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Background & Aims: A plethora of second-line therapies have been recently introduced for hepatocellular carcinoma (HCC) treatment with promising results. A meta-analysis of second-line treatments for HCC has been performed to better tailor their use based on improved patient stratification and to identify the best available option. Methods: Pubmed, Scopus, Web of Science, and ClinicalTrials.gov were searched for randomized controlled trials evaluating second-line treatment for advanced HCC in patients already treated with sorafenib. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS) and drug withdrawal due to adverse events. Network meta-analyses were performed considering placebo as the basis for comparison in efficacy and safety analyses. Subgroup stratification considered gender, age, sorafenib-responsiveness and drug tolerability, viral infection, macrovascular invasion, HCC extrahepatic spread, performance status, and alpha-fetoprotein levels. Results: Fourteen phase II or III randomized controlled trials, involving 5,488 patients and 12 regimens, were included in the analysis. Regorafenib (hazard ratio (HR) = 0.63, 95% confidence interval (CI) = 0.50–0.79), cabozantinib (HR = 0.76, 95% CI = 0.63–0.92), and ramucirumab (HR = 0.82, 95% CI = 0.70–0.76) significantly prolonged OS compared with placebo. Cabozantinib (HR = 0.44, 95% CI = 0.36–0.52), regorafenib (HR = 0.46, 95% CI = 0.37–0.56), ramucirumab (HR = 0.54, 95% CI = 0.43–0.68), brivanib (HR = 0.56, 95% CI = 0.42–0.76), S-1 (HR = 0.60, 95% CI = 0.46–0.77), axitinib (HR = 0.62, 95% CI = 0.44–0.87), and pembrolizumab (HR = 0.72, 95% CI = 0.57–0.90) significantly improved PFS compared with placebo. None of the compared drugs deemed undoubtedly superior after having performed a patients' stratification. Conclusions: The results of this network meta-analysis suggest the use of regorafenib and cabozantinib as second-line treatments in HCC. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Autoimmune uveitis (AU), an inflammatory non-infectious process of the vascular layer of the eye, can lead to visual impairment and, in the absence of a timely diagnosis and suitable therapy, can even result in total blindness. The majority of AU cases are idiopathic, whereas fewer than 20 % are associated with systemic diseases. The clinical severity of AU depends on whether the anterior, intermediate, or posterior part of the uvea is involved and may range from almost asymptomatic to rapidly sight-threatening forms. Race, genetic background, and environmental factors can also influence the clinical picture. The pathogenetic mechanism of AU is still poorly defined, given its remarkable heterogeneity and the many discrepancies between experimental and human uveitis. Even so, the onset of AU is thought to be related to an aberrant T cell-mediated immune response, triggered by inflammation and directed against retinal or cross-reactive antigens. B cells may also play a role in uveal antigen presentation and in the subsequent activation of T cells. The management of AU remains a challenge for clinicians, especially because of the paucity of randomized clinical trials that have systematically evaluated the effectiveness of different drugs. In addition to topical treatment, several different therapeutic options are available, although a standardized regimen is thus far lacking. Current guidelines recommend corticosteroids as the first-line therapy for patients with active AU. Immunosuppressive drugs may be subsequently required to treat steroid-resistant AU and for steroid-sparing purposes. The recent introduction of biological agents, such as those targeting tumor necrosis factor-α, is expected to remarkably increase the percentages of responders and to prevent irreversible sight impairment. This paper reviews the clinical features of AU and its crucial pathogenetic targets in relation to the current therapeutic perspectives. Also, the largest clinical trials conducted in the last 12 years for the treatment of AU are summarized and critically discussed. [ABSTRACT FROM AUTHOR]

The tonsils provide defense of the upper aerodigestive tract against pathogens. Although long known to undergo functional changes with age, the precise changes occurring within tonsillar B cell populations remain undefined. In the present study, we investigated age-related changes in palatine tonsillar B cell subsets and immunoglobulin (Ig) isotypes. Palatine tonsils were obtained from forty-two tonsillectomy patients without tonsillitis who were divided into three groups: young children (4-9 years), adolescents (10-19 years), and adults (20-60 years). Tonsillar B cells were then analyzed by flow cytometry. Using expression of CD38 and IgD to define B cell subsets, we found that the frequency of germinal center (GC) B cells in the tonsils was significantly higher, and the frequency of memory B cells lower, in young children as compared to adolescents and adults. Within the GC B cell subsets, adults had a higher frequency of IgA cells and a lower frequency of IgM cells as compared to individuals in the younger age groups. Moreover, young children had a higher frequency of IgG cells in the GC B cell subsets than did individuals in the older age groups. We also observed an abundance of IgM cells among memory B cells and plasmablasts in young children and IgA cells in adults. In summary, the proportion of GC B cells in palatine tonsillar B cells decreases with age, while the proportion of memory B cells increases with age. In addition, Ig isotypes in tonsils preferentially switch from IgM to IgA as individuals age. [ABSTRACT FROM AUTHOR]

Patients with lymphoproliferative disorders, candidate to autologous stem cell transplantation (ASCT), require mobilization with chemotherapy and granulocyte colony -stimulating factor (G-CSF). This study looked for differences in hematopoietic peripheral stem cells (HPSCs) mobilization in response to the three available G-CSFs, namely lenograstim, filgrastim, and pegfilgrastim. Between 2000 and 2012, 146 patients (66 M and 80 F) who underwent ASCT for multiple myeloma, non-Hodgkin's lymphoma or Hodgkin's lymphoma were studied. All patients received induction therapy and then a mobilization regimen with cyclophosphamide plus lenograstim, or filgrastim, or pegfilgrastim. From days 12 to 14, HPSCs were collected by two to three daily leukaphereses. Our results show that high-dose cyclophosphamide plus lenograstim achieved adequate mobilization and the collection target more quickly and with fewer leukaphereses as compared to filgrastim and pegfilgrastim. No differences between the three regimens were observed regarding toxicity and days to WBC and platelet recovery. Thus, lenograstim may represent the ideal G-CSF for PBSC mobilization in patients with lymphoproliferative diseases. Further studies are needed to confirm these results and better understand the biological bases of these differences. [ABSTRACT FROM AUTHOR]

Conventional radiographic skeletal survey has been for many years the gold standard to detect the occurrence of osteolytic lesions in patients with multiple myeloma (MM). However, the introduction of more sensitive imaging procedures has resulted in an updated anatomic and functional Durie and Salmon 'plus' staging system and has remarkably changed the diagnostic and prognostic approach to this tumor. It is now established that fluorine-fluorodeoxyglucose (F-FDG) positron-emission tomography (PET) combined with low-dose computed tomography (CT), shortly designated PET/CT, exhibits a higher screening and diagnostic sensitivity and specificity over the skeleton X-ray. In patients with monoclonal gammopathy of undetermined significance and in those with smoldering MM, PET/CT is consistently unable to detect focal and/or diffuse marrow abnormalities. Conversely, based on a systematic review of 18 studies comprising almost 800 MM patients, PET/CT was able to detect MM osteolytic lesions with a sensitivity of approximately 80-90 % and a specificity of 80-100 %. Importantly, a poor degree of concordance has also been emphasized between PET/CT and whole-body magnetic resonance imaging (WB-MRI) in that when both techniques were applied to the same patients, double-positive results were recorded in approximately 30 % of the cases, but in the majority of them, a higher number of lesions were revealed with PET/CT than with MRI. Double-negative results, on the other hand, were found in about 22 % of the patients. Because PET/CT is able to identify tumor foci throughout the body, it can be usefully applied to the study of solitary bone plasmacytoma and extra-medullary plasmacytoma: In both conditions, the detection of additional, previously overlooked sites of skeletal involvement would falsify the diagnosis of single-district disease, upstage the tumor, and therefore require a different therapeutic approach. In addition, although PET/CT is poorly sensitive to diffuse bone marrow infiltration, it can anticipate a site of impending fracture throughout the body and can discriminate old from new pathologic fractures. MRI should, however, be preferred when vertebral bodies are suspected to be involved and the risk of vertebral fracture is to be assessed. PET/CT is a sensitive and reliable procedure to evaluate the response to chemotherapy and/or radiotherapy, which is shown by a remarkable reduction and sometimes total disappearance of FDG accumulation in the involved bony structures, although these structures remain morphologically abnormal. Conversely, an increased focal uptake of FDG in apparent remission patients often precedes clinically overt relapse. PET/CT should be preferred to other imaging techniques to assess the remission status after autologous stem cell transplantation. In patients with primary and remission-induced non-secretory MM, the use of PET/CT may help to early detect single or multiple districts of focal non-secretory relapse. Osteonecrosis of the jaw, its location, and extent in MM patients receiving bis-phosphonates are better defined by both PET/CT and contrast-enhanced MRI compared with dental panoramic views derived from cone beam CT imaging. Little is known as to the possible role of PET/CT in the assessment of disease extension, tumor load, and response to therapy in patients with Waldenström's macroglobulinemia (WM). In a study conducted on 35 WM patients, comparative PET/CT before and after therapy was able to detect positive findings in 83 % of the patients, in contrast with the previous results achieved with conventional imaging that reported visceral involvement in much lower percentages. Similarly scanty are the data on the use of PET/CT in localized and systemic amyloidosis, given the small number of patients studied so far. A retrospective study has shown that, at variance from Iodine-serum amyloid P component (I-SAP) scintigraphy, which was found to be positive in about one-third of the patients with localized amyloidosis, an increased FDG uptake was detected at the amyloid site in virtually all of them. On the contrary, none of the patients with systemic amyloidosis showed an increased FDG uptake in sites of known deposition, whereas I-SAP scintigraphy tested positive in the large majority of them. In another study, however, no such remarkable difference of positive PET/CT scans between localized and systemic amyloidosis was reported. Finally, false-positive and false-negative PET/CT findings can occur in different conditions that should be kept in mind to avoid wrong or omitted diagnoses. [ABSTRACT FROM AUTHOR]

Apocynin is known to suppress the production of reactive oxygen species (ROS) by inhibiting NADPH oxidases, specifically phagocytic NADPH oxidase (PHOX or NOX2). Given the pro-inflammatory effects of ROS, apocynin has been studied extensively for its use as a therapeutic agent in various disease models. While the effects of apocynin on neutrophils and monocytes have been investigated, it remains to be elucidated whether apocynin modulates the effector function of T cells. In the present study, we examined the effect of apocynin on CD8 T cells and further investigated its mechanism of action. We found that apocynin directly inhibited the production of pro-inflammatory cytokines such as TNF-α, IFN-γ, and IL-2 in anti-CD3/anti-CD28-stimulated CD8 T cells. The action of apocynin was upstream of the protein kinase C and calcium signaling in the T cell receptor signaling pathway because apocynin did not inhibit cytokine production in phorbol 12-myristate 13-acetate/ionomycin-stimulated CD8 T cells. Electrophoretic mobility shift assays revealed that apocynin attenuated anti-CD3/anti-CD28-induced NF-κB activation in CD8 T cells. In the experiments with NOX2-deficient mice, we demonstrated that apocynin inhibited TNF-α production of CD8 T cells in a NOX2-independent manner. Taken together, we demonstrated that apocynin, a well-known NOX2 inhibitor, suppressed the cytokine production of CD8 T cells. We also showed the NOX2-independent action of apocynin in the inhibition of TNF-α production in CD8 T cells. [ABSTRACT FROM AUTHOR]

Genital papilloma is caused by human papilloma virus (HPV) infection and recurs frequently. Although T cells are known to play a critical role in the control of HPV infection and papilloma development, the function and phenotype of these cells in the lesion remain to be elucidated. In the present study, we examined the function and phenotype of CD4 T cells isolated from the lesions of primary ( n = 9) and recurrent ( n = 11) genital papillomas. In recurrent papillomas, the frequency of proliferating (Ki-67) CD4 T cells was significantly reduced compared with primary papillomas. Cytokine production was evaluated by intracellular cytokine staining in anti-CD3/anti-CD28-stimulated CD4 T cells. CD4 T cells from recurrent lesions showed impaired production of IL-2, IFN-γ, and TNF-α. Of interest, the frequency of cytokine-producing CD4 T cells significantly correlated with the frequency of Ki-67CD4 T cells. We also studied expression of programmed death-1 (PD-1), a T-cell exhaustion marker. The frequency of PD-1CD4 T cells was significantly increased in recurrent lesions and inversely correlated with the frequency of cytokine-producing CD4 T cells. The functional significance of PD-1 expression was determined in blocking assays with anti-PD-L1, which restored cytokine production of CD4 T cells from recurrent lesions. Taken together, in recurrent genital papilloma lesions, proliferation, and cytokine production by CD4 T cells are impaired and the PD-1/PD-L1 interaction is responsible for the functional impairment of CD4 T cells. [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE) occurs roughly in one out of five cancer patients and is the second cause of death in this population. When all cancer patients are considered together, a sevenfold increased risk for VTE has been calculated. Over the last 20 years, a number of risk factors have been recognized. These have been used in several risk assessment models aimed at identifying high-risk patients who are therefore candidates for thromboprophylaxis. An easily applicable and reliable risk score is based on the cancer site, hemoglobin levels, pre-chemotherapy platelet and leukocyte counts as well as body mass index. The additional measurement of two biomarkers, namely D-dimer and soluble P-selectin, may improve estimates of the cumulative VTE probability. A variable incidence of VTE has been determined in patients with specific types of malignancy, with the highest odds in those with pancreatic cancer followed by head and neck tumors. In terms of histotype, the risk of VTE is significantly higher in patients with adenocarcinoma than in those with squamous cell carcinoma and in patients with high-grade versus low-grade tumors. Cancer therapy may also be responsible for VTE; specifically, the presence of an indwelling central venous catheter, immunomodulatory drugs such as thalidomide and lenalidomide, monoclonal antibodies, such as bevacizumab, erythropoiesis-stimulating agents and hormonal therapy with tamoxifen place patients at higher risk. The pathogenesis of cancer-related VTE is poorly understood but is likely to be multifactorial. 'Virchow's triad,' comprising stasis consequent to a decreased blood flow rate, an enhanced blood clotting tendency such as accompanies inflammation and growth factor expression, and structural modifications in blood vessel walls, is thought to play a central role in the induction of VTE. The prophylaxis and treatment of VTE are based on well-established drugs such as vitamin K antagonists and unfractionated and low-molecular-weight heparins as well as on an expanding group of new oral anticoagulants, including fondaparinux, rivaroxaban, apixaban and dabigatran. Furthermore, aspirin has been shown to prevent arterial thrombosis and to reduce the rate of major vascular events. Guidelines for the general management of VTE in cancer patients and in those with an indwelling central venous catheter have been recently developed with the aim of selecting the most rational therapeutic approach for each clinical situation. The main features of VTE based on our own observations of 92 cancer patients and 159 patients with non-neoplastic disease are briefly described herein. [ABSTRACT FROM AUTHOR]