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Unilateral adrenal infarction is a rare cause of acute abdomen in pregnancy (AAP). Its presentation is non-specific and requires a high index of suspicion with a low threshold to obtain radiographic imaging for diagnosis. Evaluating AAP is challenging as diagnostic radiographic imaging is often limited in relation to radiation exposure to the developing fetus. We describe a case of a 24-year-old pregnant female who presented with severe acute abdominal pain. The patient’s pain was refractory to intravenous analgesics and ultrasonography was inconclusive. Computed tomography (CT) scan was not obtained due to the risk of radiation exposure to the developing fetus. Due to the persistence of pain and suspicions for other serious etiologies, magnetic resonance imaging (MRI) was completed and the patient was diagnosed with acute unilateral adrenal infarction. In this case report, unilateral adrenal infarction was likely secondary to elevated plasma factor VIII levels. Even with the physiological elevation of factor VIII levels during pregnancy, levels greater than 150 IU/dL confer greater than five-fold increased risk of venous thrombosis. Once hemorrhage is excluded, patients should be started on therapeutic anticoagulation to prevent progression of adrenal infarct or infarction of the contralateral adrenal gland. Prompt recognition and treatment of acute adrenal infarction during pregnancy are of paramount importance to prevent adverse outcomes for both the mother and fetus.

19 pags., 7 figs., 2 tabs., Taspase1 is an Ntn-hydrolase overexpressed in primary human cancers, coordinating cancer cell proliferation, invasion, and metastasis. Loss of Taspase1 activity disrupts proliferation of human cancer cells in vitro and in mouse models of glioblastoma. Taspase1 is synthesized as an inactive proenzyme, becoming active upon intramolecular cleavage. The activation process changes the conformation of a long fragment at the C-terminus of the α subunit, for which no full-length structural information exists and whose function is poorly understood. We present a cloning strategy to generate a circularly permuted form of Taspase1 to determine the crystallographic structure of active Taspase1. We discovered that this region forms a long helix and is indispensable for the catalytic activity of Taspase1. Our study highlights the importance of this element for the enzymatic activity of Ntn-hydrolases, suggesting that it could be a potential target for the design of inhibitors with potential to be developed into anticancer therapeutics., This project has been funded in whole with Federal funds from the National Cancer Institute (NCI), National Institutes of Health (NIH), under Chemical Biology Consortium contract no. HHSN261200800001E.

Proteases can play essential roles in severe human pathology, ranging from degenerative and inflammatory illnesses to infectious diseases, with some, such as Taspase1, involved in growth and progression of tumors at primary and metastatic sites. Taspase1 is a N-terminal nucleophile (Ntn)-hydrolase overexpressed in primary human cancers, coordinating cancer cell proliferation, invasion, and metastasis. Loss of Taspase1 activity disrupts proliferation of human cancer cellsin vitroand in mouse xenograft models of glioblastoma, thus this protein has the potential to become a novel anticancer drug target. It belongs to the family of Ntn-hydrolases, a unique family of proteins synthesized as enzymatically inactive proenzymes that become activated upon cleavage of the peptide bond on the N-terminal side of a threonine residue, which then becomes the catalytic site nucleophile. The activation process simultaneously changes the conformation of a long domain at the C-terminus of the alpha-subunit for which no full-length structural information exists and its function is poorly understood. Here we present a novel cloning strategy to generate a fully active, circularly permuted form of Taspase1 to determine the crystallographic structure of catalytically active human Taspase1 to 3.04Å. We discovered that this region forms a long helical domain and is indispensable for the catalytic activity of Taspase1. Together, our study highlights the importance of this element for the enzymatic activity of Ntn-hydrolases and suggests that this long domain could be a novel target for the design of inhibitors with the potential to be developed into anticancer therapeutics.

The L-type amino acid transporter 1 (LAT1, SLC7A5) transports essential amino acids across the blood—brain barrier (BBB) and into cancer cells. To utilize LAT1 for drug delivery, potent amino acid promoieties are desired, as prodrugs must compete with millimolar concentrations of endogenous amino acids. To better understand ligand—transporter interactions that could improve potency, we developed structural LAT1 models to guide the design of substituted analogues of phenylalanine and histidine. Furthermore, we evaluated the structure—activity relationship (SAR) for both enantiomers of naturally occurring LAT1 substrates. Analogues were tested in cis-inhibition and trans-stimulation cell assays to determine potency and uptake rate. Surprisingly, LAT1 can transport amino acid-like substrates with wide-ranging polarities including those containing ionizable substituents. Additionally, the rate of LAT1 transport was generally nonstereoselective even though enantiomers likely exhibit different binding modes. Our findings have broad implications to the development of new treatments for brain disorders and cancer.

Objective Uncontrolled rapid release of drugs can reduce their therapeutic efficacy and cause undesirable toxicity; however, controlled release from reservoir materials helps overcome this issue. The aims of this study were to determine the release profiles of ketoprofen and spironolactone from a pH-responsive self-assembling DPA-MPC-DPA triblock copolymer gel and elucidate underlying physiochemical properties. Methods Drug release profiles from DPA50-MPC250-DPA50 gel (pH 7.5), over 32 h (37 °C), were determined using UV-Vis spectroscopy. Nanoparticle size was measured by dynamic light scattering (DLS) and critical micelle concentration (CMC) by pyrene fluorescence. Polymer gel viscosity was examined via rheology, nanoparticle morphology investigated using scanning transmission electron microscopy (STEM) and the gel matrix observed using cryo-scanning electron microscopy (Cryo-SEM). Key Findings DPA50-MPC250-DPA50 copolymer (15% w/v) formed a free-standing gel (pH 7.5) that controlled drug release relative to free drugs. The copolymer possessed a low CMC, nanoparticle size increased with copolymer concentration, and DLS data were consistent with STEM. The gel displayed thermostable viscosity at physiological temperatures, and the gel matrix was a nanostructured aggregation of smaller nanoparticles. Conclusions The DPA50-MPC250-DPA50 copolymer gel could be used as a drug delivery system to provide the controlled drug release of ketoprofen and spironolactone.

© 2016 Elsevier Ltd Large neutral amino acid transporter 1 (LAT1) is a solute carrier protein located primarily in the blood–brain barrier (BBB) that offers the potential to deliver drugs to the brain. It is also up-regulated in cancer cells, as part of a tumor's increased metabolic demands. Previously, amino acid prodrugs have been shown to be transported by LAT1. Carboxylic acid bioisosteres may afford prodrugs with an altered physicochemical and pharmacokinetic profile than those derived from natural amino acids, allowing for higher brain or tumor levels of drug and/or lower toxicity. The effect of replacing phenylalanine's carboxylic acid with a tetrazole, acylsulfonamide and hydroxamic acid (HA) bioisostere was examined. Compounds were tested for their ability to be LAT1 substrates using both cis-inhibition and trans-stimulation cell assays. As HA-Phe demonstrated weak substrate activity, its structure–activity relationship (SAR) was further explored by synthesis and testing of HA derivatives of other LAT1 amino acid substrates (i.e., Tyr, Leu, Ile, and Met). The potential for a false positive in the trans-stimulation assay caused by parent amino acid was evaluated by conducting compound stability experiments for both HA-Leu and the corresponding methyl ester derivative. We concluded that HA's are transported by LAT1. In addition, our results lend support to a recent account that amino acid esters are LAT1 substrates, and that hydrogen bonding may be as important as charge for interaction with the transporter binding site.

The storage duration of platelet (PLT) units is limited to 5 to 7 days. This study investigates whether PLT storage duration is associated with patient outcomes in critically ill patients.This study was a retrospective analysis of critically ill patients admitted to the intensive care unit (ICU) of two hospitals in Australia who received one or more PLT transfusions from 2008 to 2014. Storage duration was approached in several different ways. Outcome variables were hospital mortality and ICU-acquired infection. Associations between PLT storage duration and outcomes were evaluated using multiple logistic regression and also by Cox regression.Among 2250 patients who received one or more PLT transfusions while in the ICU, the storage duration of PLTs was available for 64% of patients (1430). In-hospital mortality was 22.1% and ICU infection rate 7.2%. When comparing patients who received PLTs of a maximum storage duration of not more than 3, 4, or 5 days, there were no significant differences in baseline characteristics. After confounders were adjusted for, the storage duration of PLTs was not independently associated with mortality (4 days vs. ≤3 days, odds ratio [OR] 0.88, 95% confidence interval [CI] 0.59-1.30; 5 days vs. ≤3 days, OR 0.97, 95% CI 0.68-1.37) or infection (4 days vs. ≤3 days, OR 0.71, 95% CI 0.39-1.29; 5 days vs. ≤3 days, OR 1.11, 95% CI 0.67-1.83). Similar results were obtained regardless of how storage duration of PLTs was approached.In this large observational study in a heterogeneous ICU population, storage duration of PLTs was not associated with an increased risk of mortality or infection.

Pulmonary neuroendocrine tumors (PNET) are histologically subclassified into typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCLC). The criteria for subclassification in cytological specimens are not well defined. In this study, we reviewed histologically confirmed 18 TC, 8 AC, 10 LCNEC, and 10 SCLC cytologic specimens from 45 patients. The following features were reviewed: small clusters, geographic sheets, trabecular structures, pseudo-rosettes, single cells, doublets, triplets or short cords, papillary-like structures, capillary vasculatures, necrosis, smear background, cell size, cell pleomorphism, amount of cytoplasm, plasmacytoid cells, spindle cells, nuclear atypia, molding, palisading and smearing, chromatin textures, nucleoli, and mitotic figure count. Based on our results, geographic clusters and necrosis were often seen in LCNEC and SCLC; while AC only showed scattered single cell necrosis. TC and AC commonly exhibited trabecular structures. Papillary-like structures and capillary vasculature were only present in TC, AC, and LCNEC. Cells forming doublets, triplets, and short cords were more commonly seen in SCLC and rarely seen in other entities. Plasmacytoid and spindle cells were only seen in TC and AC. Nuclear smearing was not identified in TC, rare in AC, focally present in LCNEC and obvious in SCLC. Mitotic figures were nearly absent in TC, ≤5/10 HPF in AT, and ≥10/10 HPF in SCLC. LCNEC showed a wide span of mitotic count ranging between 2 and 16/10 HPF. In this study, we propose a set of cytological features that are essential for subclassification of PNETs in cytologic specimens. Diagn. Cytopathol. 2013;41:689–696. © 2013 Wiley Periodicals, Inc.

Fibrotic obliteration of the small airways leading to progressive airflow obstruction, termed bronchiolitis obliterans syndrome (BOS), is the major cause of poor outcomes after lung transplantation. We recently demonstrated that a donor-derived population of multipotent mesenchymal stem cells (MSCs) can be isolated from the bronchoalveolar lavage (BAL) fluid of human lung transplant recipients. Herein, we study the organ specificity of these cells and investigate the role of local mesenchymal progenitors in fibrogenesis after lung transplantation. We demonstrate that human lung allograft–derived MSCs uniquely express embryonic lung mesenchyme–associated transcription factors with a 35,000-fold higher expression of forkhead/winged helix transcription factor forkhead box (FOXF1) noted in lung compared with bone marrow MSCs. Fibrotic differentiation of MSCs isolated from normal lung allografts was noted in the presence of profibrotic mediators associated with BOS, including transforming growth factor-β and IL-13. MSCs isolated from patients with BOS demonstrated increased expression of α-SMA and collagen I when compared with non-BOS controls, consistent with a stable in vivo fibrotic phenotype. FOXF1 mRNA expression in the BAL cell pellet correlated with the number of MSCs in the BAL fluid, and myofibroblasts present in the fibrotic lesions expressed FOXF1 by in situ hybridization. These data suggest a key role for local tissue-specific, organ-resident, mesenchymal precursors in the fibrogenic processes in human adult lungs.

Treatment and prognoses of diffuse parenchymal lung diseases (DPLDs) varies by diagnosis. Obtaining a uniform diagnosis among observers is difficult.Evaluate diagnostic agreement between academic and community-based physicians for patients with DPLDs, and determine if an interactive approach between clinicians, radiologists, and pathologists improved diagnostic agreement in community and academic centers.Retrospective review of 39 patients with DPLD. A total of 19 participants reviewed cases at 2 community locations and 1 academic location. Information from the history, physical examination, pulmonary function testing, high-resolution computed tomography, and surgical lung biopsy was collected. Data were presented in the same sequential fashion to three groups of physicians on separate days.Each observer's diagnosis was coded into one of eight categories. A kappa statistic allowing for multiple raters was used to assess agreement in diagnosis. Interactions between clinicians, radiologists, and pathologists improved interobserver agreement at both community and academic sites; however, final agreement was better within academic centers (kappa = 0.55-0.71) than within community centers (kappa = 0.32-0.44). Clinically significant disagreement was present between academic and community-based physicians (kappa = 0.11-0.56). Community physicians were more likely to assign a final diagnosis of idiopathic pulmonary fibrosis compared with academic physicians.Significant disagreement exists in the diagnosis of DPLD between physicians based in communities compared with those in academic centers. Wherever possible, patients should be referred to centers with expertise in diffuse parenchymal lung disorders to help clarify the diagnosis and provide suggestions regarding treatment options.

Purpose To report clinical and histopathologic features and biologic behavior of orbital myxomas and angiomyxomas. Design Noncomparative retrospective case series. Participants Patients with histopathologic diagnoses of orbital myxoma or angiomyxoma. Methods Clinical metadata and features were obtained from the medical record. Neoplasms were studied by routine histopathology, special stains, and immunohistochemistry. Main Outcome Measures Final diagnosis, based on histopathology, special stains, and immunohistochemistry, and clinical course from analysis of metadata and clinical features. Results Three myxomas and 3 angiomyxomas were identified in 5 males and 1 female. Median age at presentation was 56 years (range, 4–69), with a follow-up ranging from 6 months to 8 years. Two angiomyxomas occurred in children ages 4 and 7 years whose tumors were locally aggressive and recurred. Recurrence also complicated one case of myxoma after incomplete excision. Pathologically, the tumors were poorly circumscribed. Histopathology showed them to be hypocellular, containing stellate and spindled cells in an abundant, loose, myxoid stroma rich in hyaluronic acid. Small blood vessels were rare in myxomas but abundant in angiomyxomas. Tumor cells were frequently immunoreactive for vimentin, CD34, and factor XIIIa. Conclusions Myxomas rarely involve orbital tissue, and no angiomyxomas of the region have been previously reported. Angiomyxomas in children may be aggressive. Vascularity and bone involvement appear to be important prognostic features for recurrence. Complete resection with a margin of healthy tissue appears to be the treatment of choice. Tumor cell immunopositivity for vimentin, CD34, and factor XIIIa may assist in the histopathologic diagnosis.

Summary A case of odontogenic sarcoma with smooth muscle differentiation arising in a 70-year-old woman is described. The lesion grew out of an extraction socket and enlarged rapidly. Radiographically, a large radiolucent lesion with ill-defined margins was observed in the left posterior mandible. Histopathologically, islands of odontogenic epithelium with a surrounding malignant mesenchymal proliferation were noted. The latter exhibited hyperchromatic oval and spindle-shaped cells with 3–4 mitoses in some high-power fields and foci of necrosis. Lesional cells demonstrated immunoreactivity with vimentin and alpha smooth muscle actin, but were negative for antibodies directed against S100, CD34 and CD31. Cytokeratins highlighted the epithelial islands, but did not react with the mesenchymal proliferation. To date, fewer than 70 cases of odontogenic sarcoma have been described in the literature. To our knowledge, this is the first report of an odontogenic malignancy showing smooth muscle differentiation.

The pathogenesis of bronchiolitis obliterans (BO), a common and devastating obliterative disorder of small airways following lung transplantation, remains poorly understood. Lesions are characterized in their early stages by lymphocyte influx that evolves into dense fibrotic infiltrates. Airway specimens taken from patients with histological BO revealed infiltrating myofibroblasts, which strongly expressed the signaling chain of the high affinity interleukin-13 (IL-13) receptor IL-13Ralpha1. Because IL-13 has proinflammatory and profibrotic actions, a contributory role for IL-13 in BO development was examined using murine models of orthotopic and heterotopic tracheal transplantation. Compared with airway isografts, allografts exhibited a significant increase in relative IL-13 mRNA and protein levels. Allogeneic tracheas transplanted into IL-13-deficient mice were protected from BO in both transplant models. Flow cytometric analysis of orthotopic transplant tissue digests revealed markedly fewer infiltrating mononuclear phagocytes and CD3(+) T lymphocytes in IL-13-deficient recipients. Furthermore, protection from luminal obliteration, collagen deposition, and myofibroblast infiltration was observed in heterotopic airways transplanted into the IL-13(-/-) recipients. Transforming growth factor-beta1 expression was significantly decreased in tracheal allografts into IL-13(-/-) recipients, compared to wild-type counterparts. These human and murine data implicate IL-13 as a critical effector cytokine driving cellular recruitment and subsequent fibrosis in clinical and ex-perimental BO.

Idiopathic interstitial pneumonias are a diverse group of lung diseases with varied prognoses. We hypothesized that changes in physiologic and radiographic parameters would predict survival. We retrospectively examined 80 patients with usual interstitial pneumonia and 29 patients with nonspecific interstitial pneumonia. Baseline characteristics were examined together with 6-month change in forced vital capacity, diffusing capacity for carbon monoxide, and ground glass infiltrate and fibrosis on high resolution computed tomography. Patients with usual interstitial pneumonia were more likely to have a statistically significant or marginally significant decline in lung volume, diffusing capacity for carbon monoxide, and an increase in ground glass infiltrates (por = 0.08) compared with patients with nonspecific interstitial pneumonia. For patients with usual interstitial pneumonia, change in forced vital capacity was the best physiologic predictor of mortality (p = 0.05). In a multivariate Cox proportional hazards model controlling for histopathologic diagnosis, gender, smoking history, baseline forced vital capacity, and 6-month change in forced vital capacity, a decrease in forced vital capacity remained an independent risk factor for mortality (decrease10%; hazard ratio 2.47; 95% confidence interval 1.29, 4.73; p = 0.006). We conclude that a 6-month change in forced vital capacity gives additional prognostic information to baseline features for patients with idiopathic interstitial pneumonia.

A patient with arteriosclerosis, diabetes mellitus, and giant cell arteritis (GCA) treated continuously with low-dose prednisone developed anterior ischemic optic neuropathy (AION) at 5 and 13 months after clinical diagnosis of GCA. At the time of late recurrent AION, there were no systemic symptoms or elevations in acute phase reactants to signal active arteritis, yet temporal artery biopsy disclosed dramatic inflammation, forcing the presumption that the infarct was aileritic. Recurrent systemic symptoms and elevation of acute phase reactants are not reliable warning signs of reactivated GCA. In patients at high risk for corticosteroid complications, late biopsy may be a reasonable guide to corticosteroid weaning.

Background: High resolution computed tomography (HRCT) has an important diagnostic role in idiopathic interstitial pneumonia (IIP). We hypothesised that the HRCT appearance would have an impact on survival in patients with IIP. Methods: HRCT scans from patients with histological usual interstitial pneumonia (UIP; n=73) or histological non-specific interstitial pneumonia (NSIP; n=23) were characterised as definite UIP, probable UIP, indeterminate, probable NSIP, or definite NSIP. Cox regression analysis examined the relationships between histopathological and radiological diagnoses and mortality, controlling for patient age, sex, and smoking status. Results: All 27 patients with definite or probable UIP on HRCT had histological UIP; 18 of 44 patients with probable or definite NSIP on HRCT had histological NSIP. Patients with HRCT diagnosed definite or probable UIP had a shorter survival than those with indeterminate CT (hazards ratio (HR) 2.43, 95% CI 1.06 to 5.58; median survival 2.08 v 5.76 years) or HRCT diagnosed definite or probable NSIP (HR 3.47, 95% CI 1.58 to 7.63; median survival 2.08 v 5.81 years). Patients with histological UIP with no HRCT diagnosis of probable or definite UIP fared better than patients with histological UIP and an HRCT diagnosis of definite or probable UIP (HR 0.49, 95% CI 0.25 to 0.98; median survival 5.76 v 2.08 years) and worse than those with a histological diagnosis of NSIP (HR 5.42, 95% CI 1.25 to 23.5; median survival 5.76 v >9 years). Conclusions: Patients with a typical HRCT appearance of UIP experience the highest mortality. A surgical lung biopsy is indicated for patients without an HRCT appearance of UIP to differentiate between histological UIP and NSIP.

It is hypothesized that the extent and severity of fibrosis and cellularity found on lung biopsy determine the prognosis and response to therapy in idiopathic pulmonary fibrosis (IPF). The objective of this study was to determine which histopathologic features predict survival in IPF. We prospectively studied 87 patients with usual interstitial pneumonia (UIP) confirmed by surgical lung biopsy. Four pathologists independently graded the extent and severity of specific histopathologic features. We used Cox proportional-hazards models to assess the effect of histopathologic patterns on patients' survival. The effects of age, sex, and smoking were also included in the analysis. Sixty-three patients died during the 17-yr study period. Survival was longer in subjects with lesser degrees of granulation/connective tissue deposition (fibroblastic foci). The degree of alveolar space cellularity, alveolar wall fibrosis, and cellularity did not affect survival. A history of cigarette smoking, the level of dyspnea, and the degree of lung stiffness at presentation were also shown to be independent factors predicting survival. The extent of fibroblastic foci present on lung biopsy predicts survival in IPF. These findings support the hypothesis that the critical pathway to end-stage fibrosis is not "alveolitis" but rather the ongoing epithelial damage and repair process associated with persistent fibroblastic proliferation. Controlling these processes, rather than stopping inflammation, appears most important in preventing progressive disease and the fatal outcome common in IPF.

Purpose We evaluated the risk and potential benefit of high-dose corticosteroid therapy in patients with idiopathic pulmonary fibrosis. Subjects and methods We prospectively studied 41 patients with previously untreated, biopsy-proven idiopathic pulmonary fibrosis. Before treatment, we calculated clinical, radiographic, and physiologic severity-of-illness scores for each patient. We scored high-resolution computerized tomographic (CT) scans for ground glass and interstitial opacity. We determined the extent of cellular infiltration, interstitial fibrosis, desquamation, and granulation in open lung biopsy samples. Patients were monitored monthly for steroid-related side effects, response to therapy at 3 months, and mortality. Results All patients experienced at least one steroid-induced side effect. Eleven (27%) patients were nonresponders, 11 (27%) were responders, and 19 (46%) remained stable. Of the 19 patients who died during a mean (+/- SD) follow-up of 3.3 +/- 2.3 years, 8 (42%) lost weight during the initial 3 months of steroid therapy; only 3 (14%) of the 22 patients still living (P = 0.08) experienced weight loss. In a multivariate analysis, greater fibrosis (hazard ratio [HR] = 1.4 per unit increase; 95% confidence interval [CI]: 1.0 to 1.9; P = 0.03) and cellularity (RR = 1.9 per unit increase; 95% CI: 1.3 to 2.8; 3, P Conclusion Corticosteroid treatment for idiopathic pulmonary fibrosis is associated with substantial morbidity. Patients who remain stable or respond to corticosteroid therapy have better survival than those who fail to respond. Whether this difference reflects an effect of treatment or less severe disease can be determined only in a randomized trial.

Study objectives: To prospectively examine the role of cyclophosphamide in patients with idiopathic pulmonary fibrosis that is unresponsive to or intolerant of high-dose steroid treatment. Design: Prospective study. Setting: Tertiary referral center. Patients: Nineteen patients with biopsy specimen-proven usual interstitial pneumonia who failed to respond (n 5 16) or experienced adverse effects (n 5 3) from corticosteroid treatment (1 mg/kg/d for 3 months). Intervention: Steroid therapy was tapered quickly, and oral cyclophosphamide, 2 mg/kg/d, was prescribed (mean duration of treatment, 6.0 6 0.9 months). Measurements and results: In 10 patients, response to therapy was determined by pretreatment and posttreatment clinical (dyspnea), radiographic (chest radiograph), and physiologic (pulmonary function, including exercise saturation) scores (CRP). Response was defined as a > 10-point drop in CRP; stable as 6 10-point change in CRP; and nonresponders as > 10-point rise in CRP. In nine patients, physiologic criteria were used to assess response; significant changes in pulmonary function were defined as follows: total lung capacity, 6 10% of baseline value; FVC, 6 10% of baseline value, diffusion capacity of the lung for carbon monoxide, 6 20% of baseline value; and resting pulse oximetry, 6 4% of baseline value. Patients who died while receiving or shortly after discontinuing cyclophosphamide were classified as nonresponders (n 5 2). Among 19 patients treated with cyclophosphamide, only 1 patient demonstrated sustained response; 7 patients remained stable and 11 deteriorated while receiving the drug. Toxicity associated with cyclophosphamide was substantial; more than two thirds of the patients developed drug-related adverse effects, and almost half discontinued the drug prematurely due to side effects. In the remaining patients, cyclophosphamide therapy was discontinued due to lack of improvement or progressive deterioration. Conclusions: Cyclophosphamide therapy is of limited efficacy in patients with idiopathic pulmonary fibrosis who fail to respond or who experience adverse effects from corticosteroid treatment, and adverse effects often complicate its use. (CHEST 2000; 117:1619‐1626)

CASE PRESENTATION A 67-year-old caucasian woman presented to the dental office with a swelling on the right side of her upper lip of 11 days’ duration (Fig. 1). The lesion measured 2 1 1 cm and was slightly dimpled in the middle. The lesion had a somewhat erythematous appearance, and small blood vessels were visible on the surface. Although the clinical appearance suggested that the lesion blended with the surrounding soft tissues, on palpation the lesion was fairly well circumscribed, not fixed to the adjacent tissue, and relatively soft. No pulsation or blanching on pressure were appreciated. The patient denied any pain or altered sensation and could not recount any history of trauma to the area.

Idiopathic pulmonary fibrosis (IPF) is associated with significant morbidity and mortality despite aggressive therapy. Thirty-eight patients with biopsy-proven IPF were studied to identify pretreatment features that could be used to predict short-term improvement in pulmonary function and improved longer term survival. In all patients, a pretreatment clinical (dyspnea), radiographic (chest radiograph), and physiologic (pulmonary function including exercise saturation) score was generated (CRP). A high-resolution CT scan (HRCT) was independently scored by four radiologists for ground glass (CT-alv) and linear opacity (CT-fib) on a scale of 0-4. Open lung biopsy samples were scored for cellular infiltration, interstitial fibrosis, desquamation, and granulation by an experienced pulmonary pathologist. All patients were treated with 3 mo of high-dose steroids and the CRP scoring repeated. Patients were divided into three groups: responders with a greater than 10-point drop in CRP (n = 10); stable with +/- 10 point change in CRP (n = 14); and nonresponders with > 10 point rise in CRP or death (n = 14). Those responding to steroids were treated for 18 mo in a tapering fashion. In all others, steroids were tapered quickly and oral cyclophosphamide prescribed. Responders (10 of 38) had a lower age (45.1+/-4.3 yr) than nonresponders (61.4+/-3.5 yr) or those remaining stable (53.1+/-3.3 yr) (p = 0.01). Pretreatment CRP was higher in responders (58.8+/-5.6) than nonresponders (40.5+/-4.7) or stable individuals (37.6+/-4.7) (p = 0.01). Cellular infiltration score of the open lung biopsies was higher in responders (7.6+/-0.6) than stable individuals (5.7+/-0.5) (p = 0.04). The CT-alv scores were higher and CT-fib scores were lower in responders than nonresponders. Receiver operating curve (ROC) analysis was employed to identify pretreatment features of longer term survival (follow-up of 29.1+/-2.3 mo). Only CT-fib (p = 0.009) and pathology fibrosis score (p = 0.03) were able to predict mortality. A pretreatment CT-fib score > or = 2.0 demonstrated 80% sensitivity and 85% specificity in predicting survival. Those patients who did not respond to initial steroid therapy demonstrated a worse long-term survival and greater likelihood of decreased pulmonary function. We demonstrate that pretherapy pulmonary function, pathologic and radiographic parameters are different in individuals who respond to initial prednisone therapy. Only HRCT imaging and pathologic fibrosis were able to reliably predict long-term survival in patients with biopsy-proven IPF.

The purpose of our study was to determine if three-level thin-section CT depicts idiopathic pulmonary fibrosis (IPF) pathology as accurately as CT obtained at 10-mm increments throughout the entire lungs.Thin-section (1.0- to 1.5-mm) images at 10-mm increments were obtained and scored prospectively in 25 consecutive patients with newly diagnosed IPF who were participating in a Special Center of Research grant for interstitial lung disease. Each patient's lobe was scored by four thoracic radiologists on a scale of 0-5 for both ground-glass attenuation and fibrosis. The radiologists used three images (limited CT) and also used the entire data set (complete CT). CT scores were compared with pathology scores from 67 open and thoracoscopic biopsies. Limited and complete scores were compared with each other (Pearson correlation coefficient). Interobserver variation in the CT scoring system was assessed using kappa values.CT fibrosis scores strongly correlated with pathology fibrosis scores for complete (r = .53, p = .0001) and limited (r = .50, p = .0001) CT. CT ground-glass scores correlated with the histologic inflammatory scores for each lobe on complete (r = .27, p = .03) and limited (r = .26, p = .03) CT. The desquamative subcomponent of the pathology inflammatory score had the highest correlation with the CT ground-glass scores (complete: r = .29, p = .01; limited: r = .33, p = .007). Good interobserver agreement existed for both the alveolar and fibrosis components of the CT scoring system (kappa values ranging from .51 to .83) for each lobe of the lung on limited and complete CT.Limited thin-section CT reveals the pathologic changes associated with IPF as well as CT obtained at 10-mm increments. An added advantage of limited thin-section CT is that it exposes patients to less radiation.

Two laboratories equipped with CAS 200 (Becton Dickinson Image Cytometry Systems, San Jose, CA) instruments participated in this study of variability of DNA analysis of bladder tumor specimens. Formalin fixed paraffin embedded specimens were disaggregated and centrifuged onto microscope slides from ten bladder tumor specimens and two specimens of normal urothelium. Sources of variability considered were Specimen, Slide, Run, Laboratory, and Error. Slides were systematically scanned and 200 cells measured followed by the operator selecting 100 nuclei with abnormal morphology. DNA index (DI) and hyperdiploid fraction (HDF) were calculated from the DNA frequency distributions. For systematic sampling, 92% of the variability was due to Specimen indicating that differences in HDF values between specimens reflect biological differences. With selective sampling, only 67% of the variability in HDF is due to Specimen differences. Other factors, Laboratory, Error, and Laboratory x Specimen interaction each accounted for approximately 10% of the variability. Similarly variability of DI with selective sampling was also higher, and less specimen dependent than systematic sampling. It is important that sampling schemes and selection criteria be carefully documented in order to control variability. Enriched (or selective) sampling for abnormal cells has the potential to increase sensitivity but specimen classification based on these measurements must depend on determination of the frequency of such cells in the total population.

Chip test practices such as functional test and Bist, and their relevance to MCM testing are summarized. Drawbacks of using these techniques, for some MCMs, are presented. Board test practices such as in-circuit test and boundary-scan, are summarized; the advantages of incorporating board test techniques for certain MCMs are given. Test strategies are categorized and compared. Appropriate MCM test equipment is discussed. Examples of using chip, board, and hybrid test approaches are then given.

Background. Although open biopsy is considered the optimal method for obtaining lung tissue for the diagnosis of diffuse infiltrative pulmonary disorders, there are no universally established guidelines concerning biopsy site selection and the ideal number of tissue samples. Relatively few investigations have been devoted to the influence exerted by the site and number of biopsy samples on the histologic diagnosis. Methods. Seventy-seven open biopsy samples obtained from different lobes of 28 patients with idiopathic pulmonary fibrosis were analyzed. The histopathologic features were evaluated semiquantitatively and the results from each sample compared with those of the other samples obtained from each patient. Results. Statistically significant differences in histophatologic features were not observed between samples. Conclusions. A single generous (2 cm or greater diameter) sample, obtained from a representative region of the radiographically most involved lobe, will suffice for diagnostic and evaluation purposes.

Objectives: To assess the sensitivity of high-resolution chest computed tomography (HRCT) in detecting idiopathic pulmonary fibrosis proved by biopsy specimen. To determine the degree of physiologic and pathologic abnormalities in patients with idiopathic pulmonary fibrosis who have a false-negative HRCT. Design: Prospective 2-year study. Setting: Tertiary care university hospital. Patients: All patients with dyspnea and suspected interstitial lung disease referred to the University of Michigan for enrollment in the Idiopathic Pulmonary Fibrosis Specialized Center of Research (SCOR) protocol were included; 25 underwent open lung biopsy and formed the final study group. Measurements: All patients underwent physiologic (pulmonary function, gas exchange, and exercise testing), radiologic (chest x-ray film and HRCT), and pathologic assessments (bronchoscopic and open lung biopsy). The results of HRCT were prospectively compared with results of standard pulmonary function tests, cardiopulmonary exercise testing, and open lung biopsy. Results: Of 25 patients who had both HRCT and open lung biopsy, 3 patients (12%) had HRCTs that demonstrated no evidence of interstitial lung disease. These three patients had less severe disease based on clinical, radiographic, and physiologic (CRP) scores, gas exchange abnormalities, and pathologic scoring of open lung biopsy specimens, compared with those with an abnormal HRCT. Conclusion: We conclude that in the evaluation of patients with dyspnea and abnormal results of pulmonary function studies, a normal HRCT does not exclude early and clinically significant interstitial lung disease. In our patient population, physiologic testing was more sensitive than HRCT in detecting mild abnormalities in patients with idiopathic pulmonary fibrosis proved by biopsy specimen.

Solitary fibrous tumors (SFTs) often involve the pleura and also may encompass the peritoneum and nonserosal sites. On occasion SFTs mimics other neoplasms, including desmoplastic mesothelioma. CD-34, initially characterized as a hematopoietic progenitor cell antigen, recently has been identified in a small number of SFTs. Based on this observation, we compared the keratin, vimentin, and CD-34 expression of 19 SFTs and eight desmoplastic mesotheliomas. Fifteen of 19 SFTs (78.9%) expressed CD-34, whereas keratin expression was absent in all SFTs. In contrast, none of the desmoplastic mesotheliomas expressed CD-34 and keratin expression was found in seven of eight (87.5%). Vimentin expression was noted in 18 of 19 SFTs and in seven of eight desmoplastic mesotheliomas. We conclude that CD-34 expression distinguishes SFT from desmoplastic mesothelioma. Additionally, the results of our study support the idea that SFT is not derived from or related to conventional mesothelium.

The early stage of idiopathic pulmonary fibrosis (IPF) is thought to involve a smaller number of alveoli and to be characterized predominantly by cellularity and minimal fibrosis, whereas advanced disease involves a large number of alveoli and is characterized predominantly by fibrosis with minimal cellularity. In addition, correlative studies have indicated that prognosis and response to therapy is determined in part by the extent of fibrosis and cellularity. This study was undertaken to determine whether pulmonary function assessment would help distinguish between the cellular and fibrotic phases of this disorder, as determined by a semiquantitative pathology scoring system that comprised four factor scores: fibrosis, cellularity, granulation/connective tissue, and desquamation. Ninety-six untreated patients with biopsy-confirmed IPF (27 never smokers, 32 current smokers, and 37 ex-smokers) were evaluated. In the group as a whole, there was no significant relationship between the fibrosis or the connective/granulation tissue factor scores and any of the physiologic parameters. The DLCO correlated with the "desquamation" and the total pathology scores, whereas the TLC and FVC correlated with the cellularity factor score. In the current smokers, the coefficient of elastic retraction, DLCO/VA, and FEV1/FVC ratio were significantly lower than in never smokers and ex-smokers, and TLC and FVC were higher than in never smokers. Also, the mean cellularity and granulation/connective tissue factor scores were significantly lower, and the desquamation factor score was significantly higher than those in never smokers and ex-smokers. Both age and smoking status were significant for the cellularity factor score, whereas for the connective/granulation tissue factor score, age was not significant but smoking status was.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary neuroendocrine tumors (PNET) are histologically subclassified into typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCLC). The criteria for subclassification in cytological specimens are not well defined. In this study, we reviewed histologically confirmed 18 TC, 8 AC, 10 LCNEC, and 10 SCLC cytologic specimens from 45 patients. The following features were reviewed: small clusters, geographic sheets, trabecular structures, pseudo-rosettes, single cells, doublets, triplets or short cords, papillary-like structures, capillary vasculatures, necrosis, smear background, cell size, cell pleomorphism, amount of cytoplasm, plasmacytoid cells, spindle cells, nuclear atypia, molding, palisading and smearing, chromatin textures, nucleoli, and mitotic figure count. Based on our results, geographic clusters and necrosis were often seen in LCNEC and SCLC; while AC only showed scattered single cell necrosis. TC and AC commonly exhibited trabecular structures. Papillary-like structures and capillary vasculature were only present in TC, AC, and LCNEC. Cells forming doublets, triplets, and short cords were more commonly seen in SCLC and rarely seen in other entities. Plasmacytoid and spindle cells were only seen in TC and AC. Nuclear smearing was not identified in TC, rare in AC, focally present in LCNEC and obvious in SCLC. Mitotic figures were nearly absent in TC, ≤5/10 HPF in AT, and ≥10/10 HPF in SCLC. LCNEC showed a wide span of mitotic count ranging between 2 and 16/10 HPF. In this study, we propose a set of cytological features that are essential for subclassification of PNETs in cytologic specimens.

Pulmonary function testing has been extensively studied in the heart-lung transplant (HLT) population and has been advocated as a screening test for rejection or infection; however, few data are available in the single-lung transplant (SLT) population. The effect of acute episodes of infection, rejection, and bronchiolitis on the pulmonary function of 30 SLT patients with varying underlying disease states was prospectively evaluated. The native disease process was obstructive in 17 (SLT-OBS), restrictive in six (SLT-IPF), and pulmonary vascular in seven (SLT-PVD). Rejection was associated with a drop in FVC from 71 +/- 15 to 62 +/- 14% of predicted, with a significant drop seen in all three subgroups. Statistically significant drops in FEV1 were also seen in the SLT-OBS and SLT-PVD subgroups but not in the SLT-IPF subgroup. A drop in FEV25-75% was seen only in SLT-PVD. The greatest fall in FVC, FEV1, and FEF25-75% was seen with bronchiolitis, followed by acute rejection. The sensitivity and specificity of spirometry as a predictor of infection or rejection were significantly lower than those previously reported for HLT, with SLT-PVD having the most and SLT-OBS the least clinically useful values. We conclude that a fall in spirometry is seen in infection and rejection in SLT and that the underlying disease state has a significant influence on the diagnostic utility of specific spirometric indices.

This paper illustrates the dedicated Scorecard element introduced in the 4.1 specification of the PMML standard, including the various design and computational options available for returning reason codes alongside each computed score. The paper is intended to help both producers and consumers of scorecards as PMML documents.

We used the technique of image analysis to simultaneously measure DNA content and nuclear morphology of 21 borderline ovarian tumors. Aneuploidy was identified in 9 of 21 tumors and was unrelated to tumor stage or nuclear grade. Morphometric nuclear features that were measured included size, shape, texture, and average density. Nuclear size and shape were positively correlated (r = 0.507), and nuclear size and average density were negatively correlated (r = -0.772). Six tumors recurred and recurrence was significantly associated with tumor aneuploidy (P = 0.046), stage III tumors (P = 0.03), and increased nuclear texture (P = 0.07). These results suggest that measurement of DNA ploidy and nuclear morphology using image analysis can provide important prognostic information in patients with borderline ovarian tumors.