Performance of the 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for antineutrophil cytoplasmic antibody-associated vasculitis in previously diagnosed adult patients from Türkiye.

Objectives: This study aimed to evaluate the applicability of the new 2022 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) criteria in Turkish adult patients previously diagnosed with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Patients and methods: One hundred sixty-four patients (96 males, 68 females; mean age: 49.6±14.4 years; range, 18 to 87 years) diagnosed with AAV by experienced rheumatologists between July 2016 and May 2022 were included in this retrospective cross-sectional study and reclassified based on the 1990 ACR criteria, the European Medicines Agency (EMEA) algorithm, and the 2022 ACR/EULAR criteria. For external validation, 83 patients (48 males, 35 females; mean age: 47.3±17.5 years; range, 19 to 81 years) diagnosed with immunoglobulin (Ig)A vasculitis were included. Results: One hundred twenty-six (76.8%) patients had granulomatosis with polyangiitis (GPA), 13 (7.9%) patients had eosinophilic granulomatosis with polyangiitis (EGPA), and 25 (15.2%) patients had microscopic polyangiitis (MPA). According to the criteria, the number of unclassified patients was nine (5.5%) for both the 2022 ACR/EULAR AAV classification criteria and the EMEA algorithm. The new criteria had an almost perfect agreement with the clinician's diagnosis (Cohen's kappa coefficient [κ]=0.858 for GPA, κ=0.820 for EGPA, and κ=0.847 for MPA). The kappa statistics for agreement of 2022 ACR/EULAR classification criteria with the EMEA algorithm were found 0.794 for GPA, 0.820 for EGPA, and 0.700 for MPA. None of the 83 patients diagnosed with IgA vasculitis could be classified as GPA, EGPA, or MPA using the new ACR/EULAR AAV classification criteria. Conclusion: The 2022 ACR/EULAR classification criteria for AAV showed substantial or perfect agreement with the clinical diagnosis and the EMEA algorithm.

Assessing safety and efficacy of TNFi treatment in late onset ankylosing spondylitis: a TURKBIO registry study.

Clinical data on the use of tumour necrosis factor inhibitors (TNFi) in late-onset ankylosing spondylitis (LoAS) are limited. The present study aimed to evaluate efficacy, safety, and treatment adherence associated with the initial use of TNFi therapy in biologic naive patients diagnosed with LoAS. Patients whose age of onset was ≥ 45 years and < 45 years were classified as having LoAS and YoAS, respectively, based on the age of symptom onset. There were 2573 patients with YoAS and 281 LoAS. Baseline disease activity measures were similar between the groups. No significant differences were seen between the two groups in response to treatment and in remaining on the first TNFi at 6, 12 and 24 months. In the LoAS group, the analysis showed that TNFi discontinuation was linked to VAS pain score (HR 1.04; 95% CI 1.01-1.06). Patient groups had similar rates of adverse events (YoAS: 8.7% vs. LoAS: 11.7%). In both biologic naive LoAS and YoAS patients, the study showed that the initial TNFi therapy was equally effective and safe.

Low relapse rate in patients with giant cell arteritis in a multi-centre retrospective Turkish Registry.

OBJECTIVES: Glucocorticoids (GC) are widely accepted as the standard first-line treatment for giant cell arteritis (GCA). However, relapse rates are reported up to 80% on GC-only protocol arms in controlled trials of tocilizumab and abatacept in 12-24 months. Herein, we aimed to assess the real-life relapse rates retrospectively in patients with GCA from Turkey. METHODS: We assembled a retrospective cohort of patients with GCA diagnosed according to ACR 1990 criteria from tertiary rheumatology centres in Turkey. All clinical data were abstracted from medical records. Relapse was defined as any new manifestation or increased acutephase response leading to the change of the GC dose or use of a new therapeutic agent by the treating physician. RESULTS: The study included 330 (F/M: 196/134) patients with GCA. The mean age at disease onset was 68.9±9 years. The most frequent symptom was headache. Polymyalgia rheumatica was also present in 81 (24.5%) patients. Elevation of acute phase reactants (ESR>50 mm/h or CRP>5 mg/l) was absent in 25 (7.6%) patients at diagnosis. Temporal artery biopsy was available in 241 (73%) patients, and 180 of them had positive histopathological findings for GCA. For remission induction, GC pulses (250-1000 methylprednisolone mg/3-7 days) were given to 69 (20.9%) patients, with further 0.5-1 mg/kg/day prednisolone continued in the whole group. Immunosuppressives as GC-sparing agents were used in 252 (76.4%) patients. During a follow-up of a median 26.5 (6-190) months, relapses occurred in 49 (18.8%) patients. No confounding factor was observed in relapse rates. GC treatment could be stopped in only 62 (23.8%) patients. Additionally, GC-related side effects developed in 64 (24.6%) patients, and 141 (66.2%) had at least one Vasculitis Damage Index (VDI) damage item present during follow-up. CONCLUSIONS: In this first multi-centre series of GCA from Turkey, we observed that only one-fifth of patients had relapses during a mean follow-up of 26 months, with 76.4% given a GC-sparing IS agent at diagnosis. At the end of follow-up, GC-related side effects developed in one-fourth of patients. Our results suggest that patients with GCA had a low relapse rate in real-life experience of a multi-centre retrospective Turkish registry, however with a significant presence of GC-associated side effects during follow-up.

Investigation of the value of hematological biomarkers in the clinical differential diagnosis of IgG4-RD.

BACKGROUND: IgG4- related disease (IgG4- RD) is a systemic fibroinflammatory disease whose pathogenesis has not been completely elucidated. Due to the novelty and complexity of the diagnostic criteria, it is difficult to distinguish from the diseases included in the differential diagnosis without tissue biopsy. This study aimed to discover new biomarkers that can help for disease diagnosis and its differential diagnosis by reviewing the relationships between neutrophil-lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and systemic inflammation response index (SIRI). METHODS: Thirty IgG4- RD, 38 granulomatous polyangiitis (GPA), and 46 sarcoidosis patients presenting to the Rheumatology Clinic meeting the criteria of 2019 American College of Rheumatology, 2012 International Chapel Hill and 1999 American Thoracic Society meeting, respectively, and 27 healthy control subjects were included. We collected data on complete blood count with automated differential values including NLR, PLR, SII, and SIRI. RESULTS: The SII and PLR values were significantly higher in patients with IgG4-RD compared to healthy controls, (SII median (minmax) 572 (102-5583) vs. 434 (172-897), PLR median (min-max) 130 (56.8-546) vs. 104 (57.5- 253) p < 0.001). SII value was found to have a significant positive correlation with CRP in IgG4-RD disease (r = 0.371; p = 0.043). While SII, SIRI, NLR, PLR parameters were not significant between the IgG4-RD and sarcoidosis groups, SII, SIRI, NLR, PLR were significantly higher in patients with GPA than in IgG4-RD patients (p < 0.001). DISCUSSION: This is the first study to review the SII, SIRI, NLR, and PLR in IgG4-RD. The obtained results suggest that the SII could beused as a new tool, for differential diagnosis and activity of the IgG4-RD.

Lacrimal gland ultrasonography and elastography as a diagnostic and activity tool for primary Sjögren's syndrome.

OBJECTIVE: To investigate the effectiveness of 2-dimensional shear wave elastography (2D-SWE) in the assessment of lacrimal gland involvement in primary Sjögren's syndrome (pSS) and to determine the association between ultrasonographic findings and clinical activity measures. METHOD: Forty-six patients who fulfilled the 2016 American College of Rheumatology/European League Against Rheumatism (EULAR) classification criteria of pSS and 23 age and gender-matched healthy control subjects were enrolled. Clinical, laboratory and labial biopsy histopathologic characteristics of patients were recorded. Disease activity of pSS and severity of ocular dryness were evaluated with EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) and Ocular Surface Disease Index (OSDI), respectively. Parotid and lacrimal gland architectures were assessed by B-mode ultrasound and 2D-SWE techniques. RESULTS: Mean shear wave elastography measurements, reflecting loss of elasticity, were remarkably higher in pSS patients compared to healthy subjects both in the lacrimal and parotid glands (8.99 ± 3.45 vs 3.68 ± 1.76 in lacrimal glands and 14.14 ± 4.39 vs 7.83 ± 1.69 in parotid glands, all P < 0.001). Shear wave elasticity of lacrimal glands was correlated with OSDI and ESSPRI scores (r = 0.69; P = 0.001 and r = 0.58; P = 0.001, respectively). A cut-off value of 4.6 kPa in the lacrimal gland elasticity discriminated pSS patients from healthy subjects with a sensitivity of 94% and specificity of 87%. CONCLUSION: Results of our study suggest that lacrimal glands lose elasticity in patients with pSS and the assessment of elasticity with 2D-SWE might help to classify patients as having pSS. Further studies are needed to validate the diagnostic utility of lacrimal 2D-SWE by including diseases other than pSS.

Prognostic significance of 18F-FDG PET/CT indices in metastatic renal cell cancer and evaluation of revised IMDC risk model by including 18F-FDG PET-CT parameters.

BACKGROUND: Prognostic markers in metastatic renal cell cancer (mRCC) are still insufficient. Any prognostic model objectively determines disease burden. PURPOSE: To investigate the relationship between 18-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) parameters and outcomes in mRCC, and to define a revised International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model for the intermediate-risk group. MATERIAL AND METHODS: A retrospective study of mRCC was conducted. To investigate the prognostic significance of 18F-FDG PET/CT parameters, maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), and metabolic tumor volume (MTV) were determined in pre-treatment images. Cutoff values were defined by ROC curve analyses and their association with outcomes was analyzed. Additionally, a TLG-adjusted IMDC model was created by stratifying intermediate-risk group patients according to TLG levels. RESULTS: The study included 52 patients. The disease control rate (DCR) was 61.5% and median overall survival (OS) was 18 months (95% confidence interval=9.2-25.8). In the univariate analyses, IMDC score, MTV, and TLG were prognostic factors for Disease Control Rate (DCR), and Eastern Cooperative Oncology Group (ECOG)-Performance Status (PS), IMDC score, lactate dehydrogenase (LDH), treatment option, MTV, and TLG were prognostic factors for OS (P < 0.05 each). In the multivariate analyses, MTV was an independent prognostic factor for DCR, and ECOG-PS, LDH, IMDC score, and TLG were independent prognostic factors for OS. According to the revised-IMDC model, the intermediate-favorable group showed longer OS than the intermediate-unfavorable group. CONCLUSION: Pretreatment MTV was independent prognostic factor for DCR and ECOG-PS, LDH, IMDC score, and TLG were independent prognostic factors for OS. Revised-IMDC model could identify patients with a worse prognosis among the IMDC intermediate-risk group.

Role of baseline 68Ga-PSMA PET/CT-derived whole-body volumetric parameters in predicting survival outcomes of metastatic castration-resistant prostate cancer patients receiving first-line treatment.

OBJECTIVE: We aimed to evaluate whether baseline 68Ga-PSMA PET/CT-derived whole-body volumetric parameters could be used as predictive biomarkers for survival in metastatic castration-resistant prostate cancer (mCRPC) patients receiving first-line treatment. MATERIALS AND METHODS: This retrospective study included 54 mCRPC patients, who underwent baseline 68Ga-PSMA PET/CT imaging within 1 month before starting first-line treatment. Pre-treatment prostate-specific antigen (PSA) levels and treatments were recorded. SUVmax, SUVmean, whole-body PSMA-derived tumor volume (wbPSMA-TV), and whole-body total lesion PSMA (wbTL-PSMA) were calculated for all patients. PSA response was defined as a decline of ≥ 50% from pre-treatment value at 12 weeks. Overall survival (OS) was measured from the start of the first-line treatment for mCRPC. RESULTS: Docetaxel and abiraterone/enzalutamide were administered to 32 and 22 patients in the first-line setting, respectively. wbPSMA-TV (rho = 0.582, p = 0.004) and wbTL-PSMA (rho = 0.564, p = 0.007) showed moderate positive correlations with PSA levels. Older age (p = 0.02), higher wbPSMA-TV (p = 0.007), higher PSA (p = 0.01), higher number of bone metastases (p = 0.02), and lack of PSA response (p = 0.03) were significantly associated with an increased risk of mortality. Multivariate analysis determined wbPSMA-TV (HR: 1.003, 95% CI 1.001-1.004, p = 0.001) and PSA response (HR: 2.241, 95% CI 1.189-4.222, p = 0.01) as independent predictors of OS. CONCLUSION: The wbPSMA-TV may be a useful tool to reflect tumor burden and predict survival outcomes in patients with mCRPC.

Real-world assessment of quality-of-life in patients with breast cancer treated with adjuvant endocrine therapy.

Objective: The aim of this study was to investigate quality-of-life (QoL) in breast cancer (BC) patients treated with adjuvant endocrine therapy (AET). Methods: We designed a cross-sectional study of 233 BC patients treated with AET and used the Functional Assessment of Cancer Therapy - Breast questionnaire. Results: No significant difference was observed between endocrine agents. Duration of AET did not affect QoL. In the entire cohort, multivariate analysis determined age (p = 0.034) and switching treatment from tamoxifen to aromatase inhibitors (p = 0.049) as significant positive coefficients of QoL, while comorbidity (p = 0.072) tended to be associated with lower scores. Education level (p = 0.001) and chemotherapy (p = 0.04) were significant predictors of QoL in the tamoxifen group, while comorbidity (p = 0.04), surgery type (p = 0.02), radiotherapy (p = 0.006) and stage (p = 0.009) had a significant impact on QoL in aromatase inhibitors group. Conclusion: Evaluating the well-being of BC patients by QoL questionnaires is of great importance to identify particular subgroups that may require supportive care.

Breast cancer (BC) remains the most common cancer among women worldwide. Hormone receptor-positive (estrogen receptor- and/or progesterone receptor-positive) BC represents 70% of all cases. Advances in the treatment of disease lead to improved patient survival. As a result, quality-of-life (QoL) becomes a major concern in clinical practice. This study aimed to assess the impact of socio-demographic, clinical and treatment-related factors on QoL among patients with BC treated with adjuvant endocrine therapy. We used the Functional Assessment of Cancer Therapy ­ Breast questionnaire to evaluate QoL. In the entire cohort, multivariate analysis determined age and switching treatment from tamoxifen to aromatase inhibitors to be significant positive coefficients of QoL, while comorbidity tended to be associated with lower scores. Education level and chemotherapy were significant determinants of QoL in the tamoxifen group, while comorbidity, surgery type, radiotherapy and disease stage had a significant impact on QoL in the aromatase inhibitor group. These findings can be utilized to identify certain subgroups that may need greater supportive care.

A real-life analysis of patients with rheumatologic diseases on biological treatments: Data from TURKBIO Registry.

OBJECTIVE: TURKBIO registry, established in 2011, is the first nationwide biological database in Turkey. This study aimed to provide an overview of TURKBIO data collected by June 2018. METHODS: The registry included adult patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), nonradiographic axial spondyloarthritis (nr-AxSpA), and psoriatic arthritis (PsA). Demographic and clinical features, disease activity markers, and other follow-up parameters, current and previous treat- ments, and adverse events were registered electronically at each visit using open-source software. The registration of patient-reported outcome measures was carried out electronically by the patients using touch screens. RESULTS: TURKBIO registry included a total of 41,145 treatment series with biologicals. There were 2,588 patients with axSpA (2,459 AS and 129 nr-axSpA), 2,036 with RA, and 428 with PsA. The total number of patients, including those with other diagnoses, was 5,718. In the follow-up period, the number of patients and also visits steadily increased by years. The yearly mean number of visits per patient was found to be 2.3. Significant improvements in disease activity and health assessment parameters were observed following the biological treatments. Biologics were often given in combination with a con- ventional synthetic disease-modifying antirheumatic drug in patients with RA. Infections were the most commonly seen adverse events, followed by allergic reactions. Tuberculosis was observed in 12 patients, malignancy in 18, and treatment-related mortality in 31. CONCLUSION: TURKBIO provided a valuable real-life experience with the use of biologics in rheumatic diseases in Turkey.

Knowledge, Practice, and Attitudes of Physicians in Low- and Middle-Income Countries on Fertility and Pregnancy-Related Issues in Young Women With Breast Cancer.

PURPOSE: Fertility and pregnancy-related issues are highly relevant for young (≤ 40 years) patients with breast cancer. Limited evidence exists on knowledge, practice, and attitudes of physicians from low- and middle-income countries (LMICs) regarding these issues. METHODS: A 19-item questionnaire adapted from an international survey exploring issues about fertility preservation and pregnancy after breast cancer was sent by e-mail between November 2019 and January 2020 to physicians from LMICs involved in breast cancer care. Descriptive analyses were performed. RESULTS: A total of 288 physicians from Asia, Africa, America, and Europe completed the survey. Median age was 38 years. Responders were mainly medical oncologists (44.4%) working in an academic setting (46.9%). Among responders, 40.2% and 53.8% reported having never consulted the available international guidelines on fertility preservation and pregnancy after breast cancer, respectively. 25.0%, 19.1%, and 24.3% of responders answered to be not at all knowledgeable about embryo, oocyte, or ovarian tissue cryopreservation, respectively; 29.2%, 23.6%, and 31.3% declared that embryo, oocyte, and ovarian tissue cryopreservation were not available in their countries, respectively. 57.6% of responders disagreed or were neutral on the statement that controlled ovarian stimulation can be considered safe in patients with breast cancer. 49.7% and 58.6% of responders agreed or were neutral on the statement that pregnancy in breast cancer survivors may increase the risk of recurrence overall or only in those with hormone receptor-positive disease, respectively. CONCLUSION: This survey showed suboptimal knowledge, practice, and attitudes of physicians from LMICs on fertility preservation and pregnancy after treatment completion in young women with breast cancer. Increasing awareness and education on these aspects are needed to improve adherence to available guidelines and to promote patients' oncofertility counseling.

Serum levels of fetuin-A as a novel biomarker for disease activity in patients with Takayasu arteritis and granulomatous polyangiitis.

OBJECTIVE: The aim of the present study was to investigate serum fetuin-A (Fet-A) levels in patients with Takayasu arteritis (TA) and granulomatous polyangiitis (GPA) and to analyze the relationship between serum Fet-A levels and disease activity scores. METHOD: Thirty-two TA and 28 GPA patients presented to the rheumatology clinic at Gazi University and met the criteria of American College of Rheumatology 1990 and 2012 International Chapell Hill meeting, respectively, and 20 healthy control subjects were included in the present study. We collected data on serum C-reactive protein (CRP), albumin, calcium, and phosphate levels as well as erythrocyte sedimentation rates. Calcification risk index (CRI) was calculated for each patient. The Birmingham Vasculitis Activity Score (BVAS) and Indian Takayasu Clinical Activity Score (ITAS), were used to assess disease activity in GPA and TA patients respectively. RESULTS: Serum Fet-A levels were significantly lower in the overall vasculitis group compared to control group (p = 0.015). In subgroup analysis, Fet-A levels were significantly lower in those with active disease, compared to control group (p = 0.001, for active TA (n = 18) and GPA (n = 17), respectively). However, there was no significant difference in serum Fet-A levels in inactive cases versus control subjects (p = 0.061, for inactive TA (n = 14) and GPA (n = 11), respectively). Serum Fet-A levels negatively correlated with BVAS (r = - 0.675) and ITAS scores (r = - 0.385), as well as with CRP and CRI. CONCLUSION: Our results suggest that serum Fet-A level could be a novel biomarker for assessment of activity status in patients with GPA or TA. Key Points • Serum Fetuin-A is negative acute phase protein and systemic calcification inhibitor synthesized in hepatocytes and secreted by various inflammation. • Serum Fetuin-A was negatively correlated with CRP, BVAS, and ITAS scores and significantly decreased in vasculitis patients with high disease activity. • Serum Fetuin-A could be a promising and useful biomarker for the assessment of disease activity for vasculitis, also that it might also be a predictor of long-term cardiovascular progression.

The impact of anti-TNF treatment on Wnt signaling, noggin, and cytokine levels in axial spondyloarthritis.

INTRODUCTION: Anti-tumor necrosis factor (anti-TNF) agents are commonly used in treatment of axial spondyloarthritis (axSpA), but clinical and radiological improvement is not achieved in all patients. We aimed to investigate the impact of anti-TNFs on inflammatory and noninflammatory parameters in patients with axSpA. METHODS: In this longitudinal study, 30 biologic naïve axSpA patients with high disease activity and 30 healthy controls were enrolled. All patients were treated with anti-TNF agents for 6 months. ASDAS-CRP, BASDAI, BASFI, BASMI, patient and physician global assessments were evaluated. C-reactive protein, COX2, TNF-α IL-6, IL-17, IL-22, IL-23, IL-33, sclerostin, dickkopf-1, and noggin levels were evaluated at baseline and at 6 months of anti-TNF treatment. RESULTS: At baseline, axSpA patients had significantly higher median (IQR) TNF-α levels, 34.4 (31.4-37.03) vs. 18.1 (12.1-28.4) pg/ml (p < 0.001), and lower DKK1, 446.7 (356.9-529.3) vs. 1088.7 (951.7-1244.4) pg/ml, and sclerostin, 312.4 (140.8-412.7) vs. 412.3 (295.4-512.8) pg/ml, compared to healthy controls (all p < 0.001). The median (IQR) serum levels of IL-17, IL-22, and IL-33 increased significantly after 6 months of anti-TNF treatment, from 93.3 (85.1-104.8) to 102.1 (86.6-114.6) pg/ml (p = 0.026), 159.2 (151.9-178.4) to 183.5 (156.3-304.6) pg/ml (p = 0.033), and 127.8 (106.6-186.1) to 147.06 (128.5-213.4) pg/ml (p = 0.016), respectively. Sclerostin and DKK-1 levels increased significantly after anti-TNF treatment from 312.4 (140.8-412.7) to 405.1 (276.3-452.5) pg/ml (p = 0.018) and 446.7 (356.9-529.3) to 881.3 (663.1-972.2) pg/ml (p < 0.001), while there was no significant change in noggin level. CONCLUSIONS: Many inflammatory cytokines increase after anti-TNF treatment and noggin is not affected by anti-TNF treatment in AxSpA. Noggin might be a therapeutic target in patients with axSpA. KEY POINTS: • Anti-TNF therapy is not sufficient for complete blockage of the inflammatory process in axial spondyloarthritis. • The increase in IL-17, IL-22, and IL-33 may decrease the efficiency of anti-TNF therapy. • Noggin might be a therapeutic target as a complementary or alternative approach to anti-TNF therapy in axial spondyloarthritis.

Prognostic Value of Tissue-Resident Memory T Cells and Tumor Microenvironmental Features in Resected Pancreatic Adenocarcinoma

Background: Pancreatic ductal adenocarcinoma differs from other solid tumors with its unique immunosuppressive microenvironment and non-immunogenic feature. There are not many studies in the literature investigating the effect of these features on prognosis. Aims: To investigate the prognostic value of tissue-resident memory T cells, tumor microenvironment features, and tumor-associated immune cells in resected pancreatic ductal adenocarcinomas. Study Design: Retrospective cross-sectional study. Methods: Of 138 patients diagnosed with pancreatic ductal adenocarcinoma between 2011 and 2018, 81 were included in the study. Specimens from operated patients were reassessed separately as peritumoral and intratumoral areas for tissue resident memory cells and tumor microenvironmental elements (tumor infiltrating lymphocytes, tumor stroma, CD204+ macrophages, PDL1+ immune cells). Disease-free survival and overall survival were defined from the date of operation to the date of recurrence and the date of first diagnosis to the date of death, respectively. If the patient was alive, the last visit date was taken into account. Results: The median age at diagnosis was 63 (range: 40-78). The median follow-up period was 18.9 months (range: 1.4-80.4 months). Median overall survival was 23.7 months (1.4-80.4 months) and median disease-free survival was 10.8 months (1.4-74.4 months). Patients with higher intra-tumoral tissue-resident memory cell counts had a longer survival trend than those having lower values (25.6 months vs. 18 months, respectively, P = .84). According to microenvironmental evaluations, lower stromal score (defined as stroma having less desmoplasia and rich in cells) and presence of peritumoral Crohn's-like inflammatory response were associated with higher survival (29.2 months vs. 19.7 months for low vs. high stromal scores, respectively, P = .16 and 30.2 months vs. 18.1 months for the presence of Crohn's-like inflammatory response P = .13). Decreased survival was observed in tumors with increased CD204+ tumor-associated macrophages which were immunosuppressive elements of the microenvironment (12 months vs. 26.3 months for intra-tumoral assessment, P = .29). Conclusion: Tissue-resident memory T cells and other microenvironmental features may be prognostic in resectable pancreatic ductal adenocarcinomas. Further studies with larger cohorts are needed for validation.

Diagnostic utility of serum biomarkers in large vessel vasculitis and their correlation with positron emission tomography.

OBJECTIVES: To investigate the association between vascular inflammation, as detected by positron emission tomography (PET) imaging and interleukin-6 (IL-6), pentraxin3, and B-cell-activating factor (BAFF) in subjects with LVV. METHODS: The study included newly diagnosed giant cell arteritis (GCA, n = 27) or Takayasu arteritis (n = 9) patients and healthy control (HC, n = 31) subjects. PET scan and blood samples were obtained before the introduction of treatments. IL-6, PTX3, and BAFF levels were determined quantitatively by enzyme-linked immunosorbent assay kits. RESULTS: Thirty-six patients with LVV (20 females, 16 males; age 64.5 ± 16.6 years) and 31 HC (14 females, 17 males; age 37.1 ± 9.6 years) were included. Serum levels of IL-6, PTX3, and BAFF were increased in patients with newly diagnosed LVV compared with healthy control subjects. In receiver operating characteristics (ROC) analysis, serum IL-6 and BAFF provided excellent discrimination of newly diagnosed LVV patients from HC (area under the ROC curve of >0.90 and >0.80, respectively). None of the inflammatory markers correlated with vascular inflammatory activity determined by PET scanning. CONCLUSIONS: Our results suggest that IL-6 and BAFF may serve as markers of large vessel vasculitis, while PTX3 is not useful. None of the inflammatory markers correlated with PET assessed vasculitis activity.

Angiogenesis and Anti-Angiogenic Treatment in Prostate Cancer: Mechanisms of Action and Molecular Targets.

Prostate cancer (PC) is the most common cancer in men and the second leading cause of cancer-related death worldwide. Many therapeutic advances over the last two decades have led to an improvement in the survival of patients with metastatic PC, yet the majority of these patients still succumb to their disease. Antiagiogenic therapies have shown substantial benefits for many types of cancer but only a marginal benefit for PC. Ongoing clinical trials investigate antiangiogenic monotherapies or combination therapies. Despite the important role of angiogenesis in PC, clinical trials in refractory castration-resistant PC (CRPC) have demonstrated increased toxicity with no clinical benefit. A better understanding of the mechanism of angiogenesis may help to understand the failure of trials, possibly leading to the development of new targeted anti-angiogenic therapies in PC. These could include the identification of specific subsets of patients who might benefit from these therapeutic strategies. This paper provides a comprehensive review of the pathways involved in the angiogenesis, the chemotherapeutic agents with antiangiogenic activity, the available studies on anti-angiogenic agents and the potential mechanisms of resistance.

Unraveling the Wide Spectrum of Melanoma Biomarkers.

The use of biomarkers in medicine has become essential in clinical practice in order to help with diagnosis, prognostication and prediction of treatment response. Since Alexander Breslow's original report on "melanoma and prognostic values of thickness", providing the first biomarker for melanoma, many promising new biomarkers have followed. These include serum markers, such as lactate dehydrogenase and S100 calcium-binding protein B. However, as our understanding of the DNA mutational profile progresses, new gene targets and proteins have been identified. These include point mutations, such as mutations of the BRAF gene and tumour suppressor gene tP53. At present, only a small number of the available biomarkers are being utilised, but this may soon change as more studies are published. The aim of this article is to provide a comprehensive review of melanoma biomarkers and their utility for current and, potentially, future clinical practice.

Phenotypic characterization of Familial Mediterranean Fever patients harboring variants of uncertain significance

Background/aim: Familial Mediterranean Fever (FMF) is the prototype of hereditary autoinflammatory disorders and caused by mutations on the MEFV gene located on the short arm of chromosome 16. Although some MEFV variants are clearly associated with disease phenotype, there are numerous variants with unknown clinical association which are termed as variants of uncertain significance (VUS). Here, we present clinical correlations of VUS in a large cohort of adult FMF patients from three tertiary centers located in Central Anatolia. Materials and methods: All patients were recruited from FMF in Central Anatolia (FiCA) cohort. Demographic (sex, age at disease onset) and clinical features (disease characteristics, attack frequency, mean colchicine dose, colchicine nonresponsiveness, amyloidosis, and persistent inflammation) of patients with VUS were compared with those harboring pathogenic variants. Disease severity and damage were also evaluated using international severity score for FMF (ISSF) and autoinflammatory disease damage index (ADDI), respectively. Results: Among 971 participants included, MEFV gene analysis results were available for 814 patients. Twenty-six (3.2%) patients had single heterozygous VUS and 54 (6.6%) had pathogenic/VUS complex heterozygous variants. Patients with single heterozygous VUS had similar demographic/clinical features, ISSF and ADDI scores compared to those with single heterozygous pathogenic variant (p > 0.05 for all). No difference was observed in the demographic and clinical features of patients with single heterozygous pathogenic mutation and pathogenic/VUS complex heterozygous variant (p > 0.05 for all). ISSF and ADDI scores were lower in pathogenic/VUS complex heterozygous patients than those harboring single pathogenic mutation (p = 0.006 and 0.004, respectively). Conclusion: Our findings suggest that patients with single heterozygous VUS has mild FMF phenotype similar to those with single pathogenic mutation. Pathogenic/VUS complex heterozygosity does not lead to a more severe clinical phenotype than having a single pathogenic variant.

Appendectomy history is associated with severe disease and colchicine resistance in adult familial Mediterranean fever patients

Background/aim: Peritonitis attacks of Familial Mediterranean Fever (FMF) usually requires emergency medical admissions and it's hard to distinguish a typical abdominal attack from surgical causes of acute abdomen. Therefore, history of abdominal surgery, particularly appendectomy, is very common in patients with FMF. However, history of appendectomy might also give some clues about the course of FMF in the adulthood. This study was to determine whether the history of appendectomy help to anticipate disease course of FMF in the adulthood. Materials and methods: All patients recruited from FMF in Central Anatolia (FiCA) cohort, comprising 971 adult subjects. All patients fulfilled the Tel Hashomer criteria. Demographic data, FMF disease characteristics, co-morbid conditions, past medical history, surgical history and disease complications were meticulously questioned and laboratory features and genotype data (if available) were recruited from patient files. Results: Appendectomy history was evident in 240 (24.7%) subjects. Disease onset was earlier and peritonitis is strikingly more prevalent (97.1% vs. 89.6%, p < 0.001) in appendectomized patients. These patients had reported almost two fold more frequent attacks in the last year compared to appendix intact patients (median 3.5 vs. 2 attacks, p = 0.001) without a difference in frequency of musculoskeletal and skin attacks. Severe disease was more common (10% vs. 5.9%, p = 0.038) due to involvement of more attack sites throughout the life and more frequent attacks. Appendectomy patients had used higher daily doses of colchicine to control disease (1.43 ± 0.6 mg vs. 1.27 ± 0.52 mg, p = 0.002) but colchicine resistance was also more common in these patients, 15% vs. 6.7% respectively, p < 0.001. Conclusion: Appendectomy history is common in FMF patients and associated with frequent serositis attacks in adulthood. These patients require higher colchicine doses with a lower rate of response and more need for Interleukin-1 antagonist therapies.

Predictors of persistent inflammation in familial Mediterranean fever and association with damage.

OBJECTIVE: Persistent inflammation is an insidious and less studied feature of FMF. We investigated clinical determinants of persistent inflammation and its associations with individual damage items. METHODS: This is a cross-sectional analysis of 917 FMF patients, who fulfilled the Tel Hashomer criteria and had at least 6 months' follow-up. Patients were stratified based on whether they had persistent inflammation. We used logistic regression analysis to investigate independent predictors of persistent inflammation and the associated individual damage items. RESULTS: One hundred and forty-two (15%) patients had persistent inflammation. Active FMF (54%) was the most prominent reason for the persistent inflammation. Spondylarthritis (16%), other inflammatory arthritis (8%) and IBD (2%) were other frequent reasons. Male gender, history of exertional leg pain, inflammatory comorbidities, M694V homozygosity, colchicine resistance, lower education levels and musculoskeletal attack dominance were found to be the independent predictors of persistent inflammation. Earlier disease onset led to a tendency towards persistent inflammation. Patients with persistent inflammation were more likely to suffer damage. There is an increased risk of developing proteinuria, amyloidosis and renal insufficiency. CONCLUSION: We identified, for the first time, the predictors of persistent inflammation in adult FMF patients and related individual damage items of the Autoinflammatory Disease Damage Index. Persistent inflammation is insidious and one of the chief causes of damage; therefore, especially patients with these predictors should be followed up more closely. If detected, underlying inflammatory comorbidities should be assessed meticulously as early detection and proper treatment strategies may favourably impact the natural history of the disease.

Diagnostic Role of 18F-Fluorodeoxyglucose Positron Emission Tomography for the Evaluation of Patients With Inflammation of Unknown Origin.

BACKGROUND: Sometimes, the underlying causes of inflammation cannot be established despite meticulous investigation, including medical history, physical examination, laboratory tests, and radiologic procedures. Rheumatologists are often faced with patients whose condition is known as inflammation of unknown origin (IUO). Differential diagnosis of IUO is diverse, and investigation of these cases is challenging and time-consuming. OBJECTIVE: The study aimed to assess the diagnostic role of positron emission tomography/computed tomography (PET/CT) in the evaluation of patients with IUO. METHODS: The study sample consisted of 97 adult patients with IUO who have not been previously diagnosed with an infectious, inflammatory, or malignant disease. The necessary data were collected from January 2015 to June 2018 with a 6-month follow-up period. The patients were screened using PET/CT after a specific diagnosis could not be established with detailed laboratory and radiologic evaluations. RESULTS: A final diagnosis was established at follow-up, and 47 (54%) of the 97 patients had inflammatory diseases, 30 (34.4%) had malignancies, and 10 (11.4%) had infections. Despite meticulous investigation, 10 patients were left undiagnosed in the follow-up. PET/CT aided diagnosis in 59 patients (60.8%), but it was not helpful in 38 patients (39.2%). PET/CT was positive in 30 (63%) of the 47 patients with inflammatory diseases, whose final diagnosis was inflammatory rheumatic disease, as follows: large-vessel vasculitis in 19 patients, polymyalgia rheumatica in 7 patients, and seronegative arthritis or other rare miscellaneous diseases in 4 patients. The sensitivity of PET/CT was 67% with a specificity and diagnostic accuracy of 100% and 71%, respectively. CONCLUSIONS: Investigation of the underlying etiology of IUO is time-consuming and challenging. PET/CT may help identify the final diagnosis more quickly by locating an obscure inflammatory site; thus, it may reduce the number of unnecessary biopsies, diagnostic time, anxiety, work loss, morbidity, and mortality.