18F-FDG PET Imaging Features of Patients With Autoimmune Lymphoproliferative Syndrome.

INTRODUCTION: Autoimmune lymphoproliferative syndrome (ALPS) is a rare immune dysregulatory condition, usually presenting in childhood with massive lymphadenopathy, splenomegaly, and an increased incidence of lymphoma. Methods to differentiate between benign ALPS adenopathy and lymphoma are needed. To this end, we evaluated the usefulness of FDG PET. METHODS: We prospectively evaluated 76 ALPS/ALPS-like patients including FS-7-associated surface antigen (FAS) germline mutation with (n = 4) and without lymphoma (n = 50), FAS-somatic (n = 6), ALPS-unknown (n = 6), and others (n = 10) who underwent FDG PET. Uptakes in 14 nodal sites, liver, and spleen were determined. RESULTS: In 76 ALPS patients, FDG PET showed uptake in multiple nodal sites in all but 1 patient. The highest SUVmax values in FAS mutation without lymphoma, FAS mutation with lymphoma, FAS somatic, ALPS-unknown, and other genetic mutations were a median (range) 9.2 (4.3-25), 16.2 (10.7-37.2), 7.6 (4.6-18.1), 11.5 (4.8-17.2), and 5.5 (0-15.3), respectively. Differences between uptake in the FAS group with and without lymphoma were statistically significant, but overlapped, making discrimination between individuals with/without lymphoma impossible. The spleen:liver uptake ratio was greater than 1 in 82% of patients. CONCLUSIONS: While statistically significant differences were observed in FAS mutation ALPS with and without lymphoma, the significant overlap in FDG uptake and visual appearance in many patients prevents discrimination between patients with and without lymphoma. Similar patterns of FDG biodistribution were noted between the various ALPS subgroups.

Adrenal morphology and associated comorbidities in congenital adrenal hyperplasia.

OBJECTIVE: Adrenonodular hyperplasia and tumour formation are potential long-term complications of congenital adrenal hyperplasia (CAH) with little known regarding the clinical implications. Our aim was to describe volumetric adrenal morphology and determine the association between radiological findings and comorbidities in adults with classic CAH. DESIGN: This was a cross-sectional study of 88 patients (mean age 29.2 ± 13 years, 47 females) with classic CAH seen in a tertiary referral centre. METHODS: CT imaging, performed at study entry or when reaching adulthood, was used to create 3-dimensional volumetric models. Clinical, genetic and hormonal evaluations were collected and correlated with adrenal morphology and tumour formation. RESULTS: Over one-third of the cohort was obese. 53% had elevated 17-OH-progesterone or androstenedione; and 60% had adrenal hyperplasia. Tumours included 11 myelolipomas, 8 benign adrenocortical adenomas, 1 pheochromocytoma and 50% of men had testicular adrenal rest tissue. CAH patients with adrenal hyperplasia had significantly higher number of comorbidities than those with morphologically normal adrenals (P = 0.03). Variables that positively correlated with adrenal volume included hypogonadal/oligomenorrhoeic status, hypertension, androstenedione, aldosterone, and triglyceride levels, and in women, low HDL and insulin resistance. Elevated aldosterone was observed in a subset of patients with simple virilizing CAH. CONCLUSIONS: Adrenocortical hyperplasia is associated with a number of comorbidities, especially hypogonadism. Aldosterone production associated with adrenal enlargement may play a role in the development of metabolic risk factors. Further studies are needed to assess the long-term impact of the excess adrenal steroid milieu associated with adrenal enlargement to develop improved management strategies for CAH.

Use of CT Imaging to Quantify Progression and Response to Treatment in Lymphangioleiomyomatosis.

BACKGROUND: In lymphangioleiomyomatosis (LAM), infiltration of the lungs with smooth muscle-like LAM cells results in cystic destruction and decline in lung function, effects stabilized by sirolimus therapy. LAM lung disease is followed, in part, by high-resolution CT scans. To obtain further information from these scans, we quantified changes in lung parenchyma by analyzing image "texture." METHODS: Twenty-six texture properties were quantified by analyzing the distribution and intensity of pixels with a computer-aided system. Both cross-sectional and longitudinal studies were performed to examine the relationships between texture properties, cyst score (percentage of lung occupied by cysts), FEV1, and diffusion capacity for carbon monoxide (Dlco), and to determine the effect of sirolimus treatment. RESULTS: In the cross-sectional study, 18 texture properties showed significant positive correlations with cyst score. Cyst score and 13 of the 18 texture properties showed significant differences in rates of change after sirolimus treatment; 11 also significantly predicted FEV1 and Dlco. CONCLUSIONS: Increased cyst score was associated with increased texture degradation near cysts. Sirolimus treatment improved lung texture surrounding cysts and stabilized cyst score. Eleven texture properties were associated with FEV1, Dlco, cyst score, and response to sirolimus. Texture analysis may be valuable in evaluating LAM severity and treatment response.

The NHLBI LAM Registry: Prognostic Physiologic and Radiologic Biomarkers Emerge From a 15-Year Prospective Longitudinal Analysis.

BACKGROUND: The natural history of lymphangioleiomyomatosis (LAM) is mainly derived from retrospective cohort analyses, and it remains incompletely understood. A National Institutes of Health LAM Registry was established to define the natural history and identify prognostic biomarkers that can help guide management and decision-making in patients with LAM. METHODS: A linear mixed effects model was used to compute the rate of decline of FEV1 and to identify variables affecting FEV1 decline among 217 registry patients who enrolled from 1998 to 2001. Prognostic variables associated with progression to death/lung transplantation were identified by using a Cox proportional hazards model. RESULTS: Mean annual decline of FEV1 was 89 ± 53 mL/year and remained remarkably constant regardless of baseline lung function. FEV1 decline was more rapid in those with greater cyst profusion on CT scanning (P = .02) and in premenopausal subjects (118 mL/year) compared with postmenopausal subjects (74 mL/year) (P = .003). There were 26 deaths and 43 lung transplantations during the evaluation period. The estimated 5-, 10-, 15-, and 20-year transplant-free survival rates were 94%, 85%, 75%, and 64%, respectively. Postmenopausal status (hazard ratio, 0.30; P = .0002) and higher baseline FEV1 (hazard ratio, 0.97; P = .008) or diffusion capacity of lung for carbon monoxide (hazard ratio, 0.97; P = .001) were independently associated with a lower risk of progression to death or lung transplantation. CONCLUSIONS: The median transplant-free survival in patients with LAM is > 20 years. Menopausal status, as well as structural and physiologic markers of disease severity, significantly affect the rate of decline of FEV1 and progression to death or lung transplantation in LAM.

The Comparative Associations of Ultrasound and Computed Tomography Estimates of Muscle Quality with Physical Performance and Metabolic Parameters in Older Men.

Estimates of muscle tissue composition may have greater prognostic value than lean body mass levels regarding health-related outcomes. Ultrasound provides a relatively low cost, safe, and accessible mode of imaging to assess muscle morphology. The purpose of this study was to determine the construct validity of muscle echogenicity as a surrogate measure of muscle quality in a sample of older, predominantly African American (AA) participants. We examined the association of rectus femoris echogenicity with mid-thigh computed tomography (CT) scan estimates of intra- and intermuscular adipose tissue (IMAT), basic metabolic parameters via blood sample analysis, muscle strength, and mobility status. This observational study was conducted at a federal medical center and included 30 community-dwelling men (age, 62.5 ± 9.2; AA, n = 24; Caucasian, n = 6). IMAT estimates were significantly associated with echogenicity (r = 0.73, p < 0.001). Echogenicity and IMAT exhibited similar associations with the two-hour postprandial glucose values and high-density lipoproteins values (p < 0.04), as well as grip and isokinetic (180°/s) knee extension strength adjusted for body size (p < 0.03). The significant relationship between ultrasound and CT muscle composition estimates, and their comparative association with key health-related outcomes, suggests that echogenicity should be further considered as a surrogate measure of muscle quality.

Active Surveillance of Nonfatty Renal Masses in Patients With Lymphangioleiomyomatosis: Use of CT Features and Patterns of Growth to Differentiate Angiomyolipoma From Renal Cancer.

OBJECTIVE: The objective of this study was to report our experience with active surveillance of nonfatty renal masses in a large cohort of patients with lymphangioleiomyomatosis (LAM), correlate their CT features and patterns of growth with histopathology results, and provide guidelines for management. SUBJECTS AND METHODS: Yearly CT examinations were performed of 367 women (age range, 21-75 years; mean age, 47 years). For the 31 patients with 37 nonfatty renal masses that were biopsied, excised, or followed for ≥ 5 years, CT enhancement characteristics and patterns of growth were compared with the histopathology results. RESULTS: Four of 37 nonfatty renal masses were biopsied without follow-up CT examinations: Two were heterogeneous renal cell carcinomas (RCCs), one was a heterogeneous nonfatty angiomyolipoma (AML), and one was homogeneous nonfatty AML. In the remaining 33 nonfatty renal masses with multiple follow-up CT examinations, two growth patterns were identified. Four showed a continuous increase in size of > 0.5 cm/y in some years, and all four in this first group were heterogeneous and were biopsy-proven RCC. The second group was composed of the remaining 29 masses. These 29 masses showed yearly no change, increase, or decrease in diameter. Eight were heterogeneous, and 21 were homogeneous. Of the masses showing a yearly increase, the increase was < 0.5 cm/y in all except one. In the one exception, the increase followed a decrease. Nine of the 29 masses were biopsied, and all nine were nonfatty renal masses (five homogeneous, four heterogeneous). CONCLUSION: Our data provide further evidence in a large prospective study with longterm follow-up that active surveillance is an appropriate strategy in the management of nonfatty renal masses in patients with LAM. Our analysis of the growth patterns reveals duration of growth in addition to growth rate as criteria for biopsy or excision. Biopsy should be reserved for nonfatty renal masses that show sustained growth or growth > 0.5 cm/y during follow-up.

11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency.

Context: Patients with 21-hydroxylase deficiency (21OHD) have long-term complications, resulting from poor disease control and/or glucocorticoid overtreatment. Lack of optimal biomarkers has made it challenging to tailor therapy and predict long-term outcomes. Objective: To identify biomarkers of disease control and long-term complications in 21OHD. Setting and Participants: Cross-sectional study of 114 patients (70 males), ages 2 to 67 years (median, 15 years), seen in a tertiary referral center. Methods: We correlated a mass-spectrometry panel of 23 steroids, obtained before first morning medication, with bone age advancement (children), adrenal volume (adults), testicular adrenal rest tumors (TART), hirsutism, menstrual disorders, and pituitary hormones. Results: Total adrenal volume correlated positively with 18 steroids, most prominently 21-deoxycortisol and four 11-oxygenated-C19 (11oxC19) steroids: 11ß-hydroxyandrostenedione (11OHA4), 11-ketoandrostenedione (11ketoA4), 11ß-hydroxytestosterone (11OHT), and 11-ketotestosterone (11ketoT) (r ≈ 0.7, P < 0.0001). Nine steroids were significantly higher (P ≤ 0.01) in males with TART compared with those without TART, including 11OHA4 (6.8-fold), 11OHT (4.9-fold), 11ketoT (3.6-fold), 11ketoA4 (3.3-fold), and pregnenolone sulfate (PregS; 4.8-fold). PregS (28.5-fold) and 17-hydroxypregnenolone sulfate (19-fold) levels were higher (P < 0.01) in postpubertal females with menstrual disorders. In males, testosterone levels correlated positively with all 11oxC19 steroids in Tanner stages 1 and 2 (r ≈ 0.7; P < 0.001) but negatively in Tanner stage 5 (r = -0.3 and P < 0.05 for 11ketoA4 and 11ketoT). In females, testosterone level correlated positively with all four 11oxC19 steroids across all Tanner stages (r ≈ 0.8; P < 0.0001). Conclusion: 11oxC19 steroids and PregS might serve as clinically useful biomarkers of disease control and long-term complications in 21OHD.

Use of PET/CT with cosyntropin stimulation to identify and localize adrenal rest tissue following adrenalectomy in a woman with congenital adrenal hyperplasia.

CONTEXT: Adrenalectomy is an experimental treatment option for select patients with congenital adrenal hyperplasia who have failed medical therapy. After adrenalectomy, adrenal rest tissue can remain in extraadrenal locations, cause recurrent hyperandrogenism, and be difficult to localize. OBJECTIVE: The aim of the study was to investigate the usefulness of positron emission tomography/computerized tomography (PET/CT) in identifying adrenal rest tissue. SUBJECT: A female with salt-wasting 21-hydroxylase deficiency who had bilateral adrenalectomy at age 17 yr presented with hyperandrogenism at age 32 yr. Pelvic magnetic resonance imaging and ultrasound imaging were nondiagnostic for the source of androgen production. METHODS AND RESULTS: A baseline F-18 labeled fluoro-2-deoxy-d-glucose (18F-FDG) PET/CT scan showed no active uptake; however, a second scan preceded by a 250-µg cosyntropin injection identified three areas of active uptake near both ovaries. Subsequent ovarian venous sampling showed elevations in 17-hydroxyprogesterone, androstenedione, and 21-deoxycortisol in both ovarian veins compared to a peripheral vein at baseline and more so after cosyntropin administration. At laparoscopy, three well-circumscribed nodules (2.4 × 0.9 × 1.3 cm, 1.2 × 1.5 × 1.5 cm, and 2 × 1.5 × 1 cm) lying lateral to the fallopian tubes adjacent to the broad ligaments were removed. The paraovarian nodules and previously removed adrenal glands had similar histology and immunohistochemistry. Postoperatively, androgen concentrations were undetectable, with no response to cosyntropin stimulation. CONCLUSIONS: Patients with CAH after an adrenalectomy may experience recurrent hyperandrogenism due to adrenal rest tissue. 18F-FDG PET/CT with cosyntropin stimulation accurately identified adrenal rest tissue not visualized with conventional imaging, allowing for successful surgical resection.

Prevalence of uterine leiomyomas in lymphangioleiomyomatosis.

OBJECTIVE: To determine the frequency of uterine leiomyomas and hysterectomy in patients with lymphangioleiomyomatosis (LAM), a disease characterized by proliferation of abnormal-appearing smooth muscle-like cells. DESIGN: Retrospective study. SETTING: Natural history study at the National Institutes of Health. PATIENT(S): 456 patients with sporadic LAM and LAM associated with tuberous sclerosis complex (LAM/TSC). INTERVENTION(S): Review of records and pelvic computed axial tomography scans. MAIN OUTCOME MEASURE(S): Prevalence of uterine leiomyomas and hysterectomy. RESULT(S): A total of 174 women had uterine leiomyomas (38%). One hundred eighteen were diagnosed by computed tomographic scan and 56 were diagnosed by hysterectomy. Among 323 patients who did not have hysterectomy, 105 of 270 patients (39%) with sporadic LAM and 13 of 53 (25%) with LAM/TSC had uterine leiomyomas. Hysterectomy was performed in 108 of 378 subjects with sporadic LAM and 25 of 78 with LAM/TSC. Fifty-six patients were found to have uterine fibroids on hysterectomy. The most common indications for hysterectomy were uterine leiomyoma, LAM, and endometriosis. CONCLUSION(S): Uterine leiomyomas are not more common in LAM than in the general population. However, in LAM, the frequency of hysterectomy is higher because of it having been recommended for treatment of LAM.

Automated quantification of high-resolution CT scan findings in individuals at risk for pulmonary fibrosis.

BACKGROUND: Automated methods to quantify interstitial lung disease (ILD) on high-resolution CT (HRCT) scans in people at risk for pulmonary fibrosis have not been developed and validated. METHODS: Cohorts with familial pulmonary fibrosis (n = 126) or rheumatoid arthritis with and without ILD (n = 86) were used to develop and validate a computer program capable of quantifying ILD on HRCT scans, which imaged the lungs semicontinuously from the apices to the lung bases during end-inspiration in the prone position. This method uses segmentation, texture analysis, training, classification, and grading to score ILD. RESULTS: Quantification of HRCT scan findings of ILD using an automated computer program correlated with radiologist readings and detected disease of varying severity in a derivation cohort with familial pulmonary fibrosis or their first-degree relatives. This algorithm was validated in an independent cohort of subjects with rheumatoid arthritis with and without ILD. Automated classification of HRCT scans as normal or ILD was significant in the derivation and validation cohorts (P < .001 and P < .001, respectively). Areas under receiver operating characteristic curves performed independently for each group were 0.888 for the derivation cohort and 0.885 for the validation cohort. Pulmonary function test results, including FVC and diffusion capacity, correlated with computer-generated HRCT scan scores for ILD (r = -0.483 and r = -0.532, respectively). CONCLUSIONS: Automated computer scoring of HRCT scans can objectively identify ILD and potentially quantify radiographic severity of lung disease in populations at risk for pulmonary fibrosis.

Imaging features of lymphangioleiomyomatosis: diagnostic pitfalls.

OBJECTIVE: The objective of this article is to illustrate CT findings that may be misinterpreted and lead to unnecessary biopsy or surgical procedures in patients with lymphangioleiomyomatosis. CONCLUSION: Sequelae of pleurodesis, acutely hemorrhagic renal angiomyolipomas, and lymphatic involvement with lymphangioleiomyomatosis including enlarged lymph nodes and lymphangioleiomyomas are common benign conditions seen in patients with lymphangioleiomyomatosis that may be misdiagnosed on CT for malignancy and may prompt unnecessary biopsy and surgery. Ruptured abdominal pelvic lymphangioleiomyomas may be mistaken for appendicitis and other acute abdominal pelvic events.

Phenotypic profiling of parents with cryptic nonclassic congenital adrenal hyperplasia: findings in 145 unrelated families.

OBJECTIVE: To comprehensively phenotype parents identified with nonclassic congenital adrenal hyperplasia (NCCAH) by family genetic studies, termed here as cryptic NCCAH and to define the incidence of cryptic NCCAH in the parents of a large cohort of patients with 21-hydroxylase deficiency. DESIGN: Genotyping was performed on 249 parents of 145 unrelated congenital adrenal hyperplasia (CAH) patients. Parents with two CYP21A2 mutations underwent extensive evaluation. RESULTS: Of the 249 parents, ten (4%; seven females and three males) were identified as having cryptic NCCAH. The majority was of ethnicities previously reported to have a higher incidence of NCCAH. Cosyntropin stimulation performed in eight parents provided biochemical confirmation (17-hydroxyprogesterone range 56-364 nmol/l) and cortisol response was ≤500 nmol/l in three parents (38%). Of the seven women (27-54 years) with cryptic NCCAH, four had prior infertility, two reported irregular menses, two had treatment for hirsutism, one had androgenic alopecia. Men were asymptomatic. All cryptic NCCAH parents reported normal puberty and had normal height. Adrenal hypertrophy and a small adrenal myelolipoma were observed in two parents; testicular adrenal rest tissue was not found. CONCLUSIONS: Parents diagnosed with NCCAH by genetic testing are mostly asymptomatic. Temporary female infertility and suboptimal cortisol response were commonly observed. Ongoing glucocorticoid therapy is not indicated in adults with CAH identified by family genotype studies unless symptomatic, but glucocorticoid stress coverage should be considered in select cases. Parents of a child with CAH have a 1:25 risk of having NCCAH; if the mother of a child with CAH has infertility, evaluation for NCCAH is indicated.

Waist circumference, BMI, and visceral adipose tissue in white women and women of African descent.

Although waist circumference (WC) is a marker of visceral adipose tissue (VAT), WC cut-points are based on BMI category. We compared WC-BMI and WC-VAT relationships in blacks and whites. Combining data from five studies, BMI and WC were measured in 1,409 premenopausal women (148 white South Africans, 607 African-Americans, 186 black South Africans, 445 West Africans, 23 black Africans living in United States). In three of five studies, participants had VAT measured by computerized tomography (n = 456). Compared to whites, blacks had higher BMI (29.6 ± 7.6 (mean ± s.d.) vs. 27.6 ± 6.6 kg/m², P = 0.001), similar WC (92 ± 16 vs. 90 ± 15 cm, P = 0.27) and lower VAT (64 ± 42 vs. 101 ± 59 cm², P < 0.001). The WC-BMI relationship did not differ by race (blacks: ß (s.e.) WC = 0.42 (.01), whites: ß (s.e.) WC = 0.40 (0.01), P = 0.73). The WC-VAT relationship was different in blacks and whites (blacks: ß (s.e.) WC = 1.38 (0.11), whites: ß (s.e.) WC = 3.18 (0.21), P < 0.001). Whites had a greater increase in VAT per unit increase in WC. WC-BMI and WC-VAT relationships did not differ among black populations. As WC-BMI relationship did not differ by race, the same BMI-based WC guidelines may be appropriate for black and white women. However, if WC is defined by VAT, race-specific WC thresholds are required.

CT of sclerotic bone lesions: imaging features differentiating tuberous sclerosis complex with lymphangioleiomyomatosis from sporadic lymphangioleiomymatosis.

PURPOSE: To determine if sclerotic bone lesions evident at body computed tomography (CT) are of value as a diagnostic criterion of tuberous sclerosis complex (TSC) and in the differentiation of TSC with lymphangioleiomyomatosis (LAM) from sporadic LAM. MATERIALS AND METHODS: Informed consent was signed by all patients in this HIPAA-compliant study approved by the institutional review board. Retrospective analysis was performed of the body CT studies of 472 patients: 365 with sporadic LAM, 82 with TSC/LAM, and 25 with TSC. The images were reviewed by using a picture archiving and communication system workstation with bone settings (window width, 1500 HU; window level, 300 HU) and fit-to-screen option. CT image characteristics assessed included shape, size, and distribution of sclerotic bone lesions with subsequent calculation of differences in the frequency of these lesions. RESULTS: Most commonly the sclerotic bone lesions were round, measured 0.3 cm (range, 0.2-3.2), and were distributed throughout the spine. The frequencies differed among the three patient groups Four or more sclerotic bone lesions were detected in all 25 (100%) of those with TSC, with a sensitivity of .89 (72 of 82) and specificity of .97 (355 of 367) in the differentiation of sporadic LAM from TSC/LAM (P < .01). CONCLUSION: The number of sclerotic bone lesions at body CT is of potential value in the diagnosis of TSC and in the differentiation of patients with sporadic LAM from those with TSC/LAM. (c) RSNA, 2010.

Serum vascular endothelial growth factor-D levels in patients with lymphangioleiomyomatosis reflect lymphatic involvement.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare multisystem disorder affecting primarily women of child-bearing age, and characterized by cystic lung destruction, tumors of the kidney (angiomyolipomas [AMLs]), and involvement of the axial lymphatics (lymphangioleiomyomas). Patients with LAM experience loss of pulmonary function attributed to the proliferation of abnormal-appearing smooth muscle-like cells (LAM cells). It is possible to group the LAM population by the presence or absence of extrapulmonary involvement (eg, AMLs, lymphangioleiomyomas, chylous effusions). Serum vascular endothelial growth factor (VEGF)-D, a lymphangiogenic factor, is higher in LAM patients than in healthy volunteers and has been proposed as a tool in the differential diagnosis of cystic lung disease. We assessed serum VEGF-D concentrations in relationship to clinical phenotype in LAM patients. METHODS: Serum VEGF-D levels were quantified by enzyme immunosorbent assay for 111 patients with LAM and 40 healthy volunteers. VEGF-D levels in patients with pulmonary LAM, with or without extrapulmonary manifestations, were compared to those of healthy volunteers. RESULTS: Serum VEGF-D levels were greater in patients with LAM compared to those of healthy volunteers (p < 0.001). However, when patient samples were grouped based on the extent of lymphatic extrapulmonary involvement (eg, lymphangioleiomyomas and adenopathy), the statistical difference was maintained only for patients with LAM with lymphatic involvement (p < 0.001), not for those patients whose disease was restricted to the lung. Serum VEGF-D levels are a good biomarker for lymphatic involvement (area under the curve [AUC], 0.845; p < 0.0001), and a fair predictor for LAM disease (AUC, 0.751; p < 0.0001). Serum levels correlated to CT scan grade (p = 0.033). CONCLUSIONS: Serum VEGF-D concentration is a measure of lymphatic involvement in patients with LAM.

Pneumothorax after air travel in lymphangioleiomyomatosis, idiopathic pulmonary fibrosis, and sarcoidosis.

BACKGROUND: The prevalence of pneumothorax associated with travel in patients with interstitial lung diseases is unknown. In patients with lymphangioleiomyomatosis (LAM), in whom pneumothorax is common, patients are often concerned about the occurrence of a life-threatening event during air travel. The aim of this study was to determine the prevalence of pneumothorax associated with air travel in patients with LAM, idiopathic pulmonary fibrosis (IPF), and sarcoidosis. METHODS: Records and imaging studies of 449 patients traveling to the National Institutes of Health were reviewed. RESULTS: A total of 449 patients traveled 1,232 times; 299 by airplane (816 trips) and 150 by land (416 trips). Sixteen of 281 LAM patients arrived at their destination with a pneumothorax. In 5 patients, the diagnosis was made by chest roentgenogram, and in 11 patients by CT scans only. Of the 16 patients, 14 traveled by airplane and 2 by land. Seven of the 16 patients, 1 of whom traveled by train, had a new pneumothorax; 9 patients had chronic pneumothoraces. A new pneumothorax was more likely in patients with large cysts and more severe disease. The frequency of a new pneumothorax for LAM patients who traveled by airplane was 2.9% (1.1 per 100 flights) and by ground transportation, 1.3% (0.5 per 100 trips). No IPF (n = 76) or sarcoidosis (n = 92) patients presented with a pneumothorax. CONCLUSIONS: In interstitial lung diseases with a high prevalence of spontaneous pneumothorax, there is a relatively low risk of pneumothorax following air travel. In LAM, the presence of a pneumothorax associated with air travel may be related to the high incidence of pneumothorax and not to travel itself.

Combination therapy in treatment of experimental pulmonary aspergillosis: in vitro and in vivo correlations of the concentration- and dose- dependent interactions between anidulafungin and voriconazole by Bliss independence drug interaction analysis.

We studied the antifungal activity of anidulafungin (AFG) in combination with voriconazole (VRC) against experimental invasive pulmonary aspergillosis (IPA) in persistently neutropenic rabbits and further explored the in vitro and in vivo correlations by using Bliss independence drug interaction analysis. Treatment groups consisted of those receiving AFG at 5 (AFG5 group) and 10 (AFG10 group) mg/kg of body weight/day, VRC at 10 mg/kg every 8 h (VRC group), AFG5 plus VRC (AFG5+VRC group), and AFG10 plus VRC (AFG10+VRC group) and untreated controls. Survival throughout the study was 60% for the AFG5+VRC group, 50% for the VRC group, 27% for the AFG10+VRC group, 22% for the AFG5 group, 18% for the AFG10 group, and 0% for control rabbits (P < 0.001). There was a significant reduction of organism-mediated pulmonary injury, measured by infarct scores, lung weights, residual fungal burdens, and galactomannan indexes, in AFG5+VRC-treated rabbits versus those treated with AFG5 and VRC alone (P < 0.05). In comparison, AFG10+VRC significantly lowered only infarct scores and lung weights in comparison to those of AFG10-treated animals (P < 0.05). AFG10+VRC showed no significant difference in other outcome variables. Significant Bliss synergy was found in vivo between AFG5 and VRC, with observed effects being 24 to 30% higher than expected levels if the drugs were acting independently. These synergistic interactions were also found between AFG and VRC in vitro. However, for AFG10+VRC, only independence and antagonism were observed among the outcome variables. We concluded that the combination of AFG with VRC in treatment of experimental IPA in persistently neutropenic rabbits was independent to synergistic at a dosage of 5 mg/kg/day but independent to antagonistic at 10 mg/kg/day, as assessed by Bliss independence analysis, suggesting that higher dosages of an echinocandin may be deleterious to the combination.

Progressive preclinical interstitial lung disease in rheumatoid arthritis.

BACKGROUND: Early detection and treatment for interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) may ameliorate disease progression. The objective of this study was to identify asymptomatic lung disease and potential therapeutic targets in patients having RA and preclinical ILD (RA-ILD). METHODS: Sixty-four adults with RA and 10 adults with RA and pulmonary fibrosis (RAPF) were referred to the National Institutes of Health, Bethesda, Maryland, and underwent high-resolution computed tomography (HRCT) and pulmonary physiology testing. Proteins capable of modulating fibrosis were quantified in alveolar fluid. RESULTS: Twenty-one of 64 patients (33%) having RA without dyspnea or cough had preclinical ILD identified by HRCT. Compared with patients without lung disease, patients with RA-ILD had statistically significantly longer histories of cigarette smoking (P< .001), increased frequencies of crackles (P= .02), higher alveolar-arterial oxygen gradients (P= .004), and higher HRCT scores (P< .001). The HRCT abnormalities progressed in 12 of 21 patients (57%) with RA-ILD. The alveolar concentrations of platelet-derived growth factor-AB and platelet-derived growth factor-BB were statistically significantly higher in patients having RA-ILD (mean [SE], 497.3 [78.6] and 1473 [264] pg/mL, respectively) than in patients having RA without ILD (mean [SE], 24.9 [42.4] and 792.7 [195.0] pg/mL, respectively) (P< .001 and P=.047, respectively). The concentrations of interferon gamma and transforming growth factor beta(2) were statistically significantly lower in patients having RAPF (mean [SE], 5.59 [1.11] pg/mL and 0.94 [0.46] ng/mL, respectively) than in patients having RA without ILD (mean [SE], 14.1 [1.9] pg/mL and 2.30 [0.39] ng/mL, respectively) (P=.001 and P=.006, respectively) or with preclinical ILD (mean [SD], 11.4 [2.6] pg/mL and 3.63 [0.66] ng/mL, respectively) (P=.04 and P=.007, respectively). Compared with patients having stable RA-ILD, patients having progressive RA-ILD had statistically significantly higher frequencies of treatment using methotrexate and higher alveolar concentrations of interferon gamma and transforming growth factor beta(1) (P=.046, P=.04, and P=.04, respectively). CONCLUSIONS: Asymptomatic preclinical ILD, which is detectable by HRCT, may be prevalent and progressive among patients having RA. Cigarette smoking seems to be associated with preclinical ILD in patients having RA, and treatment using methotrexate may be a risk factor for progression of preclinical ILD. Quantification of alveolar proteins indicates that potential pathogenic mechanisms seem to differ in patients having RA-ILD and symptomatic RAPF.

Metabolic syndrome traits in long-term survivors of pediatric sarcoma.

PURPOSE: The metabolic syndrome (MS), a cluster of central obesity, dyslipidemia, hyperglycemia, and hypertension, conveys an increased risk of type 2 diabetes and cardiovascular disease. This cross-sectional study investigated the prevalence of metabolic syndrome traits (MST) in long-term survivors of pediatric sarcoma (SARC) who received multi-modality therapy (MMT). METHODS: Thirty-two SARC survivors (predominantly Ewings; median age 36.5; median age at MMT 15) underwent body composition, activity, and psychosocial analysis. Serum endocrine and inflammatory parameters and urine beta(2)-microglobulin (B2M) were evaluated. The prevalence of MST was compared to age- and gender-matched U.S. population data. RESULTS: SARC survivors were more likely to have two or more MST (OR 2.38 95% CI: [1.14, 5.04]). Analysis of individual MST demonstrated higher prevalence of hypertension (OR 2.61 95% CI: [1.20, 5.59]), hypertriglyceridemia (OR 3.63 95% CI: [1.75, 7.60]), and male visceral abdominal obesity (20-39 years old OR 4.63 95% CI: [0.91, 21.63], 40-59 years old OR infinity). Survivors 18-39 years old had a higher prevalence of the MS (OR 4.29 95% CI: [1.50, 11.21]), defined as three or more MST. Plasminogen activator inhibitory activity (P = 0.016) and B2M (P = 0.027) increased with increasing numbers of MST. In males, total testosterone declined (P = 0.0027) as the number of MST increased. Average (P = 0.014) and maximum (P = 0.021) activity levels decreased as the number of MST increased. CONCLUSION: After a median follow up of 17 years, adult SARC survivors of MMT had an increased prevalence of MST, especially those less than 40 years old. The development of MST in this population was associated with decreased testosterone and activity levels.