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Rosanna Dammacco,1 Giovanni Alessio,1 Ermete Giancipoli,2 Patrizia Leone,3 Anna Cirulli,3 Leonardo Resta,4 Angelo Vacca,3 Franco Dammacco3 1Department of Ophthalmology and Neuroscience, University of Bari “Aldo Moro”, Medical School, Bari, Italy; 2Department of Biomedical Sciences, Ophthalmology Unit, University of Sassari, Sassari, Italy; 3Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, Medical School, Bari, Italy; 4Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Medical School, Bari, ItalyCorrespondence: Franco DammaccoDepartment of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, Medical School, Polyclinic, Piazza Giulio Cesare, 11, Bari 70124, ItalyTel +39 080 5478 863Fax +39 080 5478 820Email francesco.dammacco@uniba.itPurpose: Giant cell arteritis (GCA), a chronic vasculitis of the large and medium-sized arteries, affects people > 50 years of age. This study assessed the prevalence of visual manifestations and other clinical features at presentation in an Italian cohort of GCA patients. Recent advances in the pathophysiology, diagnosis, and therapy of GCA are also reviewed.Methods: This retrospective, single-center study conducted by the ophthalmology and internal medicine clinics of one university recruited 56 patients from 2005 to 2016 and followed them for 11– 54 months.Results: Ocular involvement was diagnosed in 19 patients (33.9%), with permanent vision loss in 19.6% (7.1% of the cohort with bilateral vision loss). Arteritic anterior and posterior ischemic optic neuropathy were diagnosed in 11 patients (57.9%) and 1 patient (5.3%), respectively, cotton wool spots in 3 patients (15.8%), central retinal artery occlusion in 2 patients (10.5%), and anterior segment ischemia and multifocal choroidal ischemia in 1 patient each (5.3%). Polymyalgia rheumatica was associated with GCA in 44.6% of the patients. The most common extra-ocular manifestation was constitutional symptoms (82.1% of the patients). Large-vessel involvement, including of the ascending aorta, aortic arch, and left axillary artery, was diagnosed by magnetic resonance or computed tomography (CT) angiography and 18FDG positron emission/CT. Glucocorticoids (GCs) remain the standard-of-care worldwide, but methotrexate, provided as a steroid-sparing drug in 41% of the patients, resulted in earlier tapering, a lower cumulative dose of GCs, and a lower rate of relapse. Among the combinations of GCs and immunosuppressive drugs proposed to treat GCA, only tocilizumab has effectively induced and maintained disease remission.Conclusion: According to our data and literature reports: a) GCA is a systemic disease; b) its diagnosis is expedited by the adjunct use of imaging techniques; c) insights into the pathogenesis of GCA may allow an improved, differentiated therapeutic approach.Keywords: giant cell arteritis, ocular manifestations, diagnostic imaging, glucocorticoids, pathogenetic advances, tocilizumab

Aims: Peripheral neuropathy (PN), the major neurological complication of chronic HCV infection, is frequently associated with mixed cryoglobulinaemia (MC) and small-vessel systemic vasculitis. While humoral and cellmediated immune mechanisms are suspected to act together in an aberrant immune response that results in peripheral nerve damage, the role of HCV remains largely speculative. The possible demonstration of HCV in peripheral nerve tissue would obviously assume important pathogenic implications. Methods: We studied sural nerve biopsies from 11 HCV-positive patients with neuropathic symptoms: five with and six without MC. In situ hybridization (ISH) and immunofluorescence studies were carried out to detect genomic and antigenomic HCV RNA sequences and HCV-encoded E2-glycoprotein, respectively. Results: Epineurial vascular deposits of E2- glycoprotein were found in four (80%) MC and in two (33.3%) non-MC patients, respectively. These findings were enhanced by the perivascular deposition of positive-, though not negative-strand replicative RNA, as also found in the nerve extracts of all patients. Mild inflammatory cell infiltrates with no deposits of immunoglobulins and/or complement proteins were revealed around small vessels, without distinct vasculitis changes between MC and non-MC patients. Conclusions: These results indicate that nerve vascular HCV RNA/E2 deposits associated to perivascular inflammatory infiltrates were similar in chronically HCV-infected patients, regardless of cryoglobulin occurrence. Given the failure to demonstrate HCV productive infection in the examined sural nerve biopsies, nerve damage is likely to result from virus-triggered immune-mediated mechanisms. [ABSTRACT FROM AUTHOR]

Background: Hepatitis C virus (HCV) chronic infection is frequently associated to autoimmune manifestations. The aim of this study was to prospectively evaluate the occurrence of clinical and/or laboratory features of autoimmunity in a cohort of 140 consecutive HCV chronically infected patients treated with direct-acting antiviral agents (DAAs) and followed-up for 96 weeks., Methods: All patients were screened for cryoglobulins, rheumatoid factor (RF), C3, C4, antinuclear antibody (ANA), anti-smooth muscle (ASMA), anti-liver kidney microsome type 1 (anti-LKM1), anti-mitochondrial antibodies (AMA), anti-neutrophil cytoplasmic antibodies (ANCA), and anti-liver cytosol type 1/soluble liver antigen (anti-LC1/SLA) autoantibodies before therapy and 12, 48 and 96 weeks after treatment. They were then grouped according to the expression of laboratory findings and related autoimmune diseases., Results: At baseline, autoimmune manifestations were found in 70 patients: 83% of them were cryoglobulinemic, whereas ANA, AMA, perinuclear ANCA (pANCA) and LKM/LC1 autoantibodies were found in the remaining 17%. An autoimmune disease was diagnosed in 9 cases, two of them featuring an autoimmune liver disease (AILD). At the end of follow-up, despite viral clearance and regression of vasculitis, cryoglobulins persisted in 12 patients (21%), and autoantibodies disappeared or decreased in most of cases but, with the exception of the 2 patients diagnosed as AILD, associated autoimmune diseases remained stable. In one patient with relapsing cryoglobulinemia and ANA positivity, type-1 autoimmune hepatitis was defined. Conversely, autoantibodies first appeared after viral clearance in 5 patients, of whom one was diagnosed with type-1 autoimmune hepatitis and one with pANCA+ primary sclerosing cholangitis., Conclusions: Following DAA-induced viral clearance, cryoglobulins may persist or reappear. Autoantibodies changed dynamically in step with the disappearance of a previously diagnosed or the occurrence of a new AILD. A longer follow-up will be necessary to establish the possible diagnosis of a newly onset AILD, the reactivation of cryoglobulinemic vasculitis and even its progression to non-Hodgkin lymphoma.

Background/objectives: To describe frequency and type of ocular manifestations in patients with cryoglobulinemic vasculitis (CV), as well as management approaches and outcomes., Subjects/methods: This was a retrospective, observational, cohort study of patients who were diagnosed with CV at a single center and regularly underwent a comprehensive ocular assessment., Results: Ophthalmologic manifestations were recorded in 16 patients (28%). The diagnoses included dry eye disease and primary Sjögren syndrome in 5 and 2 patients, respectively; peripheral ulcerative keratitis and anterior scleritis in 1 patient each; hyperviscosity syndrome and hypertensive retinopathy in 2 patients each; and Purtscher- like retinopathy in 3 patients. Twelve patients (75%) were anti-HCV/HCV RNA-positive, 11 of whom achieved a sustained virologic response (SVR) following treatment with interferon-α2b plus ribavirin or direct-acting antivirals. All patients were treated with ocular lubricants. Systemic therapeutic measures, including glucocorticoids, immunosuppressive and biologic agents, induced the disappearance or ≥50% reduction of cryoglobulins and major signs of vasculitis in 11 patients (68.7%). In the remaining 5 patients (31.3%), cryoglobulins and CV manifestations remained unchanged or decreased by <50%. The corresponding ophthalmologic assessment showed a variable degree of improvement in the ocular symptoms in all but 2 patients (87.5%). The best corrected visual acuity following treatment improved in 26 eyes, was unchanged in 3 eyes, and worsened in 3 eyes., Conclusions: Eye involvement is not a rare event in CV patients. A timely diagnosis and the correct employment of the available therapeutic measures may result in a favorable outcome of the ocular and extra-ocular manifestations., (© 2023. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

We identified STAT1 gain of function (GOF) in a 32-year-old female with pallor, weakness, cough, and dyspnea admitted to our Division of Medicine. She had severe oral ulcers (OU), type 1 diabetes (T1DM), and pancytopenia. Bone marrow (BM) biopsy showed the absence of erythroid precursors. Peripheral blood parameters such as neutrophils < 500/mL, reticulocytes < 2%, and BM hypo-cellularity allowed to diagnose severe aplastic anemia. A heterozygous variant (p.520T>C, p.Cys174Arg) of STAT1 was uncovered. Thus, p.Cys174Arg mutation was investigated as potentially responsible for the patient's inborn immunity error and aplastic anemia. Although STAT1 GOF is rare, aplastic anemia is a more common condition; therefore, we explored STAT1 functional role in the pathobiology of BM failure. Interestingly, in a cohort of six patients with idiopathic aplastic anemia, enhanced phospho-STAT1 levels were observed on BM immunostaining. Next, the most remarkable features associated with STAT1 signaling dysregulation were examined: in both pure red cell aplasia and aplastic anemia, CD8 +  T cell genetic variants and mutations display enhanced signaling activities related to the JAK-STAT pathway. Inborn errors of immunity may represent a paradigmatic condition to unravel crucial pathobiological mechanisms shared by common pathological conditions. Findings from our case-based approach and the phenotype correspondence to idiopathic aplastic anemia cases prompt further statistically powered prospective studies aiming to elucidate the exact role and theragnostic window for JAK/STAT targeting in this clinical context. Nonetheless, we demonstrate how a comprehensive study of patients with primary immunodeficiencies can lead to pathophysiologic insights and potential therapeutic approaches within a broader spectrum of aplastic anemia cases., (© 2023. The Author(s).)

Purpose: We describe ophthalmic manifestations, therapy, and outcomes in 16 patients with Takayasu arteritis (TA)., Methods: Takayasu retinopathy was detected in 15 eyes of 9 patients and hypertensive retinopathy in 14 eyes of 7 patients., Results: Visual acuity was normal in 7 eyes, 20/40 to 20/200 in 20 eyes, counting fingers in 2 eyes, hand motion in 2 eyes, and no light perception in 1 eye. Glucocorticoids associated with immunosuppressive agents induced a sustained remission in 13 patients. Three relapsing-refractory patients were given the monoclonal antibody tocilizumab, which led to partial and complete response in 1 and 2 patients respectively. Steroid-induced cataracts developed in 4 patients. Restenosis and the consequent recurrence of visual symptoms were detected in 2 of 9 patients who underwent a patency procedure for their stenotic lesions., Conclusions: Ocular manifestations were a common feature (37.2%) in our cohort of TA patients and were frequently responsible for severe visual deterioration., Abbreviations: BCVA: best-corrected visual acuity; FFA: fundus fluorescein angiography; GC: glucocorticoids; HR: hypertensive retinopathy; ITAS: Indian Takayasu activity score; OCT: optical coherence tomography; TA: Takayasu arteritis; TR: Takayasu retinopathy.

Immunoglobulins that reversibly precipitate at temperatures below 37 °C are called cryoglobulins (CGs). Cryoglobulinemia often manifests as cryoglobulinemic vasculitis (CV), whose symptoms range in severity from purpuric eruptions to life-threatening features. The majority of CV patients are infected with hepatitis C virus (HCV), whereas lymphoproliferative disorders or connective tissue diseases (CTD) are commonly diagnosed among patients with CV of non-infectious origin. In the absence of detectable associated disease, cryoglobulinemia is classified as "essential" (EMC). All HCV-positive CV patients should be given direct-acting antiviral agents (DAAs) that are consistently able to induce a sustained virologic response (SVR). Glucocorticoids (GCs) can mitigate CV-associated vasculitis, but they have no role as maintenance therapy. Cyclophosphamide restrains the hyperactive phase(s) of the disease and the post-apheresis rebound of newly synthesized CGs. Its use has been largely replaced by rituximab (RTX) in patients unresponsive to DAAs, patients progressing to B-cell non-Hodgkin lymphoma (B-NHL) and patients in whom CV persists or reappears after clearance of HCV. Therapeutic apheresis is an emergency treatment for CV patients with hyperviscosity syndrome. HCV-positive CV patients are at an increased risk of developing NHL, but the achievement of SVR can effectively prevent HCV-related NHL or induce the remission of an already established lymphoma, even without chemotherapy. The treatment of patients with IgM or IgG monoclonal cryoglobulins and an underlying immunoproliferative disorder is based on the regimens adopted for patients with the same B-cell malignancies but without circulating CGs. For patients with CTD, GCs plus alkylating agents or RTX are similarly effective as first-line therapy and in the relapse/refractory setting. In patients with EMC, treatment should consist of GCs plus RTX, with the dose of GCs tapered as soon as possible to reduce the risk of infectious complications., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Ocular manifestations of granulomatosis with polyangiitis (GPA) have been reported in a limited number of studies and with largely variable frequency. Here we report on the clinical, diagnostic, and therapeutic features of a cohort of 63 GPA patients, with particular regard to 22 of them with ophthalmic involvement (35%)., Methods: Clinical manifestations, results of immunological findings, histopathological pictures, imaging data, Birmingham Vasculitis Activity Score, therapeutic regimens, and outcomes were retrospectively analyzed. At diagnosis, in addition to a structured clinical assessment, all patients underwent a comprehensive ophthalmologic examination., Results: The most frequently involved organs were kidneys, lungs, ear/nose/throat, and eyes. Ocular manifestations were bilateral in 32%. The three most commonly diagnosed ophthalmologic manifestations were scleritis (36%), retro-orbital pseudotumor or orbital mass (23%), and episcleritis (13%). Ocular and systemic involvement were simultaneously present at onset in 41% of the patients; systemic involvement was followed by ocular lesions in 36%; ocular inflammation was followed by systemic manifestations in 18%; and an orbital mass in the absence of systemic disease characterized 5%. Glucocorticoids plus cyclophosphamide and glucocorticoids plus rituximab were the combined therapies most frequently employed during remission induction and remission maintenance, respectively. Persistent ophthalmologic and extra-ocular remissions were achieved in 77 and 64% of the patients, respectively. One to three systemic relapses were diagnosed in 7 patients (31.8%). At the last follow-up, a visual outcome 20/40 or better in 31 (70%) of 44 eyes was determined., Conclusions: The eye was involved in over one third of our patients with GPA. Increased awareness, early diagnosis, and multi-specialty collaboration are critical in achieving a favorable outcome of GPA., (© 2023. The Author(s).)

Giant cell arteritis (GCA), frequently associated with polymyalgia rheumatica (PMR), and Takayasu's arteritis (TAK) are characterized by extensive vascular remodeling that results in occlusion and stenosis. The pathophysiological mechanisms underlying the onset of GCA/PMR and TAK are still hypothetical. However, similarities and differences in the immunopathology and clinical phenotypes of these diseases point toward a possible link between them. The loss of tolerance in the periphery, a breakdown of tissue barriers, and the development of granulomatous vasculitis define a disease continuum. However, statistically powered studies are needed to confirm these correlations. In addition to glucocorticoids, inhibition of the interleukin-6 axis has been proposed as a cornerstone in the treatment of GCA/PMR and TAK. Novel biologic agents targeting the pathogenic pathway at various levels hold promise to achieve glucocorticoid-free sustained remission., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: To investigate the ocular manifestations in 91 Waldenström's macroglobulinemia (WM) patients., Methods: Retrospective, cross-sectional, observational analysis., Results: Ocular impairments, detected in 19 patients, included flame-shaped hemorrhages, venous sausaging, papilledema, macular detachments, or central retinal vein occlusion in 16 patients; paraproteinemic keratopathy in 2; and a CANOMAD syndrome in 1. Best-corrected visual acuity was ≥0.5 logMAR units in 11 of 38 eyes. Intraocular pressure was increased in seven eyes. Genetic analysis in seven patients showed a mutation in the MYD88 gene in six patients and a nonsense mutation in the CXCR4 gene in five patients. Plasmapheresis followed by chemotherapy with or without the addition of rituximab resulted in improvement or normalization of the ophthalmological findings in 15 patients., Conclusion: The ocular manifestations of WM are protean and potentially sight threatening. Recent advances in genomic profiling and chemotherapy have remarkably improved the hematological and ophthalmological outcomes of these patients.

Purpose: To provide an overview of the ocular features of rheumatoid arthritis (RA) and of the ophthalmic adverse drug reactions (ADRs) that may be associated with the administration of antirheumatic drugs., Methods: A systematic literature search was performed using the PubMed, MEDLINE, and EMBASE databases. In addition, a cohort of 489 RA patients who attended the Authors' departments were examined., Results: Keratoconjunctivitis sicca, episcleritis, scleritis, peripheral ulcerative keratitis (PUK), and anterior uveitis were diagnosed in 29%, 6%, 5%, 2%, and 10%, respectively, of the mentioned cohort. Ocular ADRs to non-steroidal anti-inflammatory drugs are rarely reported and include subconjunctival hemorrhages and hemorrhagic retinopathy. In patients taking indomethacin, whorl-like corneal deposits and pigmentary retinopathy have been observed. Glucocorticoids are frequently responsible for posterior subcapsular cataracts and open-angle glaucoma. Methotrexate, the prototype of disease-modifying antirheumatic drugs (DMARDs), has been associated with the onset of ischemic optic neuropathy, retinal cotton-wool spots, and orbital non-Hodgkin's lymphoma. Mild cystoid macular edema and punctate keratitis in patients treated with leflunomide have been occasionally reported. The most frequently occurring ADR of hydroxychloroquine is vortex keratopathy, which may progress to "bull's eye" maculopathy. Patients taking tofacitinib, a synthetic DMARD, more frequently suffer herpes zoster virus (HZV) reactivation, including ophthalmic HZ. Tumor necrosis factor inhibitors have been associated with the paradoxical onset or recurrence of uveitis or sarcoidosis, as well as optic neuritis, demyelinating optic neuropathy, chiasmopathy, and oculomotor palsy. Recurrent episodes of PUK, multiple cotton-wool spots, and retinal hemorrhages have occasionally been reported in patients given tocilizumab, that may also be associated with HZV reactivation, possibly involving the eye. Finally, rituximab, an anti-CD20 monoclonal antibody, has rarely been associated with necrotizing scleritis, macular edema, and visual impairment., Conclusion: The level of evidence for most of the drug reactions described herein is restricted to the "likely" or "possible" rather than to the "certain" category. However, the lack of biomarkers indicative of the potential risk of ocular ADRs hinders their prevention and emphasizes the need for an accurate risk vs. benefit assessment of these therapies for each patient., (© 2021. The Author(s).)

Takayasu arteritis (TAK) is a rare granulomatous vasculitis of unknown etiology that mainly affects the aorta and its major branches. The aim is to describe the clinical features, diagnostic procedures, pathogenesis, and management of TAK in a longitudinal cohort of patients recruited within a single region of southern Italy. The cohort included 43 patients who were diagnosed with TAK and followed up according to a standard protocol, in a collaboration between four university tertiary referral centers and a regional hospital. Clinical and imaging classification criteria were those established by the American College of Rheumatology. Thirty-five patients (81.4%) were female, and the mean age at disease onset was 32.6 (range 16-54) years. Angiographic assessment of the vascular involvement allowed disease classification in five different types. Clinical features ranged from constitutional symptoms in the early inflammatory stage of the disease to cardiovascular ischemic symptoms in the late, chronic stage. Noninvasive imaging techniques were employed to assess the extent and severity of the arterial wall damage and to monitor the clinical course and response to therapy. Medical treatment, based on pathogenetic insights into the roles of humoral and cell-mediated immune mechanisms, included glucocorticoids mostly combined with steroid-sparing immunosuppressive agents and, in patients with relapsing/refractory disease, biologic drugs. Significant clinical and angiographic differences have been detected in TAK patients from different geographic areas. Patients with life-threatening cardiovascular and neurologic manifestations as well as sight-threatening ophthalmologic signs and symptoms should be promptly diagnosed, properly treated, and closely followed up to avoid potentially severe consequences.

Microarray was utilized to determine if a genetic signature associated with resistance to carfilzomib (CFZ) could be identified. Twelve human myeloma (MM) cell lines (HMCLs) were treated with CFZ and a cell-viability profile was assessed categorizing HMCLs as sensitive or resistant to CFZ. The gene expression profiles (GEP) of untreated resistant versus sensitive HMCLs revealed 29 differentially expressed genes. TOP2A, an enzyme involved in cell cycle and proliferation, was overexpressed in carfilzomib-resistant HMCLs. TOP2A protein expression levels, evaluated utilizing trephine biopsy specimens acquired prior to treatment with proteasome inhibitors, were higher in patients failing to achieve a response when compared to responding patients. Logistic-regression analysis confirmed that TOP2A protein expression was a highly significant predictor of response to PIs (AUC 0.738). Further, the combination of CFZ with TOP2A inhibitors, demonstrated synergistic cytotoxic effects in vitro , providing a rationale for combining topoisomerase inhibitors with CFZ to overcome resistance in MM.

Purpose: To describe the ocular manifestations in a cohort of patients with systemic sarcoidosis (SS). Recent advances in the pathophysiology, diagnosis, and therapy of SS are also discussed., Methods: Data from 115 Italian patients diagnosed between 2005 and 2016 were retrospectively reviewed. All but the first 17 patients underwent a comprehensive ophthalmologic examination. The diagnosis was based on clinical features, the demonstration of non-caseating granulomas in biopsies from involved organs, and multiple imaging techniques. Data on broncho-alveolar lavage fluid analysis, calcemia, calciuria, serum angiotensin-converting enzyme levels and soluble interleukin-2 receptor levels were retrieved when available., Results: Ocular involvement, detected in 33 patients (28.7%), was bilateral in 29 (87.9%) and the presenting feature in 13 (39.4%). Anterior uveitis was diagnosed in 12 patients (36.4%), Löfgren syndrome and uveoparotid fever in one patient each (3%), intermediate uveitis in 3 patients (9.1%), posterior uveitis in 7 (21.2%), and panuveitis in 9 (27.3%). First-line therapy consisted of corticosteroids, administered as eyedrops (10 patients), sub-Tenon's injections (1 patient), intravitreal implants (9 patients), or systemically (23 patients). Second-line therapy consisted of steroid-sparing immunosuppressants, including methotrexate (10 patients) and azathioprine (10 patients). Based on pathogenetic indications that tumor necrosis factor (TNF)-α is a central mediator of granuloma formation, adalimumab, targeting TNF-α, was employed in 6 patients as a third-line agent for severe/refractory chronic sarcoidosis., Conclusion: Uveitis of protean type, onset, duration, and course remains the most frequent ocular manifestation of SS. Diagnostic and therapeutic advancements have remarkably improved the overall visual prognosis. An ophthalmologist should be a constant component in the multidisciplinary approach to the treatment of this often challenging but intriguing disease.

Cardiovascular disease (CVD) is a major complication of systemic lupus erythematosus (SLE) and is now a leading cause of death for these patients. In this study, 23 SLE patients asymptomatic for CVD underwent a comprehensive echocardiographic examination to detect subclinical cardiac involvement. According to their SELENA-SLEDAI score, they were divided into two groups: SELENA-SLEDAI ≤ 12 (n = 13, 12 females) and SELENA-SLEDAI > 12 (n = 10, all females), indicative of mild-to-moderate and severe SLE, respectively. Patients in the latter group had significant increases in left ventricular (LV) mass, LV end-diastolic volume, left atrial volume and right heart parameters (pulmonary arterial pressure, tricuspid regurgitation velocity and diameter of the inferior cava) compared to the mild-to-moderate group. Alterations of the early to late diastolic trans-mitral flow velocity (E/A) were found in 39% of patients, equally distributed between the two groups. The Framingham score of all patients correlated directly with LV mass, interventricular septum thickness and posterior wall thickness, but did not significantly differ between patients with severe and mild-to-moderate SLE. These findings reveal the presence of early-stage, and thus clinically silent, diastolic dysfunction in patients with severe SLE. They demonstrate the poor predictive value of the Framingham score in CVD risk stratification of patients with SLE, thus highlighting the crucial role of echocardiography in the diagnostic workup of these patients.

Purpose : To describe the ophthalmic manifestations of amyloidosis and the corresponding therapeutic measures. Methods : The 178 patients included in the study had different types of amyloidosis, diagnosed at a single internal medicine institution (Bari, Italy). To provide a comprehensive review of the types of amyloidosis that can be associated with ocular involvement, the images and clinical descriptions of patients with amyloidosis structurally related to gelsolin, keratoepithelin and lactoferrin were obtained in collaborations with the ophthalmology departments of hospitals in Mainz (Germany) and Helsinki (Finland). Results : Overall, ocular morbidity was detected in 41 of the 178 patients with amyloidosis (23%). AL amyloidosis was diagnosed in 18 patients with systemic disease, 3 with multiple myeloma, and 11 with localized amyloidosis. AA amyloidosis was detected in 2 patients with rheumatoid arthritis and 3 with Behçet syndrome, and transthyretin amyloidosis in 4 patients. The treatment of AL amyloidosis is based on chemotherapy to suppress the production of amyloidogenic L-chains and on surgical excision of orbital or conjunctival masses. AA amyloidosis is managed by targeting the underlying condition. Vitreous opacities and additional findings of ocular involvement in patients with transthyretin amyloidosis indicate the need for pars plana vitrectomy. Gelsolin amyloidosis, characterized by lattice corneal amyloidosis and polyneuropathy, results in recurrent keratitis and corneal scarring, such that keratoplasty is inevitable. In patients with lattice corneal dystrophies associated with amyloid deposits of keratoepithelin fragments, corneal transparency is compromised by deposits of congophilic material in the subepithelial layer and deep corneal stroma. Patients with established corneal opacities are treated by corneal transplantation, but the prognosis is poor because recurrent corneal deposits are possible after surgery. In patients with gelatinous drop-like dystrophy, the amyloid fibrils that accumulate beneath the corneal epithelium consist of lactoferrin and can severely impair visual acuity. Keratoplasty and its variants are performed for visual rehabilitation. Conclusion : A routine ophthalmic follow-up is recommended for all patients with established or suspected amyloidosis, independent of the biochemical type of the amyloid. Close collaboration between the ophthalmologist and the internist will facilitate a more precise diagnosis of ocular involvement in amyloidosis and allow the multidisciplinary management of these patients. Abbreviations: CD: corneal dystrophy; CLA: corneal lattice amyloidosis; CNS: central nervous system; CT: computed tomography; FAP: familial amyloidotic polyneuropathy; GDLCD: gelatinous drop-like corneal dystrophy; GLN: gelsolin; LCD: lattice corneal dystrophy; MRI: magnetic resonance imaging; OLT: orthotopic liver transplantation; TEM: transmission electron microscopy; TGFBI: transforming growth factor β induced; TTR: transthyretin.

The role of CD5 + B cells in patients with HCV infection and HCV-related disorders, including mixed cryoglobulinemia (MC), has been addressed in previous reports with conflicting results. We established a correlation between CD5/CD20 expression on circulating B lymphocytes, characterizing monoclonal B cell lymphocytosis (MBL), and clinical features in a cohort of 45 patients with chronic HCV hepatitis [without MC: 23 patients (MC- group); with MC: 22 patients (MC+ group)], and 45 HCV-negative healthy subjects as controls. By flow cytometry analysis, three B cells phenotypes were singled out: 1) CD5 + CD20 dim (CLL-like phenotype); 2) CD5 + CD20 bright (atypical phenotype); and 3) CD5 - CD20 + phenotype. CD5 + CD20 bright cells were reduced in MC- patients (p=0.049). CD5 + CD20 dim B cells were significantly higher in group B than in the control group (p=0.003). ROC curve analysis in MC+ patients showed the highest positive likelihood ratio at ≥7.35% (p=0.008) for CLL-like phenotype and at ≤63.6% (p=0.03) for the CD5 - CD20 + B cell phenotype. HCV infection was associated with a higher frequency of CLL-like (odds ratio=16, p=0.002) and a lower frequency of atypical (odds ratio: 3.1, p=0.02) and CD5 - CD20 + (odds ratio: 11, p=0.01) phenotypes. The association with higher levels of CLL-like phenotype progressively increased from group of MC- patients (odds ratio: 9.3, p=0.04) to the group of MC+ patients (odds ratio: 25.1, p=0.0003). CONCLUSIONS: The occurrence of a CLL-like pattern may allow to identify HCV-infected patients at risk of developing MC and eventually non-Hodgkin lymphoma, who should require a closer surveillance and a longer follow-up., (Copyright © 2019. Published by Elsevier B.V.)

Pemphigus diseases (PDs) and mucous membrane pemphigoid (MMP) are a group of immune-mediated mucocutaneous disorders clinically characterized by the formation of blisters, erosions and ulcers. The skin and mucous membranes are predominantly affected, with the oropharyngeal mucosa as the initially involved site. Ocular involvement is also a frequent feature of these diseases. Because of the considerable overlap in their clinical presentations, the diagnosis of PDs vs. MMP can be challenging. A recognition of their specific immunological and histopathologic features is crucial in the differential diagnosis. Treatment modalities include systemically administered corticosteroids, steroid-sparing immunosuppressive agents, and biologic therapies (rituximab, intravenous immunoglobulins, and anti-tumor necrosis factor agents). Topical, oral, conjunctival, or intralesional corticosteroids as well as anti-inflammatory drugs and antibiotics are prescribed as needed., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Cryoglobulins are circulating immunoglobulins that reversibly precipitate at temperatures below 37 °C. Type-II cryoglobulins consist of monoclonal IgM/polyclonal IgG immune complexes (ICs), whereas in type-III cryoglobulins both IgM and IgG are polyclonal. The clinical condition resulting from the presence of cryoglobulins in the blood is called mixed cryoglobulinemia (MC), which can be asymptomatic or manifest as cryoglobulinemic vasculitis (CV). Type-I cryoglobulins, consisting of a single monoclonal isotype, are detected in patients with lymphoproliferative disorders. It is now established that > 90% of MCs are associated with HCV infection. Clinically, the spectrum of symptoms may range in severity from occasional purpuric eruptions to life-threatening features. In addition to the development of liver cirrhosis and hepatocellular carcinoma, the possible progression of HCV-positive CV patients to B-cell non-Hodgkin lymphoma (B-NHL) has been reported. The pathogenetic role played by HCV infection in the onset of B-NHL is suggested by regression of the latter following the achievement of a sustained virologic response (SVR). For several years, interferon-α alone or combined with ribavirin has been the standard of care. However, the rates of clinical, biochemical, and virologic responses have been low, and the occurrence of relapse frequent. The addition of rituximab has resulted in a higher rate of responses. With the advent of direct-acting antiviral agents, SVR has been achieved in ~ 95% of CV patients. However, in a minority of patients, despite SVR, CV may persist or reappear over variable lengths of time from the completion of therapy. The eventual appearance of B-NHL is also possible.

Background: Several new drugs are approved for treatment of patients with multiple myeloma (MM), but no validated biomarkers are available for the prediction of a clinical outcome. We aimed to establish whether pretreatment blood and bone marrow plasma concentrations of major cytokines and angiogenic factors (CAFs) of patients from a phase 3 trial of a MM treatment could have a prognostic and predictive value in terms of response to therapy and progression-free and overall survival and whether these patients could be stratified for their prognosis., Methods: Blood and bone marrow plasma levels of Ang-2, FGF-2, HGF, VEGF, PDGF-β, IL-8, TNF-α, TIMP-1, and TIMP-2 were determined at diagnosis in MM patients enrolled in the GIMEMA MM0305 randomized controlled trial by an enzyme-linked immunosorbent assay (ELISA). These levels were correlated both reciprocally and with the type of therapy and patients' characteristics and with a group of non-MM patients as controls., Results: No significant differences were detected between the blood and bone marrow plasma levels of angiogenic cytokines. A cutoff for each CAF was established. The therapeutic response of patients with blood plasma levels of CAFs lower than the cutoff was better than the response of those with higher levels in terms of percentage of responding patients and quality of response., Conclusion: FGF-2, HGF, VEGF, and PDGF-β plasma levels at diagnosis have predictive significance for response to treatment. The stratification of patients based on the levels of CAFs at diagnosis and their variations after therapy is useful to characterize different risk groups concerning outcome and response to therapy., Trial Registration: Clinical trial information can be found at the following link: NCT01063179.

Interactions of multiple myeloma (MM) cells with endothelial cells (ECs) enhance angiogenesis and MM progression. Here, we investigated the role of Notch signaling in the cross talk between ECs and MM cells enabling angiogenesis. MMECs showed higher expression of Jagged1/2 ligands, of activated Notch1/2 receptors, and of Hes1/Hey1 Notch target genes than ECs from monoclonal gammopathy of undetermined significance patients, suggesting that homotypic activation of Notch pathway occurs in MM. MM cells co-cultured with MMECs triggered Notch activation in these cells through a cell-to-cell contact-dependent way via Jagged1/2, resulting in Hes1/Hey1 overexpression. The angiogenic effect of Notch pathway was analyzed through Notch1/2·siRNAs and the γ-secretase inhibitor MK-0752 by in vitro (adhesion, migration, chemotaxis, angiogenesis) and in vivo (Vk12598/C57B/6 J mouse model) studies. Activated Notch1/2 pathway was associated with the overangiogenic MMEC phenotype: Notch1/2 knockdown or MK-0752 treatment reduced Hes1/Hey1 expression, impairing in vitro angiogenesis of both MMECs alone and co-cultured with MM cells. MM cells were unable to restore angiogenic abilities of treated MMECs, proving that MMEC angiogenic activities closely rely on Notch pathway. Furthermore, Notch1/2 knockdown affected VEGF/VEGFR2 axis, indicating that the Notch pathway interferes with VEGF-mediated control on angiogenesis. MK-0752 reduced secretion of proangiogenic/proinflammatory cytokines in conditioned media, thus inhibiting blood vessel formation in the CAM assay. In the Vk12598/C57B/6 J mouse, MK-0752 treatment restrained angiogenesis by reducing microvessel density. Overall, homotypic and heterotypic Jagged1/2-mediated Notch activation enhances MMECs angiogenesis. Notch axis inhibition blocked angiogenesis in vitro and in vivo, suggesting that the Notch pathway may represent a novel therapeutic target in MM., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Endothelial cells (EC) line the bone marrow microvasculature and are in close contact with CD8 + T cells that come and go across the permeable capillaries. Because of these intimate interactions, we investigated the capacity of EC to act as antigen-presenting cells (APC) and modulate CD8 + T cell activation and proliferation in bone marrow of patients with multiple myeloma (MM) and monoclonal gammopathy of undetermined significance. We found that EC from MM patients show a phenotype of semi-professional APC given that they express low levels of the co-stimulatory molecules CD40, CD80 and CD86, and of the inducible co-stimulator ligand (ICOSL). In addition, they do not undergo the strong switch from immunoproteasome to standard proteasome subunit expression which is typical of mature professional APC such as dendritic cells. EC can trap and present antigen to CD8 + T cells, stimulating a central memory CD8 + T cell population that expresses Foxp3 and produces high amounts of IL-10 and TGF-β. Another CD8 + T cell population is stimulated by professional APC, produces IFN-γ, and exerts antitumor activity. Thus, two distinct CD8 + T cell populations coexist in the bone marrow of MM patients: the first population is sustained by EC, expresses Foxp3, produces IL-10 and TGF-β, and exerts pro-tumor activity by negatively regulating the second population. This study adds new insight into the role that EC play in MM biology and describes an additional immune regulatory mechanism that inhibits the development of antitumor immunity and may impair the success of cancer immunotherapy.

Rationale: Type I cryoglobulinemia is a rare and life-threatening condition. It occurs mainly in B-cell lymphoproliferative disorder. In almost half of the patients, type I cryoglobulinemia is characterized by severe cutaneous involvement., Patient Concerns: A 71-year-old man comes to our observation because of the onset of persistence of paresthesia and painful acrocyanosis in the fingers and toes. IgG-k multiple myeloma treated with chemotherapy and radiation therapy on the left iliac wing characterized his clinical history. At the evaluation of response after the first-line therapy, the patient achieved a very good partial response. At the time of progression, the same myelomatous disease has taken a typical behavior of cryoglobulinemia., Diagnoses: Type I multiple myeloma-associated cryoglobulinemia was diagnosed., Interventions: The patient underwent to an immediate composite therapeutic approach based on prostanoid infusion, plasmapheresis along with second-line chemotherapy., Outcomes: Despite the rapid biochemical response, the ischemia of the feet worsened. Moreover, a bacterial infection overlapped. The surgical amputation of both feet was necessary. Allowing MM cytoreduction continuation the patient's clinical condition became stabilized., Lessons: Though rare, type I cryoglobulinemia can be associated with plasma cell dyscrasias. Any delay in diagnosis and the start of therapy can cause worsening of organ damage and endanger the patient's life. Therapeutic strategies in these cases should be directed to the underlying diseases.

Multiple myeloma is commonly associated with a reduction of non-paraprotein immunoglobulins, resulting in a higher risk of infections that represent the leading cause of the patients' death. Therefore, immunoglobulin replacement therapy appears a logical approach. A total number of 46 myeloma patients were randomly enrolled: 24 of them were assigned to receive subcutaneous immunoglobulins, and 22 were controls. The primary endpoint was the evaluation of the annual rate of severe infections in immunoglobulins-receiving patients as compared with those untreated. Subcutaneous immunoglobulins-treated patients showed a significantly lower number of severe infections per year. Adverse events were limited to the site of infusion and were easily manageable. Health-related quality of life was significantly better in subcutaneous immunoglobulins-receiving patients. By decreasing the rate of infections, the prophylactic administration of SCIg improves both adherence to chemotherapy and health-related quality of life, and is cost-effective by reducing the need of hospitalization and the use of antibiotics., (Copyright © 2017. Published by Elsevier Inc.)

The mammalian Target of Rapamycin (mTOR) is an intracellular serine/threonine kinase that mediates intracellular metabolism, cell survival and actin rearrangement. mTOR is made of two independent complexes, mTORC1 and mTORC2, activated by the scaffold proteins RAPTOR and RICTOR, respectively. The activation of mTORC1 triggers protein synthesis and autophagy inhibition, while mTORC2 activation promotes progression, survival, actin reorganization, and drug resistance through AKT hyper-phosphorylation on Ser473. Due to the mTOR pivotal role in the survival of tumor cells, we evaluated its activation in endothelial cells (ECs) from 20 patients with monoclonal gammopathy of undetermined significance (MGUS) and 47 patients with multiple myeloma (MM), and its involvement in angiogenesis. MM-ECs showed a significantly higher expression of mTOR and RICTOR than MGUS-ECs. These data were supported by the higher activation of mTORC2 downstream effectors, suggesting a major role of mTORC2 in the angiogenic switch to MM. Specific inhibition of mTOR activity through siRNA targeting RICTOR and dual mTOR inhibitor PP242 reduced the MM-ECs angiogenic functions, including cell migration, chemotaxis, adhesion, invasion, in vitro angiogenesis on Matrigel ® , and cytoskeleton reorganization. In addition, PP242 treatment showed anti-angiogenic effects in vivo in the Chick Chorioallantoic Membrane (CAM) and Matrigel ® plug assays. PP242 exhibited a synergistic effect with lenalidomide and bortezomib, suggesting that mTOR inhibition can enhance the anti-angiogenic effect of these drugs. Data to be shown indicate that mTORC2 is involved in MM angiogenesis, and suggest that the dual mTOR inhibitor PP242 may be useful for the anti-angiogenic management of MM patients., Competing Interests: CONFLICTS OF INTEREST The authors declare that there are no competing financial interests in relation to this work.

Common variable immunodeficiency (CVID) is an immunodeficiency disorder with a high incidence of gastrointestinal manifestations and an increased risk of gastric carcinoma and lymphoma. This review discusses the latest advancements into the immunological, clinical and diagnostic aspects of gastric malignancies in patients with CVID. The exact molecular pathways underlying the relationships between CVID and gastric malignancies remain poorly understood. These include genetics, immune dysregulation and chronic infections by Helicobacter pylori . Further studies are needed to better stratify the risk for cancer in these patients, to elaborate surveillance programs aimed at preventing these complications, and to develop new and more effective therapeutic approaches., Competing Interests: The authors declare no conflict of interest.

Purpose: To assess the prevalence of the ocular manifestations related to the disease and/or ascribable to the administration of potentially toxic drugs in a cohort of 98 patients with systemic lupus erythematosus (SLE)., Methods: Retrospective, observational study reporting the experience of two tertiary referral centers., Results: Overall, an ocular involvement was detected in 29 patients (29.6%), sometimes preceding of months the diagnosis of SLE, more often revealed at diagnosis or throughout its course. More than a single ocular manifestation was found in 20 of the 29 patients with ophthalmological findings (68.9%). The array of ocular morbidity included, in a decreasing order of frequency, cataracts, keratoconjunctivitis sicca, glaucoma, discoid lesions of eyelids, episcleritis, retinopathy, vortex keratopathy, choroidopathy and retinal detachment, central retinal vein occlusion, and hydroxychloroquine-induced toxic maculopathy., Conclusions: It is advised that a multidisciplinary team for the diagnosis and treatment of SLE should regularly include the presence of an ophthalmologist.

The heavy chain diseases (HCDs) are rare B-cell malignancies characterized by the production of a monoclonal immunoglobulin heavy chain without an associated light chain. There are three types of HCD, defined by the class of immunoglobulin heavy chain produced: IgA (α-HCD), IgG (γ-HCD), and IgM (μ-HCD). Alpha-HCD is the most common and usually occurs as intestinal malabsorption in a young adult from a country of the Mediterranean area. Gamma- and μ-HCDs are rarer and associated with a B-cell non-Hodgkin lymphoma that produces an abnormal Ig heavy chain. These patients may occasionally be diagnosed with a monoclonal gammopathy of undetermined significance (MGUS). Fanconi syndrome, on the other hand, can be primary (inherited) or secondary (acquired). The only exception to this rule is the idiopathic form. Adult acquired Fanconi syndrome can be a rare complication of a monoclonal gammopathy. At diagnosis, most patients have an MGUS or smoldering multiple myeloma, with renal failure and evidence of osteomalacia. During follow-up, patients can develop an end-stage renal disease. Chemotherapy provides little benefit on renal function., Competing Interests: Competing interests: The authors have declared that no competing interests exist.

Accumulating evidence indicates that the success of cancer therapy depends not only on a combination of adequate procedures (surgery, chemotherapy and radiotherapy) that aim to eliminate all tumor cells, but also on the functional state of the host immune system. HLA and KIR molecules, in particular, are critical to the interactions between tumor cells and both innate and adaptive immune cells such as NK cells and T cells. Different KIR-HLA gene combinations as well as different HLA expression levels on tumor cells associate with variable tumor prognosis and response to treatment. On the other hand, different therapies have different effects on HLA molecules and immune cell functions regulated by these molecules. Here, we provide an overview of the KIR-HLA system, a description of its alterations with clinical relevance in diverse tumor types, and an analysis of the consequences that conventional cancer therapies may have on it. We also discuss how this knowledge can be exploited to identify potential immunological biomarkers that can help to select patients for tailored therapy.

Background: The efficacy and safety of direct-acting antiviral agents (DAAs) were evaluated in a cohort of prospectively enrolled patients with hepatitis C virus (HCV)-related mixed cryoglobulinaemia (MC), an immune complex-mediated vasculitis of small and medium vessels in which the pathogenetic role of HCV has been clearly established., Methods: Twenty-two patients received DAAs. Clinical and laboratory features were recorded at baseline, every 4 weeks until the end of treatment (EoT), and 12 weeks afterwards. Primary efficacy endpoints were (a) sustained virological response 12 weeks after therapy completion (SVR12), (b) regression of symptomatology (clinical response) and (c) cryoglobulin disappearance or cryocrit reduction ≥50% (immunological response). Complete response (CR) was defined as the occurrence of all three primary endpoints; partial response (PR) was defined as the occurrence of SVR12, with or without either immunological or clinical response; and no response was defined as missing the achievement of all three endpoints., Results: All patients reached SVR12. Compared with basal values, mean cryocrit values were significantly decreased at EoT and SVR12. A significant reduction of alanine transaminase and a parallel increase of complement component C4 levels were also detected. Rheumatoid factor activity was significantly reduced at EoT but not at SVR12. At SVR12, a CR was established in 14 patients (63.7%) and a PR in 8 patients (36.3%). In one patient with small lymphocytic lymphoma, the tumour progressed despite viral clearance. Mild adverse events were recorded in nine patients (40.9%)., Conclusions: The response rates induced by the use of DAAs in patients with MC were remarkably higher than those previously achieved with pegylated interferon-α/ribavirin, with or without rituximab. A much longer follow-up is desirable to achieve useful information in terms of persistent viral clearance and clinical response.

Cryoglobulinemic vasculitis (CV) is a small-to-medium-vessel vasculitis that appears in 10-15 % of patients chronically infected with hepatitis C virus (HCV). The classic symptom triad of CV, purpura/asthenia/arthralgia, is accompanied by clinical features that include glomerulonephritis, neuropathy, interstitial pneumonitis, and cardiomyopathy, ranging in their severity from mild to life threatening. The risk of developing non-Hodgkin lymphoma is also higher. The cumulative 10-year survival rate of CV patients is significantly lower than in the age- and sex-matched general population, with death typically caused by nephropathy, malignancies, liver involvement, and severe infections. Unfailing serological stigmata include both a cryoglobulin IgM fraction with rheumatoid factor activity and decreased complement C4 levels. On peripheral B cells, the expression of the CD81 B cell receptor is reduced while that of the CD19 receptor is increased. A monoclonal B cell lymphocytosis develops in almost one-third of patients. HCV-related proteins (but not HCV-RNA genomic sequences) can be detected on biopsy samples by immunofluorescence and immunohistochemistry and involve the vessel lumen, vessel walls, and the perivascular spaces of the skin, kidney, and peripheral nerves, supporting the pathogenetic role of HCV in the onset of a widespread microvasculitis. Based on the demonstration of HCV infection in the large majority of CV patients, a therapeutic regimen consisting of once-weekly pegylated interferon-α and the daily administration of ribavirin results in a sustained virologic response in ~50 % of patients. In those with refractory and relapsing disease, addition of the anti-CD20 monoclonal antibody rituximab has significantly increased the overall response rates. The extension to CV of latest-generation direct-acting antivirals, strikingly successful in non-CV HCV-positive patients, has yielded high complete response rates according to the few studies published thus far.

Gene expression profiling (GEP) of normal thyroid tissue from 43 patients with thyroid carcinoma, 6 with thyroid adenoma, 42 with multinodular goiter, and 6 with Graves-Basedow disease was carried out with the aim of achieving a better understanding of the genetic mechanisms underlying the role of normal cells surrounding the tumor in the thyroid cancer progression. Unsupervised and supervised analyses were performed to compare samples from neoplastic and non-neoplastic diseases. GEP and subsequent RT-PCR analysis identified 28 differentially expressed genes. Functional assessment revealed that they are involved in tumorigenesis and cancer progression. The distinct GEP is likely to reflect the onset and/or progression of thyroid cancer, its molecular classification, and the identification of new potential prognostic factors, thus allowing to pinpoint selective gene targets with the aim of realizing more precise preoperative diagnostic procedures and novel therapeutic approaches.This study is focused on the gene expression profiling analysis followed by RT-PCR of normal thyroid tissues from patients with neoplastic and non-neoplastic thyroid diseases. Twenty-eight genes were found to be differentially expressed in normal cells surrounding the tumor in the thyroid cancer. The genes dysregulated in normal tissue samples from patients with thyroid tumors may represent new molecular markers, useful for their diagnostic, prognostic and possibly therapeutic implications., Competing Interests: All the authors declare no conflict of interests.

Multiple myeloma (MM) is the second most common hematological malignancy. Although it can affect different organs, the bone compartment stands out both in terms of prevalence and clinical impact. Despite the striking advances in MM therapy, bone disease can remarkably affect the patient's quality of life. The occurrence and extension of bone marrow and extra-medullary involvement should be carefully assessed to confirm the diagnosis, to locate and whenever possible prevent dreadful complications such as pathological fractures and spinal cord compression, and to establish suitable therapeutic measures. Many imaging techniques have been proposed for the detection of MM skeletal involvement. With the development of more sophisticated imaging tools, it is time to use the right technique at the right time. Based on the review of the literature and our own experience, this article discusses advantages and disadvantages of the different imaging methods in the work-up of MM patients, with particular emphasis on the role that PET/CT can play. It is emphasized that whole body low-dose computed tomography should be the preferred imaging technique at baseline. However, bone marrow infiltration and extra-medullary manifestations are better detected by whole body magnetic resonance imaging. Positron emission tomography/computed tomography, on the other hand, combines the benefits of the two mentioned imaging procedures and is particularly useful not only for the detection of osteolytic lesions unrevealed by conventional X-ray, but also in the assessment of prognosis and therapeutic response., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

It was believed that vasculogenesis occurred only during embryo life and that postnatal formation of vessels arose from angiogenesis. Recent findings demonstrate the existence of Endothelial Precursor Cells (EPCs), which take partin postnatal vasculogenesis. EPCs are recruited from the bone marrow under the stimulation of growth factors and cytokines and reach the sites of neovascularization in both physiological and pathological conditions such as malignancies where they contribute to the "angiogenic switch" and tumor progression. An implementation of circulating EPCs in the bloodstream of patients with haematological malignancies has been demonstrated. This increase is strictly related to the bone marrow microvessel density and correlated with a poor prognosis. The EPCs characterization is a very complex process and still under investigation. This literature review aims to provide an overview of the functional and biological role of EPCs in haematological malignancies and to investigate their potential as a new cancer therapeutic target.

Autoimmune hepatitis is an acute or mostly chronic liver disease that can affect both adults and children and has a clear prevalence for the female sex. A definite etiology has not been established, but it is known that genetic predisposing profiles and exogenous trigger factors are involved. The main diagnostic criteria include typical histological features, the occurrence of serum auto-antibodies, and increased levels of transaminases and gamma-globulins. Instances of autoimmune hepatitis sharing features with other autoimmune liver diseases have also been observed. An imbalance of the immune system with persistent activation of effector T cells has been emphasized to account for the sustained liver injury. Clinical manifestations are variable both at presentation and throughout the course of the disease, ranging from an asymptomatic state or the occurrence of non-specific symptoms to the features of end-stage liver disease such as jaundice, ascites, and gastrointestinal bleeding. A clinical and biochemical remission is achieved in at least 80% of patients receiving corticosteroids with or without the addition of azathioprine. Alternative therapeutic schedules have been proposed for unresponsive and intolerant patients. Given that relapse often occurs after therapy withdrawal, maintenance treatment is usually required.

Since its identification in 1989, hepatitis C virus (HCV) has emerged as a worldwide health problem with roughly 185 million chronic infections, representing individuals at high risk of developing cirrhosis and liver cancer. In addition to being a frequent cause of morbidity and mortality due to liver disease, HCV has emerged as an important trigger of lymphoproliferative disorders, owing to its lymphotropism, and of a wide spectrum of extra-hepatic manifestations (HCV-EHMs) affecting different organ systems. The most frequently observed HCV-EHMs include mixed cryoglobulinemia and cryoglobulinemic vasculitis, B-cell non-Hodgkin's lymphoma, nephropathies, thyreopathies, type 2 diabetes mellitus, cardiovascular diseases, and several neurological conditions. In addition, neuropsychiatric disorders and neurocognitive dysfunction are reported in nearly 50% of patients with chronic HCV infection, which are independent of the severity of liver disease or HCV replication rates. Fatigue, sleep disturbance, depression and reduced quality of life are commonly associated with neurocognitive alterations in patients with non-cirrhotic chronic HCV infection, regardless of the stage of liver fibrosis and the infecting genotype. These manifestations, which are the topic of this review, typically occur in the absence of structural brain damage or signal abnormalities on conventional brain magnetic resonance imaging (MRI), although metabolic and microstructural changes can be detected by in vivo proton magnetic resonance spectroscopy, perfusion-weighted and diffusion tensor MRI, and neurophysiological tests of cognitive processing. Several lines of evidence, including comparative and longitudinal neuropsychological assessments in patients achieving spontaneous or treatment-induced viral clearance, support a major pathogenic role for HCV in neuropsychiatric and neurocognitive disorders.

Many researchers have speculated that the clinical progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) is driven by defects in dendritic cell (DC) function. However, evidence supporting this assumption is controversial, and no mechanism for the putative DC dysfunction has been demonstrated thus far. We studied DC subsets from the bone marrow of MM patients compared with those of MGUS patients and control subjects. We found that myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) accumulate in the bone marrow during the MGUS-to-MM progression. After engulfment of apoptotic tumor plasma cells via CD91, bone marrow mDCs and pDCs mature and are able to activate tumor-specific CD8(+) T cells. However, by interacting directly with CD28 on live (nonapoptotic) tumor plasma cells, bone marrow mDCs downregulate the expression of proteasome subunits in these cells, thus enabling their evasion from human leukocyte antigen (HLA) class I-restricted CD8(+) T-cell killing. These results suggest that DCs play a dual, but opposing, role in MM: for one, DCs activate CD8(+) T cells against tumor plasma cells and, for the other, DCs protect tumor plasma cells from CD8(+) T-cell killing. This information should be taken into account in designing immunotherapy approaches to enhance immune surveillance in MGUS and to break down immune tolerance in MM., (© 2015 by The American Society of Hematology.)