Search

Background: The objective of this study was to assess the efficacy of (90)Y-DOTA-D-Phe1-Tyr3 octreotide ((90)Y-DOTATOC) therapy with a fixed activity of 2.56 GigaBequerels bimonthly in patients with advanced stage, well differentiated neuroendocrine carcinomas. Methods: In total, 38 patients were enrolled in this phase 2A protocol. All patients had gastroenteropancreatic neuroendocrine tumors in sharp clinical and radiologic progression despite previous surgery, chemotherapy, and biotherapy. Their survival rate after therapy with (90)Y-DOTATOC was compared with a chronologic control group of patients who had received biotherapy and chemotherapy and with results from a previous similar study. The progression-free survival rate after peptide receptor radionuclide therapy with (90)Y-DOTATOC was determined for all patients until they had documented disease progression according to Response Criteria in Solid Tumors, tumor-related death, or censoring. Results: Seventeen patients (43.6%) had a partial response, 10 patients (25.6%) had stable disease, and 11 patients (28.2%) had progressive disease. A statistically significant difference was observed (P < .001) between the response to (90)Y-DOTATOC treatment and the response to biotherapy with somatostatin analogs and chemotherapy and also between the current results and the results from a previous similar study (P < .05). At the time of the current evaluation with ongoing follow-up for 30 patients, the median progression-free survival was 22.3 months. Conclusions: The results from this phase 2 study indicated that the treatment of metastatic neuroendocrine tumors with fixed (90)Y-DOTATOC activity is useful and safe. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate the accuracy of (11)C-choline positron emission tomography/computed tomography (PET/CT) in restaging patients affected by prostate cancer and suspected relapse due to prostate-specific antigen (PSA) increase. We also aimed to determine a PSA cutoff that is most suited to the study in terms of best compromise between sensitivity and specificity. Secondary endpoints were a comparison between (11)C-choline PET/CT and histological results, clinical findings, and radiological imaging (CT and magnetic resonance imaging).Materials and Methods: We retrospectively evaluated 210 patients (median ± SD age 70 ± 7 years) affected by prostate cancer who underwent (11)C-choline PET/CT.Results: (11)C-choline PET/CT imaging was positive in 116 (55.2%) patients and negative in 94 (44.8%). Receiver operating characteristic (ROC) analysis showed that the highest accuracy (sensitivity 76.8%, specificity 92.5%) for the whole population was achieved when the PSA level of 1.26 ng/ml level was used as the cutoff value for interpreting the results (P = 0.0001 and the area under the ROC curve AUC 0.897). For patients treated with surgery or surgery plus radiotherapy the cutoff was 0.81 ng/ml (sensitivity 73.2%, specificity 86.1%). For patients treated with radiotherapy alone, the cutoff was 2.0 ng/ml (sensitivity 81.8%, specificity 92.9%).Conclusion: Our results indicate that (11)C-choline PET/CT is a useful diagnostic tool in patients affected by prostate cancer and a relapsed PSA level. The highest accuracy for all patients is obtained with a PSA cutoff level of 1.26 ng/ml, above which the imaging study is performed (0.81 ng/ml for patients treated with surgery or surgery plus radiotherapy and 2.0 ng/ml for patients treated with radiotherapy alone). [ABSTRACT FROM AUTHOR]

Differentiated thyroid carcinoma (DTC) is a slow-growing tumor that represents 1% of all malignant tumors and is the most frequent endocrine cancer. ¹⁸F-Fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG-PET/CT) imaging is an increasingly important imaging tool in oncology and is still under investigation in numerous studies looking into its efficacy and cost-effectiveness. Despite the fact that ¹⁸F-FDG-PET/CT has been shown to be a powerful and accurate diagnostic tool in patients affected by DTC with high serum thyroglobulin (Tg) levels and negative radioiodine (¹³¹I) total body scan, its definitive role is not completely clear, in particular regarding the role of thyroid stimulating hormone (TSH) and Tg value "cutoff" over which is better to perform the study. In this review, these issues are analyzed to clarify controversial aspects and identify established cornerstones. In particular, the literature analysis suggests that levothyroxine withdrawal is preferable in cases of relatively low Tg levels (<10 ng/ml) and good clinical compliance to hypothyroidism. Moreover, recombinant thyrotropin stimulating hormone (rTSH) could be a preferable alternative in patients clinically unable to tolerate therapy withdrawal. A Tg cutoff level over which to perform the study seems to be 10 ng/ml, a reasonable value maintaining high accuracy in terms of a good compromise between sensitivity and specificity. [ABSTRACT FROM AUTHOR]

We report a case of a 38-year-old man affected by the human immunodeficiency virus (HIV) with a diagnosis of Castleman's disease, plasmablastic type human herpes virus 8 infection, and Kaposi sarcoma based on a histological examination of one cervical lymph node biopsy. The patient underwent (18)F-2-fluoro-2-deoxyglucose positron emission tomography/computed tomography ((18)F-FDG-PET/CT). (18)F-FDG-PET/ CT seems to be a valuable tool in patients with HIV-associated Castleman's disease and Kaposi sarcoma. It allows accurate staging and identifies more sites of disease than conventional CT. [ABSTRACT FROM AUTHOR]

Purpose: Systemic vasculitis is a multisystem disease characterized by inflammation of blood vessels. Diagnosing extension of the disease and evaluating the response to therapy are cornerstones in the clinical management of vasculitis, and imaging has a pivotal role in this field.Materials and Methods: We have evaluated nine patients with large-vessel vasculitis by (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG-PET/CT) before and after treatment with corticosteroid.Results: The evaluation of eight patients was negative at follow-up studies after therapy, and one was unchanged.Conclusions: (18)F-FDG-PET/CT is a useful, accurate tool for establishing the diagnosis of large-vessel vasculitis and for evaluating disease extension in these patients. Despite the small number of patients enrolled, our study confirms this statement and offers preliminary evidence that it could also be a reliable, accurate tool for monitoring therapy in conjunction with clinical and biochemical findings. [ABSTRACT FROM AUTHOR]

Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas that derive from peripheral nerves or from cells associated with the nerve sheath. Magnetic resonance imaging is the main diagnostic imaging modality for evaluating MPNSTs. Computed tomography (CT) of the chest is the main imaging modality used to screen for distant disease, and bone scanning is considered useful for identifying selected metastases. Fluorodeoxyglucose positron emission tomography (FDG-PET) has been useful for differentiating malignant nerve sheath tumors from benign lesions and appears to be able to forecast prognosis. We report a case of a patient with neurofibromatosis 1 (NF1) with a histological diagnosis of MPNST, which was diagnosed by biopsy of a posterior right thigh mass examined by (18)F-FDG-PET/CT. [ABSTRACT FROM AUTHOR]

We report a case of a 75-year-old man with a history of a malignant melanoma with massive bilateral adrenal gland metastases diagnosed by F18-FDG-PET/CT after 10 years of negative follow-up. [ABSTRACT FROM AUTHOR]

The present work tested the estrogenic activity of three weak environmental estrogens p,p′DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane], p,p′DDE [1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene] and βBHC [β-benzene-hexachloride] in the transgenic estrogen-reporter mouse model (ERE-tK-LUC). By a time dependent analysis of the transgenic reporter expression (luciferase), we showed that all these chemicals modulated the estrogen receptors (ERs) in the whole body, although with a different efficacy and depending upon the tissue analyzed. Peak activity was registered at 16h of treatment with 5000μg/kg of each compound.Organochlorines are lipophylic molecules that accumulate in fat. During weight loss they are mobilized and their concentration increases in blood. We tested whether after experimental accumulation in fat tissue, followed by a 48h period of fasting, these compounds could be modulated to reach sufficient levels to activate the ERs in target tissues. This experimental setting produced results that were different from those obtained following acute treatments. In loaded mice, fasting induced βBHC mobilization resulted in strong ER activation in the liver, lung, eye, cerebellum, hypothalamus and cortex. p,p′DDT mobilization had no effect in these tissues, but efficiently acted in the testis, where, on the contrary, βBHC inhibited reporter expression. During fasting, βBHC, p,p′DDT and the metabolite p,p′DDE increased in blood concentration, from 2.7 ± 0.36, 0.65 ± 0.01 and 0.48 ± 0.06μg/ml to 9.51 ± 1.1, 4.98 ± 0.77 and 6.0 ± 0.71μg/ml, respectively. We conclude that these organochlorines modulate differently the expression of estrogen regulated genes in a tissue- and compound-specific manner and that their action is dependent on the energy balance. Moreover, we show that this mouse model is suitable to detect the estrogenic activity of chemicals with variable structures such as alkyl phenols and polychlorobiphenyls. [Copyright &y& Elsevier]

Introduction: Haemophagocytic lymphohistiocytosis (HLH) is a rare and serious immunological syndrome that involves a strong activation of cytotoxic T lymphocytes and macrophages. HLH determines a cytokine-mediated tissue injury with a contemporary multi-organ failure and a high fatality rate., Material and Methods: A retrospective study was performed considering the medical records of paediatric patients who underwent a bone marrow aspirate for suspect HLH. The biomarkers evaluated were among those included in the HLH-2004. Lactate dehydrogenase (LD) was also evaluated. Haemophagocytosis was evaluated in bone marrow blood smear slides., Results: Enrolled were 11 patients included in the HLH group and 8 patients as controls. Haemoglobin and fibrinogen resulted lower in HLH patients than in controls, while blood triglycerides, serum ferritin and LD resulted increased. Blood triglycerides and fibrinogen discriminated HLH cases perfectly, with a sensitivity and specificity of 100%. Ferritin had a sensitivity of 100% and a specificity of 83% (cut off ≥3,721 µg/L) and LD of 73% and of 100% (the cut off ≥1,903 U/L). Haemoglobin was found to have a sensitivity of 75% and a specificity of 100% (cut off ≤ 96 g/L). Total haemophagocytes cell counts were not different between patients and controls. Only the increased number of phagocytized nucleated red blood cells (NRBC) was found to be significantly increased in the patients. Erythrocytes phagocytosis (≥4/1,000 cells) only tended towards significance., Conclusions: The blood biomarkers showed better diagnostic performance than the morphological evaluation. Among the different cell lineages engulfed by haemophagocytes, the best diagnostic performance was obtained by phagocytosed mature erythrocytes and immature nucleated erythrocytes., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Anemia is the main extraintestinal comorbidity of Inflammatory Bowel Disease (IBD). Differentiating the type of anemia in these disorders is still a challenge. Hepcidin could be a promising biomarker to identify iron deficiency anemia (IDA), anemia of chronic disease (ACD) and the concomitant presence of both IDA and ACD., Methods: To evaluate the potential role of hepcidin dosage in the management of anemia in IBD patients, we performed a systematic review by a comprehensive literature analysis of original papers reporting the dosage of hepcidin in IBD patients. In all the articles reviewed, the dosage of ferritin was reported, and the correlation between hepcidin and ferritin has been used to compare these two biomarkers., Results: A total of 12 articles concerning the dosage of hepcidin in IBD were included, comprising in total of 976 patients. The results of the hepcidin values in IBD patients when compared with controls were conflicting. In fact, four articles described an increase in this biomarker, three showed a decrease and five did not find significant differences. The correlation with ferritin was positive and significant. In three studies, some differences between hepcidin dosages and ferritin levels indicate a possible role when IDA and ACD could be present at the same time., Conclusions: Considering the contradictory data of the studies, the diagnostic role of hepcidin as a biomarker remains elusive in IBD patients. These differences could be due to the clinical characteristics of the patients enrolled that should be better defined in the future. A suitable clinical trial should be designed to outline the possible role of hepcidin in differentiating IDA, ACD and concomitant IDA and ACD in IBD patients. At the moment, ferritin still remains the best marker to diagnose these conditions, in addition to hemoglobin, transferrin saturation and CRP as recommended by the ECCO guidelines.

The remarkable variability of response to vaccines against SARS-CoV-2 is apparent. The present study aims to estimate the extent to which the host genetic background contributes to this variability in terms of immune response and side effects following the administration of the BNT162b2 vaccine. We carried out a genome wide association study (GWAS) by genotyping 873 Italian healthcare workers who underwent anti-SARS-CoV-2 vaccination with the BNT162b2 vaccine and for whom information about anti-SARS-CoV-2 spike antibodies titers and vaccine side effects were available. The GWAS revealed a significant association between the HLA locus and the anti-SARS-CoV-2 Spike antibodies level at 2 months following the first dose of vaccine (SNP: rs1737060; p = 9.80 × 10 -11 ). In particular, we observed a positive association between the antibody levels and the presence of the HLA-A*03:01 allele. The same allele was found associated with a 2-2.4-fold increased risk of experiencing specific side effects such as fever, chills and myalgia and a 1.5-1.8-fold increased risk of joint pain, nausea, fatigue, headache and asthenia, independently of age and sex. This study confirms that the heterogeneity in the immune response to the BNT162b2 vaccine and in its side effects are at least partially influenced by genetic variants. This information, integrated with individual biological and lifestyle-related correlates, could be of use in the definition of algorithms aimed at the identification of subjects in which the administration of additional vaccine doses would be particularly beneficial to maintain immunity against the virus., (© 2023 The Authors. HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)

Autoimmune diseases are generally characterized by a multifactorial etiology and are often associated with a genetic predisposition. Both iron metabolism and the inflammatory cytokine system have been shown to play a pivotal role in the dysregulation of the immune response in many different autoimmune conditions, rheumatologic diseases included. The purpose of this work was to analyze the frequency of mutations altering the expression of IL-6 or influencing iron metabolism in patients affected by autoimmune diseases such as Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). In this study, 144 patients were enrolled: 77 and 67 patients were affected by RA and SLE, respectively. In these cohorts, the frequency of the IL-6 polymorphism -174G>C located in the IL-6 gene promoter was tested. Moreover, the frequencies of the three HFE gene variations associated with iron overload were analyzed: p.His63Asp, p.Ser65Cys and p.Cys282Tyr. The two mutations p.His63Asp and p.Ser65Cys in the HFE gene did not reach statistical significance in any of the comparisons, regardless of the statistical model, cohorts of patients and control populations analyzed. The frequencies of the p.Cys282Tyr mutation and the IL-6 polymorphism -174G>C were found to be overall significantly decreased in RA and SLE patients when the Dominant model and Allele contrast were adopted with both the Odds Ratio and Chi-square. Although further investigation is needed, the examination of the frequencies of the -174G>C IL-6 promoter polymorphism and HFE mutations may add some valuable information on the interplay linking iron metabolism, inflammation and immunity in autoimmune diseases such as SLE and RA.

Objectives: Heterozygous mutations in the granulin ( GRN ) gene may result in haploinsufficiency of progranulin (PGRN), which might lead to frontotemporal dementia (FTD). In this study, we aimed to perform analytical and clinical validation of a commercial progranulin kit for clinical use., Methods: Analytical validation parameters including assay precision, selectivity, measurement range, dilution linearity, interferences and sample stability were tested according to previously described procedures. For clinical validation, PGRN levels were measured in plasma from 32 cognitively healthy individuals, 52 confirmed GRN mutation carriers, 25 C9orf72 mutation carriers and 216 patients with different neurodegenerative diseases of which 70 were confirmed as non-mutation carriers., Results: Among the analytical validation parameters, assay precision and repeatability were very stable (coefficients of variation <7 %). Spike recovery was 96 %, the measurement range was 6.25-400 μg/L and dilution linearity ranged from 1:50-1:200. Hemolysis did not interfere with progranulin levels, and these were resistant to freeze/thaw cycles and storage at different temperatures. For the clinical validation, the assay was capable of distinguishing GRN mutation carriers from controls and non- GRN mutation carriers with very good sensitivity and specificity at a cut-off of 57 μg/L (97 %, 100 %, respectively)., Conclusions: In this study, we demonstrate robust analytical and diagnostic performance of this commercial progranulin kit for implementation in clinical laboratory practice. This easy-to-use test allows identification of potential GRN mutation carriers, which may guide further evaluation of the patient. This assay might also be used to evaluate the effect of novel PGRN-targeting drugs and therapies., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

Persistent inflammation, despite anti-retroviral therapy (ART), is an independent predictor of mortality and comorbidities in HIV infection. Multiple factors, including lifestyle and chronic viral coinfections, may contribute. Several of these factors are also associated with a chronic inflammation in the general population. Little is known about the degree to which these factors influence inflammation in HIV infection, particularly within the first year of ART. The purpose of this study was to distinguish the effects of factors (gender, body mass index, cholesterol and triglyceride levels, smoke habit and cytomegalovirus seropositivity), known to contribute to inflammation, on inflammation biomarkers over the first year of ART in HIV-infected patients. Linear mixed model analysis revealed significant biomarker decreases [soluble CD14 (s-CD14), soluble CD163 (s-CD163) and D-dimer (DD)], or increases [C Reactive Protein (CRP) and interleukin-6 (IL-6)] over time in the whole cohort, differences in most categories (genders for IL-6, smoke habit for s-CD14, cytomegalovirus infection for s-CD163 and IL-6) and in some category × time interactions [gender for interleukin-7 (IL-7)], cytomegalovirus infection for s-CD14 and cholesterol levels for s-CD14 and Tumor Necrosis Factor α (TNF-α)]. This explorative longitudinal study suggests further investigations on targeting inflammation pathophysiology in HIV-infected patients on ART., (Copyright © 2021. Published by Elsevier Ltd.)

The anti-malarial drugs chloroquine (CQ) and primarily the less toxic hydroxychloroquine (HCQ) are currently used to treat autoimmune diseases for their immunomodulatory and anti-thrombotic properties. They have also been proposed for the treatment of several viral infections, due to their anti-viral effects in cell cultures and animal models, and, currently, for the treatment of coronavirus disease 2019 (COVID-19), the pandemic severe acute respiratory syndrome caused by coronavirus 2 (Sars-Cov-2) infection that is spreading all over the world. Although in some recent studies a clinical improvement in COVID-19 patients has been observed, the clinical efficacy of CQ and HCQ in COVID-19 has yet to be proven with randomized controlled studies, many of which are currently ongoing, also considering pharmacokinetics, optimal dosing regimen, therapeutic level and duration of treatment and taking into account patients with different severity degrees of disease. Here we review what is currently known on the mechanisms of action of CQ and HCQ as anti-viral, anti-inflammatory and anti-thrombotic drugs and discuss the up-to-date experimental evidence on the potential mechanisms of action of CQ/HCQ in Sars-Cov2 infection and the current clinical knowledge on their efficacy in the treatment of COVID-19 patients. Given the role of iron in several human viral infections, we also propose a different insight into a number of CQ and HCQ pharmacological effects, suggesting a potential involvement of iron homeostasis in Sars-Cov-2 infection and COVID-19 clinical course., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: E.Q.R. received travel grants from Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare, Janssen-Cilag, Merck Sharp & Dohme and consultancy fees from Janssen-Cilag, ViiV Healthcare and Merck Sharp & Dohme. The remaining authors declare that they have no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Anemia is the main extra-gastrointestinal symptom in inflammatory bowel diseases (IBDs). Interleukin-6 (IL-6) and other cytokines are secreted and act in the microenvironment of the small intestine mucous membrane of IBD patients. Iron is essential for multiple cell functions and its homeostasis is regulated by the hepcidin-ferroportin axis. Hepcidin (HEPC) is mainly produced by the liver in response to iron needs but is also an acute phase protein. During inflammation, hepcidin is upregulated by IL-6 and is responsible for iron compartmentalization within cells, in turn causing anemia of inflammation. Tissues other than liver can produce hepcidin in response to inflammatory stimuli, in order to decrease iron efflux at a local level, then acting in an autocrine-paracrine manner. In IBDs and, in particular, in celiac disease (CeD), IL-6 might trigger the expression, upregulation and secretion of hepcidin in the small intestine, reducing iron efflux and exacerbating defective iron absorption. 7-Hydroxymatairesinol (7-HMR) belongs to the family of lignans, polyphenolic compounds produced by plants, and has nutraceutical antioxidant, anti-inflammatory and estrogenic properties. In this mini-review we revise the role of inflammation in IBDs and in particular in CeD, focusing our attention on the close link among inflammation, anemia and iron metabolism. We also briefly describe the anti-inflammatory and estrogenic activity of 7-HMR contained in foods that are often consumed by CeD patients. Finally, considering that HEPC expression is regulated by iron needs, inflammation and estrogens, we explored the hypothesis that 7-HMR consumption could ameliorate anemia in CeD using Caco-2 cells as bowel model. Further studies are needed to verify the regulation pathway through which 7-HMR may interfere with the local production of HEPC in bowel.

The use of combination anti-retroviral therapy (cART) correlates with longer and healthier life and with nearly normal life expectancy in people living with HIV. However, cART does not completely restore health. Chronic immune activation and inflammation persist in treated patients and have been described as predictors for clinical events and mortality in HIV-infected patients. Limited information is available on the impact of the various cART regimens on inflammation/immunoactivation. The aim of this work was to explore the impact of elvitegravir, dolutegravir, raltegravir (integrase strand transfer inhibitors, INSTIs) and atazanavir (protease inhibitor, PI) on several soluble markers of immune activation and inflammation during the first year of effective combination anti-retroviral therapy (cART). We conducted an observational retrospective cohort study in HIV-infected cART-naïve patients who initiated an INSTI or atazanavir regimen between March 2015 and February 2016 and a serum sample was available at baseline, 6 and 12 months after initiation. We compared the trend of D-Dimer, TNF- α, IL-2, IL-6, IL-7, IL-10, CCL4/MIP1-β, CCL5/RANTES, s-CD14, s-CD163, hs-CRP levels among the 4 arms of treatment. Percentage of variation from baseline was also measured for all markers. A total of 36 patients were included. We observed heterogeneous modifications in inflammation markers among arms. In particular, we noted that EVG have significant negative effect on s-CD14, hs-CRP, IL-6 and D-Dimer in respect to other INSTIs and this different effect occurs mainly during the first 6 months of cART. IL-7 values increased in the three arms with INSTIs (significantly only in EGV, 159.8%, p = 0.0003) and decreased significantly in patients on PI (-48.96%; p = 0.04) over the period. In conclusion, our results provide further data on changes of inflammatory marker levels, especially for the new INSTIs. Our data show that among INSTIs, EVG seems to have a worse impact on inflammation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)