SESSION TYPE: Cancer Cases IIPRESENTED ON: Tuesday, October 23, 2012 at 11:15 AM - 12:30 PM

INTRODUCTION:

Ipilimumab is a recently developed human monoclonal antibody against cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) used in the treatment of metastatic melanoma. CTLA-4 blockade results in enhanced immune response not only to tumor cells, but also to normal host tissues, which is the cause of most of ipilimumab' s adverse effects.

CASE PRESENTATION:

A 58 year-old Caucasian woman was admitted with two weeks of cough and worsening dyspnea. On initial presentation, the patient was severely hypoxic and had rapidly progressive dyspnea. Past medical history was significant for recently diagnosed metastatic melanoma of the foot, cryptogenic cirrhosis, stroke and a positive anti-cardiolipin antibody. Home medications included ursodiol, citalopram, aspirin, amlodipine, ezetimibe and metoprolol. Her only cancer treatment to date was ipilimumab which was started two months earlier. She had no known drug allergies or environmental exposures and denied any tobacco, illicit drug or alcohol use. On exam, the patient was afebrile, in moderate respiratory distress with oxygen saturation of 74% on room air. She had crackles in the lower half of both lung fields and bilateral lower extremity edema. Laboratory work up was unremarkable. Chest roentgenogram revealed new bilateral patchy infiltrates with predominantly lower lobe distribution. Subsequently, the patient became increasingly hypoxic. She was started on broad-spectrum antibiotics and 1mg/kg of Solumedrol. Chest imaging (Figure 1A and 1B) showed extensive, patchy, bilateral peribronchial consolidation most prominent in the lower lobes. Fiberoptic bronchoscopy with bronchoalveolar lavage and transbronchial biopsies was performed. Cytopathological and microbiological analysis showed no evidence of infection. Bronchoalveolar lavage showed lymphocytic alveolitis. The biopsy specimens revealed an organizing pneumonia pattern (Figure 2A). Her dyspnea and hypoxia improved and she was discharged home after ten days of hospitalization. Systemic steroids were tapered over six weeks after discharge. Repeat chest imaging (Figure 2B) showed resolution of the infiltrates six weeks later.

DISCUSSION:

To our knowledge, this is the first report of pulmonary toxicity caused by ipilimumab which manifested on pathology as organizing pneumonia.

CONCLUSIONS:

This case highlights the importance of considering ipilimumab lung injury in patients presenting with respiratory symptoms or pulmonary infiltrates since this presentation could mimic other etiologies such as infection and delay institution of appropriate therapy1) Culver ME, Gatesman ML, Mancl EE, Lowe DK. Ipilimumab: a novel treatment for metastatic melanoma. Ann Pharmacother. 2011 Apr;45(4):510-9.DISCLOSURE: The following authors have nothing to disclose: Igor Barjaktarevic, Nida Qadir, Anu Suri, Jean Santamauro, Diane StoverNo Product/Research Disclosure InformationMemorial Sloan Kettering Cancer Center, New York, NY.

SESSION TYPE: ILD Cases IPRESENTED ON: Monday, October 22, 2012 at 01:45 PM - 03:00 PM

INTRODUCTION:

We present a case of pulmonary capillaritis and diffuse alveolar hemorrhage (DAH) in association with anti-PL-12 antisynthetase antibodies.

CASE PRESENTATION:

A previously healthy 32 years old woman was admitted to an outside hospital with worsening shortness of breath. Her physical examination was significant for oxygen desaturation with exertion and bilateral, basilar crackles. Her skin, joints, and physical examination was unremarkable. Chest imaging was performed (figure 1). Her erythrocyte sedimentation rate was 54 mm/h. Anti-nuclear antibody, anti-smith, anti-ribonucleoprotein, anti-SSA Ro, anti-SSB La, anti-cardiolipin, beta-2- glycoprotein, and scleroderma antibodies were all negative. The anti-neutrophil cytoplasmic antibody against myeloperoxidase (p-ANCA) and proteinase 3 (c-ANCA) were negative. Complement, creatine kinase, and aldolase were normal. A myositis antibody panel was moderately positive for PL-12 antibodies (Mayo Medical Laboratories, Rochester MN). She underwent VATS right upper and lower lobe wedge biopsies (figure 2). She was started on prednisone. Her activities remained limited by dyspnea on exertion. She was discharged home on oxygen and prednisone and seen in our clinic four months after the initial presentation for a second opinion. She was initiated on rituximab infusion therapy 375 mg/m2 once weekly for four weeks in combination with intravenous methylprednisolone for three days and subsequent steroid taper. Nine months after her initial presentation her symptoms have improved and she remains on maintenance therapy with mycophenolate.

DISCUSSION:

Pulmonary capillaritis with DAH is extremely rare in patients with antisynthetase syndrome (AS), but has been described with other autoimmune disorders. Two cases of polymyositis and capillaritis with DAH have been previously described (1). One of the patients had AS with anti-Jo-1 antibodies detected. The initial therapy of choice for AS is corticosteroids. Other immunosuppressant therapies have been successfully used, but there have been no comparison studies. Pulmonary capillaritis with DAH is also treated with steroids and immunosuppresants. In a recent study, rituximab was non-inferior to cyclophosphamide for inducing remission in ANCA associated vasculitis (2). One group successfully used rituximab to treat a case of life threatening AS.

CONCLUSIONS:

Moderately positive anti-PL-12 antibodies should be considered in the differential in patients who present with idiopathic DAH and pulmonary capillaritis.1) Schwarz MI, Sutarik JM, Nick JA, Leff JA, Emlen JW, Tuder RM. Pulmonary capillaritis and diffuse alveolar hemorrhage. A primary manifestation of polymyositis. Am J Respir Crit Care Med. 1995;151(6):2037-40.2) Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221-32.DISCLOSURE: The following authors have nothing to disclose: Carlos Kummerfeldt, John Huggins, Ellen Riemer, James Ravenel, Timothy Whelan, Steven SahnNo Product/Research Disclosure InformationMedical University of South Carolina, Charleston, SC.

Abstract Paraquat is a highly toxic herbicide capable of generating oxidative stress and producing brain damage after chronic exposure. The aim of this research was to investigate the contribution of mitochondria to the molecular mechanism of apoptosis in an in vivo experimental model of paraquat neurotoxicity. Sprague-Dawley adult female rats received paraquat (10 mg/kg i.p.) or saline once a week during a month. Paraquat treatment increased cortical and striatal superoxide anion levels by 45% and 18%, respectively. As a consequence, mitochondrial aconitase activity was significantly inhibited in cerebral cortex and striatum. Paraquat treatment increased cortical and striatal lipid peroxidation levels by 16% and 28% respectively, as compared with control mitochondria Also, cortical and striatal cardiolipin levels were decreased by 13% and 49%, respectively. Increased Bax and Bak association to mitochondrial membranes was observed after paraquat treatment in cerebral cortex and striatum. Also, paraquat induced cytochrome c and AIF release from mitochondria. These findings support the conclusion that a weekly dose of paraquat during four weeks induces oxidative damage that activates mitochondrial pathways associated with molecular mechanisms of cell death. The release of apoptogenic proteins from mitochondria to cytosol after paraquat treatment would be the consequence of an alteration in mitochondrial membrane permeability due to the presence of high superoxide anion levels. Also, our results suggest that under chronic exposure, striatal mitochondria were more sensitive to paraquat oxidative damage than cortical mitochondria. Even in the presence of a high oxidative stress in striatum, equal levels of apoptosis were attained in both brain areas.

Protein Z (PZ) is a vitamin K-dependent factor characterized by its homology to other vitamin K-dependent factors (factor VII, IX, X, protein C), but lacks any enzymatic activity. Instead, PZ acts as a cofactor for the inhibition of factor Xa by the serpin protein Z-dependent protease inhibitor (ZPI). PZ deficiency was associated with a procoagulant state, highlighted by excessive FXa secretion and thrombin production, and was linked with several thrombotic disorders, including arterial vascular and venous thromboembolic diseases. A role for PZ-ZPI in regulating physiologic pregnancy was demonstrated, highlighted by the progressive elevation in PZ levels in the first trimester of gestation, which then steadily declines towards delivery. An association between altered plasma PZ concentrations and adverse pregnancy outcome (recurrent miscarriage, stillbirth, preeclampsia, intrauterine growth restriction, and placental abruption) was reported. The mechanism by which PZ deficiency leads to adverse pregnancy outcome is not clear, but is multifactorial. It may be attributed to anti-PZ IgG and IgM autoantibodies, which apparently act independently of classical anti-phospholipid antibodies (lupus anticoagulant, anti-cardiolipin, and anti-ß2-glycoprotein I antibodies). PZ deficiency was also reported to be constitutional, and a number of variants in the PZ gene (PROZ) and ZPI genes were linked with specific adverse pregnancy complications. This review summarizes the relationship between adverse pregnancy outcome and acquired and constitutional deficiency PZ-ZPI, so as in order to understand whether or not protein Z deficiency could be considered as risk factor for poor pregnancy outcome.

Multidrug resistance is a serious barrier to successful treatment of many human diseases, including cancer, wherein chemotherapeutics are exported from target cells by membrane-embedded pumps. The most prevalent of these pumps, the ATP-Binding Cassette transporter P-glycoprotein (P-gp), consists of two homologous halves each comprising one nucleotide-binding domain and six transmembrane helices. The transmembrane region encapsulates a hydrophobic cavity, accessed by portals in the membrane, that binds cytotoxic compounds as well as lipids and peptides. Here we use mass spectrometry (MS) to probe the intact P-gp small molecule-bound complex in a detergent micelle. Activation in the gas phase leads to formation of ions, largely devoid of detergent, yet retaining drug molecules as well as charged or zwitterionic lipids. Measuring the rates of lipid binding and calculating apparent KD values shows that up to six negatively charged diacylglycerides bind more favorably than zwitterionic lipids. Similar experiments confirm binding of cardiolipins and show that prior binding of the immunosuppressant and antifungal antibiotic cyclosporin A enhances subsequent binding of cardiolipin. Ion mobility MS reveals that P-gp exists in an equilibrium between different states, readily interconverted by ligand binding. Overall these MS results show how concerted small molecule binding leads to synergistic effects on binding affinities and conformations of a multidrug efflux pump.

The interaction of dietary fats and carbohydrates on liver mitochondria were examined in male FBNF1 rats fed 20 different low-fat, isocaloric diets. Animal growth rates and mitochondrial respiratory parameters were essentially unaffected, but mass spectrometry-based, mitochondrial lipidomics profiling revealed increased levels of cardiolipins (CLs), a family of phospholipids essential for mitochondrial structure and function, in rats fed saturated or trans fat-based diets with a high glycemic index. These mitochondria showed elevated monolysocardiolipins (a CL precursor/product of CL degradation), elevated ratio of trans PC (18:1/18:1) to cis PC (18:1/18:1) (a marker of thiyl radical stress), and decreased ubiquinone Q9 -- the latter two of which imply a low-grade mitochondrial redox abnormality. Extended analysis demonstrated: (i) dietary fats and, to a lesser extent, carbohydrates induce changes in the relative abundance of specific CL species; (ii) Fatty acid (FA) incorporation into mature CLs undergoes both positive (>400-fold) and negative (2.5-fold) regulation; and, (iii) dietary lipid abundance and incorporation of FAs into both the CL pool and specific mature tetra-acyl CLs are inversely related, suggesting previously unobserved compensatory regulation. This study reveals previously unobserved complexity/regulation of the central lipid in mitochondrial metabolism.

Mitochondrial membrane composition may be a critical factor in the mechanisms of the aging process by influencing the propagation of reactions involved in mitochondrial function during periods of high stress. Changes affecting either lipid class or fatty acid compositions could affect phospholipid properties and alter mitochondrial function and cell viability. In the present study, mitochondrial membrane phospholipid compositions were analyzed throughout the life cycle of Nothobranchius rachovii. Mitochondrial phospholipids showed several changes with age. Proportions of cardiolipin decreased and those of sphingomyelin increased between 11- and 14-month-old fish. Fatty acid compositions of individual phospholipids in mitochondria were also significantly affected with age. These data suggest increasing damage to mitochondrial lipids during the life cycle of N. rachovii that could be one of the main factors related with and contributing to degraded mitochondrial function associated with the aging process.

A 14-month-old boy was transferred because of dilated and hypertrophied left ventricle, neutropenia, and developmental delay. After checking computed tomographic angiography with contrast-dye, the patient showed acute exacerbation and finally died from multi-organ failure despite intensive cares. From genetic analysis, we revealed that the patient had Barth syndrome and found a novel hemizygous frame shift mutation in his TAZ gene, c.227delC (p.Pro76LeufsX7), which was inherited from his mother. Herein, we report a patient with Barth syndrome who had a novel mutation in TAZ gene and experienced unexpected acute exacerbation after contrast dye injection for computed tomographic angiography.

Immune-mediated thrombocytopenic purpura (ITP) is recognized as a cell-specific autoimmune disorder, yet, multifactorial in origin. The development of thrombocytopenia is well proven to be mediated by both humoral (anti-platelet antibodies) and cellular (T-cell) mediated mechanisms. In some cases other autoantibodies are also induced, eg, antinuclear antibody (ANA), anti-dsDNA, and anti-cardiolipin, in addition to anti-platelet antibodies. The persistance of these autoantibodies during the course of ITP could herald future development of another autoimmune disease, eg, systemic lupus erythematosus (SLE) or anti-phospholipid syndrome (APS). Due to the better understanding of the pathophysiology of ITP, new novel therapies were introduced aiming to achieve long-lasting remissions. In this review we will focus on the autoimmune nature of the disease and on some of the mechanisms of action of these new therapies.

Objective:

Overweight and obesity are established risk factors for venous thromboembolism (VTE). We examined the difference in the frequency of primary antiphospholipid antibody syndrome (PAPS) in VTE patients according to their BMI. Design and

Methods:

We included 998 VTE patients treated at our institution between 2009 and 2011 in a retrospective data analysis. Thrombophilia screening including evaluation for APS (lupus anticoagulant, anti-cardiolipin, and anti-B2-glycoprotein-I IgG and IgM antibodies) was performed in all patients.

Results:

PAPS was diagnosed in 6.8% (24/355) of normal weight (BMI < 24 kg/m(2) ) VTE patients, in 11.1% (50/452) of overweight (BMI 25-30 kg/m(2) ) VTE patients, and in 15.7% (30/191) of obese (BMI > 31 kg/m(2) ) VTE patients. The difference of PAPS occurrence between these groups was statistically significant (P = 0.001). PAPS patients demonstrated higher fibrinogen levels as compared to non-PAPS patients (median 416.0 md/dl vs. 352.0 mg/dl, P = 0.001). Furthermore, fibrinogen levels increased significantly according to the body weight of patients (median normal weight patients 330.0 mg/dl vs. overweight patients 359.0 mg/dl vs. obese patients 415.0 mg/dl, P = 0.001).

Conclusion:

PAPS seems to be more frequent in overweight and obese patients. As PAPS patients showed significantly higher fibrinogen levels and as fibrinogen levels increased significantly according to the body weight of patients, an elevated inflammatory state in overweight and obese patients as a reason for the increased PAPS occurrence can be assumed.