旁正常组织LAMβ1、ARPC4、Cx26的mRNA表达;Western blot检测肿瘤组织及癌旁正常组织LAMβ1、ARPC4、Cx26蛋白表达,免疫组织化学法检测LAMβ1、ARPC4、Cx26蛋白在结直肠癌组织及癌旁组织中的表达阳性率,并分析LAMβ1、ARPC4、Cx26蛋白表达与患者临床病理特征的关系。结果RT PCR结果显示,结直肠癌组织中LAMβ1、ARPC4、Cx2的mRNA表达相较于癌旁组织上调。Western blot检测结果显示,结直肠癌组织中LAMβ1、ARPC4、Cx26蛋白表达高于癌旁组织（P<005）。免疫组化结果显示,LAMβ1、ARPC4、Cx26着色主要分布于肿瘤细胞的细胞膜和细胞质中。不同性别、年龄、肿瘤大小结直肠癌患者LAMβ1、ARPC4、Cx26表达比较,差异无统计学意义（P>005）;不同分化程度、临床分期、浸润深度、淋巴结转移、远处转移结直肠癌患者LAMβ1、ARPC4、Cx2表达比较,差异具有统计学意义（P<005）。Pearson相关性分析结果显示,结直肠癌肿瘤组织中LAMβ1、ARPC4、Cx26的mRNA表达量存在正相关性（P<005）,其蛋白表达之间同样存在正相关性（P<005）。结论LAMβ1、ARPC4、Cx26表达升高与结直肠癌的侵袭、转移有关。     

Use of complementary therapies among breast and prostate cancer patients during treatment: a multisite study

PURPOSE: The purpose of this study was to compare the use of complementary therapies (CT) among breast and prostate cancer patients during active cancer treatment. The authors compared use and beliefs about the role of CT in cancer recovery. METHODS: A self-report survey was completed by 126 breast cancer patients and 82 prostate cancer patients as part of a multisite research project. The self-report questionnaire inquired about the use of various CTs, sources of information about CT, reasons for using CT, beliefs about the benefits and risks of CT, demographic characteristics, and cancer treatment history. RESULTS: Most of the respondents were older than 50 years, Caucasian, married, had attended or completed college, and were less than 1 year post-diagnosis. Prostate cancer patients were significantly older than the breast cancer patients (P < .001). Several differences emerged between the groups. Compared to the prostate cancer patients, significantly more of the breast cancer patients reported using CT because they wanted to reduce the risk of recurrence (P < .01), play a more active role in recovery (P < .01), help manage stress (P < .01), take a more holistic approach (P < .01), or boost the immune system (P < .01). More of the prostate cancer patients reported using CT to have more control of their recovery (P < .05). The 2 groups also differed significantly (P < .01) on several beliefs about the potential benefits and risks of using CT. CONCLUSIONS: Most of the patients in this study had used some form of CT since the time of their diagnosis. Differences among breast and prostate cancer patients with regard to their use of CT during cancer treatment should be considered by oncology professionals who are discussing this topic with their patients.     

Inhibition of angiogenesis and murine tumour growth by laminarin sulphate.

LAM S5 is a polysulphated derivative of the glucan laminarian that inhibits basic fibroblast growth factor (bFGF) binding and the bFGF-stimulated proliferation of fetal bovine heart endothelial (FBHE) cells. This report demonstrates that LAM S5 has anti-angiogenic activity, as shown by inhibition of tubule formation by endothelial cells cultured on Matrigel and inhibition of vascularisation of the chick chorioallantoic membrane. In addition, LAM S5 caused a tumour growth delay of the murine RIF-1 tumour of 2.6 days (P = 0.01).     

鞍区肿瘤的CT与临床诊断：附91例分析

Ninety-one patients with parasellar lesions proved by pathology and surgery from July 1982 to May 1987 and 22 patients misdiagnosed clinically or by CT are reported. The authors found that: 1. Besides the main group of parasellar lesions such as pituitary tumor, meningioma, and craniopharyngioma, some rare disease like glioma, pituitary carcinoma, chordoma, olfactory neuroblastoma, Rathke's pouch and tuberculoma of optic nerve were also found which comprised 12% (11/91) in this series. They should be considered in differential diagnosis; 2. Correct diagnosis was made when CT findings conformed well with the clinical features. Over-emphasis of clinical features or neglect of CT findings should be discouraged as they may lead to erroneous diagnosis; 3. In this series, the highest correct diagnosis rates were: pituitary tumor (95%), parasellar meningioma (78%) and craniopharyngioma (50%). It is difficult to make a correct diagnosis for these rare disease entities before operation; and 4. CT scan cannot completely replace angiography and ventriculography when they are needed for differential diagnosis.