Aberrant Lipid Metabolism in Macrophages Is Associated with Granuloma Formation in Sarcoidosis.

Rationale: Chronic sarcoidosis is a complex granulomatous disease with limited treatment options that can progress over time. Understanding the molecular pathways contributing to disease would aid in new therapeutic development. Objectives: To understand whether macrophages from patients with nonresolving chronic sarcoidosis are predisposed to macrophage aggregation and granuloma formation and whether modulation of the underlying molecular pathways influence sarcoidosis granuloma formation. Methods: Macrophages were cultivated in vitro from isolated peripheral blood CD14+ monocytes and evaluated for spontaneous aggregation. Transcriptomics analyses and phenotypic and drug inhibitory experiments were performed on these monocyte-derived macrophages. Human skin biopsies from patients with sarcoidosis and a myeloid Tsc2-specific sarcoidosis mouse model were analyzed for validatory experiments. Measurements and Main Results: Monocyte-derived macrophages from patients with chronic sarcoidosis spontaneously formed extensive granulomas in vitro compared with healthy control participants. Transcriptomic analyses separated healthy and sarcoidosis macrophages and identified an enrichment in lipid metabolic processes. In vitro patient granulomas, sarcoidosis mouse model granulomas, and those directly analyzed from lesional patient skin expressed an aberrant lipid metabolism profile and contained increased neutral lipids. Conversely, a combination of statins and cholesterol-reducing agents reduced granuloma formation both in vitro and in vivo in a sarcoidosis mouse model. Conclusions: Together, our findings show that altered lipid metabolism in sarcoidosis macrophages is associated with its predisposition to granuloma formation and suggest cholesterol-reducing therapies as a treatment option in patients.

FDG uptake patterns in isolated and systemic cardiac sarcoidosis.

AIMS: We aimed to investigate the pre-treatment characteristics and treatment responses of isolated and systemic cardiac sarcoidosis (ICS and SCS) from FDG-PET/CT studies and to compare the prognoses of the two groups. METHODS: FDG-PET/CT images taken before and after treatment of 31 ICS and 91 SCS patients were analyzed retrospectively. Treatment response and recurrence were determined from the course of FDG-PET/CT. Treatment response and the incidence of both recurrence and major adverse cardiac events (MACE) were assessed in 16 ICS and 35 SCS patients who had been treated for more than 2 years. RESULTS: A focal uptake pattern was more often observed than a focal-on-diffuse uptake pattern in both the ICS (74.2%) and SCS (63.7%) groups. Right ventricular involvement was significantly more frequent in SCS than ICS (44.0% vs. 9.6%, p < .001). SUVmax, cardiac metabolic volume (CMV), and cardiac metabolic activity (CMA) were significantly higher in SCS than ICS (SUVmax, 9.1 ± 4.1 vs. 4.8 ± 2.1; CMV, 118.0 ± 111.3 ml vs. 68.3 ± 94.7 ml; CMA, 541.6 ± 578.7 MBq vs. 265.1 ± 396.0 MBq, p < .001). Treatment responses in the two groups were similar, and complete resolution of cardiac uptake after immunosuppressive treatment was obtained in 62.5% of ICS patients and 77.1% of SCS patients (not significantly different). Likewise, no significant difference was found in the incidence of recurrence (40.0% for ICS, 44.4% for SCS) or MACE (25.0% for ICS, 22.8% for SCS). CONCLUSION: SCS patients had more active and extensive CS lesions than ICS patients before treatment, but the two groups showed similar treatment responses and prognoses.

Could different aqueous humor and plasma cytokine profiles help differentiate between ocular sarcoidosis and ocular tuberculosis?

OBJECTIVE AND DESIGN: A cross-sectional single-center study was conducted to assess cytokine levels in aqueous humor (AH) and plasma of three different uveitis entities: definite ocular sarcoidosis (OS), definite OS associated with QuantiFERON®-TB Gold test positivity (Q + OS) and presumed tubercular uveitis (TBU). SUBJECTS: Thirty-two patients (15 OS, 5 Q + OS, 12 TBU) were included. METHODS: Quantification of selected cytokines was performed on blood and AH samples collected before starting any treatment. Statistical analysis was conducted using the Kruskal-Wallis test, the Mann-Whitney or Fisher test and the Principal Component Analysis (PCA). RESULTS: IL-6, IL-8 and IP-10 levels were higher in AH samples than in peripheral blood. In AH samples, BLC, IL-8 and IP-10 were significantly higher in definite OS than in presumptive TBU. There were no statistically significant differences in terms of cytokine levels between Q + OS and presumptive TBU. PCA showed a similar cytokine pattern in the latter two groups (IFNγ, IL-15, IL-2, IP-10, MIG), while the prevalent expression of BLC, IL-10 and MIP-3 α was seen in definite OS. CONCLUSIONS: The different AH and plasma cytokine profiles observed in OS compared to Q + OS and TBU may help to differentiate OS from TBU in overlapping clinical phenotypes of granulomatous uveitis (Q + OS).

PD1, CTLA4 and TIGIT Expression on T and NK Cells in Granulomatous Diseases: Sarcoidosis and ANCA-Associated Vasculitis.

Sarcoidosis is a granulomatous diseases affecting the lungs. Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a histologically granulomatous B-mediated disorder characterized by activated T cells. The expression of immune checkpoint (IC) molecules (PD1, CTLA4, TIGIT) on T- and NK-cells negatively regulate the T-cell immune function. The present study aimed to explore the peripheral distribution of IC molecules to better elucidate their peripheral tolerance failure, which might reflect the development of diseases. Patients referred to Respiratory Diseases and Rheumatology Unit of Siena University Hospital were prospectively and consecutively enrolled. Healthy subjects were also enrolled as a control group. Multicolor flow cytometric analysis was performed to detect IC molecules in the peripheral blood of patients. Twenty-three patients were consecutively and prospectively enrolled in the study: 11 patients had an AAV diagnosis and 12 had sarcoidosis. CD4+PD1+ cells were higher in sarcoidosis and GPA than in HC (p = 0.0250 and p = 0.0253, respectively). CD56+CTLA4+ were higher in sarcoidosis than GPA, MPA and HC (p = 0.0085, p = 0.0042 and p = 0.0004, respectively). CTLA4+NK cells clustered for 100% of sarcoidosis patients according to decision tree analysis, while PD1+CD4 and CD8 cells for clustered for 100% of GPA patients. Our analyses showed substantial differences between sarcoidosis and AAV, further confirming the immunological peculiarity of this disease. Despite these advances, the pathogenesis remains incompletely understood, indicating an urgent need for further research to reveal the distinct immunological events in this process, with the hope to open up new therapeutic avenues and, if possible, to develop preventive measures.

Elevated IL-15 concentrations in the sarcoidosis lung are independent of granuloma burden and disease phenotypes.

Sarcoidosis is a systemic granulomatous disease predominantly affecting the lungs. The mechanisms promoting disease pathogenesis and progression are unknown, although interleukin-15 (IL-15) has been associated with the immune-mediated inflammation of sarcoidosis. Because the identification of a mechanistically based, clinically relevant biomarker for sarcoidosis remains elusive, we hypothesized this role for IL-15. Pulmonary sarcoidosis granuloma formation was modeled using trehalose 6,6'-dimicolate (TDM), which was administered into wild-type and three lineages of mice: those overexpressing IL-15, deficient in IL-15, and deficient in IL-15 receptor α. The number of granulomas per lung was counted and normalized to the wild type. IL-15 concentrations were measured in the bronchoalveolar lavage (BAL) from healthy controls and subjects with sarcoidosis in our cohort, where associations between IL-15 levels and clinical manifestations were sought. Findings were validated in another independent sarcoidosis cohort. TDM administration resulted in similar granuloma numbers across all lineages of mice. IL-15 concentrations were elevated in the BAL of both human cohorts, irrespective of disease phenotypes. In exploratory analysis, an association with obesity was observed, and various other soluble mediators were identified in the BAL of both cohorts. Although IL-15 is enriched in the sarcoidosis lung, it was independent of disease pathogenesis or clinical manifestations in our mouse model and human cohorts of sarcoidosis. An association with obesity perhaps reflects the ongoing inflammatory processes of these comorbid conditions. Our findings showed that IL-15 is redundant for disease pathogenesis and clinical progression of sarcoidosis.

Altered retinal oxygen metabolism in patients with combined ocular and central nervous system sarcoidosis.

OBJECTIVE: To evaluate retinal oxygen metabolism by retinal oximetry for ocular and CNS diseases in a cross-sectional study of sarcoidosis. METHODS: Overall 201 eyes from 103 biopsy-verified sarcoidosis patients were included and divided into four groups depending on the organ affection: (i) sarcoidosis without ocular or CNS affection, (ii) ocular sarcoidosis, (iii) CNS sarcoidosis, and (iv) combined ocular and CNS sarcoidosis. Retinal oximetry was obtained and analysed, with the mean retinal arteriolar and venular saturation as well as arteriovenous difference as principal outcomes. Comparison between groups was done in a multi linear regression model adjusted for age, sex, duration of sarcoidosis, best corrected visual acuity and retinal oximetry quality. RESULTS: Mean (s.d.) age was 50.5 (13.4) (95% CI: 47.9, 53.1) years and 52.2% were males. Eyes of the combined Ocular/CNS group had a higher retinal arteriovenous difference than eyes of the Non-ocular/no-CNS group (42.1% vs 37.7%, P = 0.012) but did not differ between other groups. Eyes in the four groups (Non-ocular/no-CNS, Ocular, CNS and Ocular/CNS) did not differ according to retinal arterial (94.5%, 93.5%, 93.5% and 94.5%, respectively) or venular (57.5%, 56.4%, 55.0% and 52.5%, respectively) oxygen saturation. CONCLUSIONS: The results of this study suggest that eyes of sarcoidosis patients with combined ocular and CNS affection have an altered oxygen metabolism indicating a subclinical eye affection that is not recognized by conventional screening methods.

The diagnostic challenge of coexistent sarcoidosis and thyroid cancer - a retrospective study.

BACKGROUND: Sarcoid lesions may mimic metastatic disease or recurrence in thyroid cancer (TC) patients as both diseases may affect the lungs and lymph nodes. We present the first study to systematically evaluate the clinical course of patients with (TC) after adjuvant radioactive iodine therapy (RIT) and concomitant sarcoidosis of the lung or the lymph nodes. METHODS: We screened 3285 patients and retrospectively identified 16 patients with TC (11 papillary thyroid cancer (PTC), 3 follicular thyroid cancer (FTC), 1 oncocytic PTC, 1 oncocytic FTC) and coexisting sarcoidosis of the lung and/or the lymph nodes treated at our institute. All patients had undergone thyroidectomy and initial adjuvant RIT. Challenges in diagnosing and the management of these patients were evaluated during long term follow-up (median 4.9 years (0.8-15.0 years)). RESULTS: Median age at first diagnosis of TC was 50.1 years (33.0-71.5 years) and of sarcoidosis 39.4 years (18.0-63.9 years). During follow-up, physicians were able to differentiate between SA and persistent or recurrent TC in 10 of 16 patients (63%). Diagnosis was complicated by initial negative thyroglobulin (Tg), positive Tg antibodies and non-specific imaging findings. Histopathology can reliably distinguish between SA and TC in patients with one suspicious lesion. CONCLUSION: Physicians should be aware of the rare coexistence of sarcoidosis and TC. Lymphadenopathy and pulmonary lesions could be metastases, sarcoidosis or even a mix of both. Therefore, this rare patient group should receive a thorough work up including histopathological clarification and, if necessary, separately for each lesion.

Feasibility of somatostatin receptor-targeted imaging for detection of myocardial inflammation: A pilot study.

BACKGROUND: Gallium-68 Dotatate binds preferentially to somatostatin receptor (sstr) subtype-2 (sstr-2) on inflammatory cells. We aimed at investigating the potential clinical use of sstr-targeted imaging for the detection of myocardial inflammation. METHODS: Thirteen patients, with suspected cardiac sarcoidosis (CS) based on clinical history and myocardial uptake on recent fluorine-18 fluorodeoxyglucose (FDG) PET, were enrolled to undergo Dotatate PET after FDG-PET (median time 37 days [IQR 25-55]). Additionally, we investigated ex-vivo the immunohistochemistry expression of sstr-2 in 3 explanted sarcoid hearts. RESULTS: All FDG scans showed cardiac uptake (focal/multifocal = 6, focal on diffuse/heterogeneous = 7), and 46% (n = 6) extra-cardiac uptake (mediastinal/hilar). In comparison, Dotatate scans showed definite abnormal cardiac uptake (focal/multifocal) in 4 patients, probably abnormal (heterogenous/patchy) in 3, and negative uptake in 6 cases. Similarly, 6 patients had increased mediastinal/hilar Dotatate uptake. Overall concordance of FDG and Dotatate uptake was 54% in the heart and 100% for thoracic nodal activity. Quantitatively, FDG maximum standardized uptake value was 5.0 times [3.8-7.1] higher in the heart, but only 2.25 times [1.7-3.0; P = .019] higher in thoracic nodes relative to Dotatate. Ex-vivo, sstr-2 immunostaining was weakly seen within well-formed granulomas in all 3 examined sarcoid heart specimens with no significant staining of background myocardium or normal myocardium. CONCLUSION: Our preliminary data suggest that, compared to FDG imaging, somatostatin receptor-targeted imaging may be less sensitive for the detection of myocardial inflammation, but comparable for detecting extra-cardiac inflammation.

FDG-PET in possible cardiac sarcoidosis: Right ventricular uptake and high total cardiac metabolic activity predict cardiovascular events.

BACKGROUND: Cardiac involvement accounts for the majority of morbidity and mortality in sarcoidosis. Pathological myocardial fluorodeoxyglucose (FDG)-uptake in positron emission tomography (PET) has been associated with cardiovascular events and quantitative metabolic parameters have been shown to add prognostic value. Our aim was to study whether the pattern of pathological cardiac FDG-uptake and quantitative parameters are able to predict cardiovascular events in patients with suspected cardiac sarcoidosis (CS). METHODS: 137 FDG-PET examinations performed in Tampere University Hospital were retrospectively analyzed visually and quantitatively. Location of pathological uptake was noted and pathological metabolic volume, average standardized uptake value (SUV), and total cardiac metabolic activity (tCMA) were calculated. Patients were followed for ventricular tachycardia, decrease in left ventricular ejection fraction, and death. RESULTS: Eleven patients had one or more cardiovascular events during the follow-up. Five patients out of 12 with uptake in both ventricles had an event during follow-up. Eight patients had high tCMA (> 900 MBq) and three of them had a cardiovascular event. Right ventricular uptake and tCMA were significantly associated with cardiovascular events during follow-up (P-value .001 and .018, respectively). CONCLUSIONS: High tCMA and right ventricular uptake were significant risk markers for cardiac events among patient with suspected CS.

The Short- and Long-Term Impact of Pulmonary Rehabilitation in Subjects with Sarcoidosis: A Prospective Study and Review of the Literature.

BACKGROUND: Sarcoidosis is a heterogeneous multisystemic disorder of unknown etiology. Dyspnea and fatigue are two of the most common and debilitating symptoms experienced by subjects with sarcoidosis. There is limited evidence regarding the short- and long-term impact of pulmonary rehabilitation (PR) on exercise capacity and fatigue in these individuals. OBJECTIVE: To evaluate the benefit of PR in subjects with pulmonary sarcoidosis at different severity stages and to review the current literature about PR in sarcoidosis. METHODS: PR included a 12-week training program of a twice-weekly 90-min workouts. Fifty-two subjects with stable pulmonary sarcoidosis were recruited. Maximal exercise capacity, defined as VO2max, was measured using the cardiopulmonary exercise test (CPET). Pulmonary function tests, 6-min walking distance (6MWD), St. George's Respiratory Questionnaire (SGRQ), and the modified Medical Research Council (mMRC) and Hospital Anxiety and Depression Scale (HADS) questionnaires were given before and after PR and following 6 months (follow-up). RESULTS: The PR program significantly increased the VO2max (1.8 ± 2.3 mL/kg/min, p = 0.002), following 12 weeks. mMRC and SGRQ scores were also improved (-0.3 ± 0.8, p = 0.03, and -3.87 ± 10.4, p = 0.03, respectively). The impact of PR on VO2max was more pronounced in subjects with pulmonary parenchymal involvement. The increase in VO2max correlated with initial disease severity (indicated by FEV1/FVC, p = 0.01). Subjects with FEV1/FVC <70% showed greater improvement in 6MWD. 6MWD also improved in those with a transfer coefficient of the lung for CO (KCO) above 80% predicted (p < 0.05). At 6-month follow-up, the VO2max, 6MWD, and SGRQ scores remained stable, thus suggesting lasting effects of PR. CONCLUSION: PR is a promising complementary therapeutic intervention for subjects with sarcoidosis. Further study is needed to validate these findings.

The Role of Oxidative Stress in Sarcoidosis.

Sarcoidosis is a rare, systemic inflammatory disease whose diagnosis and management can pose a challenge for clinicians and specialists. Scientific knowledge on the molecular pathways that drive its development is still lacking, with no standardized therapies available and insufficient strategies to predict patient outcome. In recent years, oxidative stress has been highlighted as an important factor in the pathogenesis of sarcoidosis, involving several enzymes and molecules in the mechanism of the disease. This review presents current data on the role of oxidative stress in sarcoidosis and its interaction with inflammation, as well as the application of antioxidative therapy in the disease.

Myocardial Accumulations of Reg3A, Reg3γ and Oncostatin M Are Associated with the Formation of Granulomata in Patients with Cardiac Sarcoidosis.

Cardiac sarcoidosis (CS) is a poorly understood disease and is characterized by the focal accumulation of immune cells, thus leading to the formation of granulomata (GL). To identify the developmental principles of fatal GL, fluorescence microscopy and Western blot analysis of CS and control patients is presented here. CS is visualized macroscopically by positron emission tomography (PET)/ computed tomography (CT). A battery of antibodies is used to determine structural, cell cycle and inflammatory markers. GL consist of CD68+, CD163+ and CD206+ macrophages surrounded by T-cells within fibrotic areas. Cell cycle markers such as phospho-histone H3, phospho-Aurora and Ki67 were moderately present; however, the phosphorylated ERM (ezrin, radixin and moesin) and Erk1/2 proteins, strong expression of the myosin motor protein and the macrophage transcription factor PU.1 indicate highly active GL. Mild apoptosis is consistent with PI3 kinase and Akt activation. Massive amounts of the IL-1R antagonist reflect a mild activation of stress and inflammatory pathways in GL. High levels of oncostatin M and the Reg3A and Reg3γ chemokines are in accordance with macrophage accumulation in areas of remodeling cardiomyocytes. We conclude that the formation of GL occurs mainly through chemoattraction and less by proliferation of macrophages. Furthermore, activation of the oncostatin/Reg3 axis might help at first to wall-off substances but might initiate the chronic development of heart failure.

Molecular profiling in sarcoidosis.

PURPOSE OF REVIEW: Sarcoidosis is a systemic disease characterized by granulomatous inflammation of unknown cause. There is extensive heterogeneity between patients with respect to the number and types of organs involved, disease course, and response to therapy. Recent research in the field has leveraged 'omics' techniques such as transcriptomics to identify important 'molecular profiles' in the disease. These tools may help in identifying clinically useful biomarkers and targets for therapy. RECENT FINDINGS: Several studies have used gene expression profiling of predesignated lists or the entire genome to find genes and markers that differentiate sarcoidosis from healthy controls, but only a few have compared sarcoidosis patients based on disease phenotypes and organ involvement. The common gene pathways that have been repeatedly identified include those related to the interferon response, T-cell receptor signaling, and the major histocompatibility complex. SUMMARY: While the molecular profiling studies to date offer the ability to compare sarcoidosis and health as well as across tissues, further longitudinal studies that include sarcoidosis patients with varying outcomes with respect to organ involvement and response to treatment are needed to identify clinically important phenotypes in the disease that can then be differentiated based on molecular features.

18-FDG-PET in a patient cohort suspected for cardiac sarcoidosis: Right ventricular uptake is associated with pathological uptake in mediastinal lymph nodes.

INTRODUCTION: In up to 65% of cardiac sarcoidosis patients, the disease is confined to the heart. Diagnosing isolated cardiac sarcoidosis is challenging due to the low sensitivity of endomyocardial biopsy. If cardiac sarcoidosis is part of biopsy-confirmed systemic sarcoidosis, the diagnosis can be based on cardiac imaging studies. We compared the imaging features of patients with isolated cardiac FDG uptake on positron emission tomography with those who had findings indicative of systemic sarcoidosis. MATERIALS AND METHODS: 137 consecutive cardiac FDG-PET/CT studies performed on subjects suspected of having cardiac sarcoidosis were retrospectively analyzed. RESULTS: 33 patients had pathological left ventricular FDG uptake, and 12 of these also had pathological right ventricular uptake. 16/33 patients with pathological cardiac uptake had pathological extracardiac uptake. 10/12 patients with both LV- and RV-uptake patterns had extracardiac uptake compared to 6/21 of those with pathological LV uptake without RV uptake. SUVmax values in the myocardium were higher among patients with abnormal extracardiac uptake. The presence of extracardiac uptake was the only imaging-related factor that could predict a biopsy indicative of sarcoidosis. CONCLUSION: Right ventricular involvement seems to be more common in patients who also have findings suggestive of suspected systemic sarcoidosis, compared with patients with PET findings indicative of isolated cardiac disease.

Balancing Altered Calcium Metabolism with Bone Health in Sarcoidosis.

Abnormal calcium metabolism in sarcoidosis patients can lead to hypercalcemia, hypercalciuria, and kidney stones. Hypercalcemia in sarcoidosis is usually due to increased activity of 1α-hydroxylase in macrophages of pulmonary granulomata, resulting in low levels of 25-hydroxyvitamin D and high levels of calcitriol. Vitamin D supplementation may be dangerous for some sarcoidosis patients and is recommended only for those with decreased 25-hydroxyvitamin D and reduced or normal calcitriol level. Diagnosis, treatment of osteoporosis, and maintenance of bone health are complex issues for sarcoidosis patients. An approach to diagnosis and treatment of bone fragility is presented.

The Role of Urinary Calcium and Chitotriosidase in a Cohort of Chronic Sarcoidosis Patients.

BACKGROUND: Calcium metabolism alterations are quite common in sarcoidosis and have been correlated with disease activity. OBJECTIVES: The aim of the study was to investigate the clinical significance of calcium metabolism alterations in patients with chronic sarcoidosis. We paid particular attention to associations with specific disease phenotypes and chitotriosidase (CTO) expression. METHODS: 212 chronic sarcoidosis patients (mean age 56.07 ± 12 years; 97 males) were retrospectively recruited. Demographic, clinical, functional, and radiological data, and serum-urinary calcium metabolism were entered into an electronical database for analysis. Levels of CTO and angiotensin-converting enzyme (ACE) were measured and bone mineral density and lung function tests were conducted. RESULTS: Hypercalciuria and hypercalcemia were observed in 18.8 and 1.8% of patients, respectively. Urinary calcium levels correlated with CTO activity (r = 0.33, p = 0.0042). Patients with worsening persistent disease showed the highest levels of urinary calcium. Diffusing capacity of the lung for carbon monoxide (DLCO) percentage correlated inversely with urinary calcium (r = 0.1482; p = 0.0397). CONCLUSIONS: Calcium metabolism alteration, particularly hypercalciuria, was observed in a significant percentage of patients of sarcoidosis. Urinary calcium was correlated with clinical status, DLCO, and serum CTO activity, suggesting its potential role as a biomarker of the activity and severity of sarcoidosis.

Key Players and Biomarkers of the Adaptive Immune System in the Pathogenesis of Sarcoidosis.

Sarcoidosis is a systemic inflammatory disease characterized by development of granulomas in the affected organs. Sarcoidosis is often a diagnosis of exclusion, and traditionally used tests for sarcoidosis demonstrate low sensitivity and specificity. We propose that accuracy of diagnosis can be improved if biomarkers of altered lymphocyte populations and levels of signaling molecules involved in disease pathogenesis are measured for patterns suggestive of sarcoidosis. These distinctive biomarkers can also be used to determine disease progression, predict prognosis, and make treatment decisions. Many subsets of T lymphocytes, including CD8+ T-cells and regulatory T-cells, have been shown to be dysfunctional in sarcoidosis, and the predominant CD4+ T helper cell subset in granulomas appears to be a strong indicator of disease phenotype and outcome. Studies of altered B cell populations, B cell signaling molecules, and immune complexes in sarcoidosis patients reveal promising biomarkers as well as possible explanations of disease etiology. Furthermore, examined biomarkers raise questions about new treatment methods and sarcoidosis antigens.

Simultaneous use of FDG-18 and 68Ga-citrate PET/CT for the differential diagnosis of sarcoidosis and malignant disease.

A 67-year-old male presented with cutaneous rash, lassitude and fatigue of three weeks. Personal history included psoriasis and sarcoidosis. Physical examination revealed macular rash on the anterior chest wall. Laboratory results were within normal limits. Chest X-ray showed normal findings. Pulmonary function tests demonstrated a mild obstructive pattern and a mild decrease in DLCO/VA. Thorax CT revealed two nodules in the right upper and middle lobe. 68Ga-citrate PET/CT did not demonstrate any active inflammatory reaction associated with sarcoidosis while 18F-FDG PET/CT revealed increased FDG uptake in the right middle lobe, upper division bronchus and in the left lower abdominal quadrant. Histopathologic examination of the colon biopsy was compatible with adenocarcinoma and bronchoscopic biopsy of the lung lesions revealed nonspecific granulomatous inflammation. BAL cytology was normal while BAL culture did not grow any pathologic organisms. Simultaneous use of 18F-FDG and 68Ga-citrate PET/CT was the hallmark for the final diagnosis in our patient. While FDG/PET has detected the pulmonary and colonic malignant foci in our patient, 68Ga-citrate PET/CT excluded the presence of active granulomatous inflammation of sarcoidosis. Simultaneous utility of these two imaging modalities in patients with sarcoidosis is of great importance in terms of guiding the clinician towards the accurate diagnostic pathway which is the hallmark for final diagnosis, especially in the presence of concomitant malignant disease.

powerTCR: A model-based approach to comparative analysis of the clone size distribution of the T cell receptor repertoire.

Sequencing of the T cell receptor (TCR) repertoire is a powerful tool for deeper study of immune response, but the unique structure of this type of data makes its meaningful quantification challenging. We introduce a new method, the Gamma-GPD spliced threshold model, to address this difficulty. This biologically interpretable model captures the distribution of the TCR repertoire, demonstrates stability across varying sequencing depths, and permits comparative analysis across any number of sampled individuals. We apply our method to several datasets and obtain insights regarding the differentiating features in the T cell receptor repertoire among sampled individuals across conditions. We have implemented our method in the open-source R package powerTCR.