INTRODUCTION:Rituximab-cyclophosphamide-doxorubicin-vincristine-prednisolone (R-CHOP) is a standard first-line treatment in large B-cell lymphoma (LBCL). Dose intensity is frequently reduced because of toxicity or concerns of tolerability. The true impact of such treatment modifications on the response rates is difficult to assess in nonrandomized comparisons because of complex and reciprocal interactions between various determinants of both variables. To avoid these confounding biases, this study was designed to analyze subsequent outcomes after a complete response is achieved with frontline therapy, aiming to uncover an independent link between R-CHOP dose-intensity and long-term outcomes in LBCL. METHODS:Patients treated between 2012 and 2024 were included. Reduced dose-intensity was predefined as more than 20% dose reduction for any one of the drugs for two cycles or a cumulative delay of ≥21 days. The primary and secondary objectives were the duration of complete response and the cumulative incidence of relapse (CIR), respectively. RESULTS:The LBCL cohort consisted of 1369 consecutive cases. For this study, 953 were eligible, with 728 and 225 patients in the dose-intense and reduced-intensity groups, respectively. Duration of complete response was significantly longer for the dose-intense group with a 3-year estimate of 87.8% vs 68.8% (hazard ratio: 0.39, p < .0001). The estimated 3-year cumulative incidence of relapse was 10.3% vs 21.4% (hazard ratio: 0.51, p = .004), favoring the dose-intense group. Reduced dose intensity was an independent risk factor on multivariate analysis for both endpoints. CONCLUSIONS:Focusing on long-term outcomes after CR, this study demonstrates an increased risk of relapse when R-CHOP intensity is reduced, providing novel evidence that complements the association between reduced treatment intensity and inferior LBCL outcomes.

Objective:Diffuse large B-cell lymphoma (DLBCL) is a biologically heterogeneous disease that is classified into germinal center B-cell (GCB) and non-GCB subtypes, which are prognostically different. The Hans algorithm is the most widely used tool based on CD10, BCL6, and MUM1 expression, but some cases with the non-GCB phenotype are still known to be misclassified. In this study, we investigate the extent to which GCET1, HGAL, and LMO2 protein expressions reflect GCB phenotype together with their roles in determining the GCB phenotype of DLBCL and their contributions to the performance of the Hans algorithm.Materials and Methods:Sixty-five cases of DLBCL-not otherwise specified, 40 cases of follicular lymphoma (FL), and 19 non-GC-derived lymphoma cases were included in this study. The DLBCL cases were grouped as CD10+ (Group A) or only MUM1+ (Group B), and the remaining cases constituted the intermediate group (Group C). GCET1, HGAL, and LMO2 expressions were evaluated.Results:In the FL group, GCET1, HGAL, and LMO2 were positive in 85%, 77.5%, and 100% of the cases, respectively. Among the non-GC-derived lymphoma cases, all three markers were negative in cases of small lymphocytic lymphoma, plasmablastic lymphoma, peripheral T-cell lymphoma, and anaplastic large cell lymphoma. GCET1 and HGAL were negative in cases of marginal zone lymphoma (MZL) and mantle cell lymphoma (MCL). Two of the 3 MZL and 2 of the 4 MCL cases were positive for LMO2. In the DLBCL group, the number of cases with GCET1, HGAL, and LMO2 positivity was 18 (90%), 17 (85%), and 20 (100%), respectively, in Group A and 0 (0%), 2 (13.3%), and 2 (13.3%), respectively, in Group B. Considering these rates, when the cases in the intermediate group were evaluated, it was concluded that 13 cases typed as non-GCB according to the Hans algorithm may have the GCB phenotype.Conclusion:GCET1, HGAL, and LMO2 are highly sensitive markers for determining the germinal center cell phenotype and can increase the accuracy of the subclassification of DLBCL cases, especially for cases that are negative for CD10.

BACKGROUND Granulocytic sarcoma (GS) is an extramedullary solid tumor composed of immature myeloid cells. GS has been associated with acute myeloid leukemia (AML), myelodysplastic syndromes or myeloproliferative diseases. Although GS can affect various tissues of the human body, it has rarely been reported in other soft tissues such as the breast, gastrointestinal, respiratory and genitourinary tracts. We report a pediatric case diagnosed with granulocytic sarcoma of the bladder and concomitant AML. CASE A twelve-year-old previously healthy girl was admitted to the pediatric urology clinic with a ten-day history of hematuria and pollakiuria. Laboratory examinations revealed anemia, thrombocytopenia and neutrophilic leukocytosis. Bone marrow aspiration results were consistent with acute myeloid leukemia -FAB subtype M2-. Abdominal magnetic resonance imaging (MRI) showed an irregularly bounded 12 cm mass on the right side of the bladder. Transurethral resection (TUR) pathology was consistent with granulocytic sarcoma. After a multimodal treatment approach, complete remission was achieved. CONCLUSIONS Malignant bladder masses are rare causes of macroscopic hematuria in childhood. The diagnostic spectrum is wide, ranging from rhabdomyosarcoma to leukemia involvement. The bladder is a rare site of extramedullary involvement in pediatric patients with AML. Multimodal treatment should be considered on a per-patient basis.

Primary central nervous system lymphoma (PCNSL) is a highly aggressive non-Hodgkin lymphoma confined to the central nervous system. Diffuse large B cell lymphoma (DLBCL) is the most common subtype, and it follows a much more aggressive course than its systemic counterpart. Differential diagnosis of PCNSL and systemic DLBCL depends on clinical staging, which is expensive and time consuming. Protein kinase C delta (PKCD) is a protein with proapopitotic properties and has a major role in negative selection of B cells in germinal centers, a regulatory function in B cell receptor (BCR) pathway and MHC II expression. Mutations identified in its gene are reported to be unique for PCNSL and not encountered in systemic DLBCL. Our aim is to evaluate immunohistochemical (IHC) expression and the mutation status of PKCD in PCNSLs and systemic DLBCLs in order to find out whether PKCD could be a novel marker that could be used in differential diagnosis of both entities. A total of 43 cases diagnosed with PCNSL, and 43 cases diagnosed with systemic DLBCL were included in the study. Immunohistochemistry for PKCD antibody and Sanger sequencing targeting exon 16 and exon 18 of PKCD gene were performed. Although immunoreactivity for PKCD was observed in all PCNSL and 95.3% of systemic DLBCL cases, strong and diffuse staining was found to be more frequent in PCNSL than systemic diffuse large B cell lymphomas (p < 0.001). However, mutations defined in literature were not encountered in our cohort. While clinical staging is still the primary way for differential diagnosis of PCNSL and systemic DLBCL, the diffuse and strong PKCD expression can be used as a supportive feature for PCNSL diagnosis.

Background. Chemotherapy with high dose methotrexate is the mainstay of treatment for Burkitt lymphoma (BL), especially to manage central nervous system (CNS) disease. However, methotrexate administration requires close drug level monitoring for appropriate folinic acid rescue, which might not be readily available in all centers. In this study, we assessed the long-term treatment outcomes of a modified Non-Hodgkin lymphoma (NHL)-Berlin-Frankfurt-Munster (BFM) 90 regimen in pediatric high-risk BL without CNS involvement. Methods. Between 1999 and 2011, 42 patients (median age: 7 years) with advanced-stage BL were treated with modified NHL-BFM 90 regimen (methotrexate at a dose of 1 g/m2). Demographic data, stage, lactate dehydrogenase (LDH) and treatment results were retrospectively evaluated. The patients were assessed for toxicity, survival and CNS recurrence. Results. Thirty-six patients had Stage III and six had Stage IV disease, respectively. The median LDH level was 1,432 IU/L. Four patients died of infectious and metabolic complications. One patient had local recurrence at the 48 < sup > th < /sup > month of the follow-up and he is in the second remission for 72 months. In Kaplan-Meier analysis, the overall survival and event-free survival rates at 10 years were found as 90 % and 88 %, respectively. None of our patients died of treatment failure. Conclusions. The administration of the reduced dose of methotrexate seems to not compromise treatment success nor increase the risk of CNS recurrence in high-risk BL without CNS involvement. The limitation of the study is that it is not randomized. Our treatment scheme might be considered for centers without methotrexate measurement facility.

Purpose Autosomal recessive (AR) CARD9 deficiency is an inherited immune disorder which results in impaired innate immunity against various fungi. Superficial and invasive fungal infections, mainly caused by Candida or Trichophyton species, are the hallmark of CARD9 deficiency. Together with the increasing number of CARD9-deficient patients reported, different pathogenic fungal species have been described such as Phialophora, Exophiala, Corynespora, Aureobasidium, and Ochroconis. Saprochaete capitata is an opportunistic infectious agent in immunocompromised patients and is a common cause of invasive fungal disease in patients with hematological malignancies. In this study, we investigated the causative genetic defect in a patient with S. capitata fungal infection which disseminated to lymph nodes and common bile duct. Methods The identification of the isolated yeast strain was made by direct microscopic examination and confirmed by internal transcribed spacer (ITS) sequencing. We applied whole exome sequencing to search for the disease-causing mutation. Sanger sequencing was used to validate the mutation in the patient and his parents. Results S. capitata was isolated from the biopsy specimen as the causative microorganism responsible for the invasive fungal disease in the patient. Whole exome sequencing revealed a homozygous c.883C > T, (p.Q295*) mutation in CARD9, confirmed by Sanger sequencing. Conclusions This is the first report of invasive Saprochaete infection associated with autosomal recessive (AR) CARD9 deficiency in the literature and thereby further extends the spectrum of fungal diseases seen in these patients.

Myasthenia gravis (MG) is an autoimmune disease mediated by autoantibodies predominantly against the acetylcholine receptor (AChR). Specific T cell subsets are required for long-term antibody responses, and cytokines secreted mainly from CD4+ T cells regulate B cell antibody production. The aim of this study was to assess the differences in the cytokine expressions of CD4+ T cells in MG patients with AChR antibodies (AChR-MG) and the effect of immunosuppressive (IS) therapy on cytokine activity and to test these findings also in MG patients without detectable antibodies (SN-MG). Clinically diagnosed AChR-MG and SN-MG patients were included. The AChR-MG patients were grouped as IS-positive and -negative and compared with age- and sex-matched healthy controls. Peripheral blood mononuclear cells were used for ex vivo intracellular cytokine production, and subsets of CD4+ T cells and circulating follicular helper T (cTfh) cells were detected phenotypically by the expression of the chemokine and the costimulatory receptors. Thymocytes obtained from patients who had thymectomy were also analyzed. IL-21, IL-4, IL-10, and IL-17A productions in CD4+ T cells were increased in AChR-MG compared to those in healthy controls. IS treatment enhanced IL-10 and reduced IFN-γ production in AChR-MG patients compared to those in IS-negative patients. Increased IL-21 and IL-4 productions were also demonstrated in SN-MG patients. Among CD4+ T cells, Th17 cells were increased in both disease subgroups. Treatment induced higher proportions of Th2 cells in AChR-MG patients. Both CXCR5+ and CXCR5− CD4+ T cells expressed higher programmed cell death protein 1 (PD-1) and inducible costimulatory (ICOS) in AChR-MG and SN-MG groups, mostly irrespective of the treatment. Based on chemokine receptors on CXCR5+PD-1+ in CD4+ T (cTfh) cells, in AChR-MG patients without treatment, the proportions of Tfh17 cells were higher than those in the treated group, whereas the Tfh1 cells were decreased compared with those in the controls. The relevance of CXCR5 and PD-1 in the pathogenesis of AChR-MG was also suggested by the increased presence of these molecules on mature CD4 single-positive thymocytes from the thymic samples. The study provides further evidence for the importance of IL-21, IL-17A, IL-4, and IL-10 in AChR-MG. Disease-related CD4+T cells are identified mainly as PD-1+ or ICOS+ with or without CXCR5, resembling cTfh cells in the circulation or probably in the thymus. AChR-MG and SN-MG seem to have some similar characteristics. IS treatment has distinctive effects on cytokine expression.

Objective:Angiotensin II promotes growth and angiogenesis via type 1 receptors (AGTR1) in certain tumors. In this study, we examine the bone marrow AGTR1 expression in multiple myeloma (MM) and its relationship with the regulation of angiogenesis and prognostic factors.Materials and Methods:Bone marrow AGTR1 mRNA levels of 39 MM patients and 15 healthy controls were analyzed with quantitative RT-PCR. Immunohistochemical staining of the tissue vascular endothelial growth factor (VEGF), CD34, and factor VIIIrAg (fVIIIrAg) was used to assess bone marrow angiogenesis.Results:Bone marrow samples of the patients showed increased VEGF, fVIIIrAg, and CD34 staining and higher AGTR1 expression levels when compared to controls. Patients with severe-diffuse bone marrow infiltration showed higher bone marrow VEGF, fVIIIrAg, CD34, and AGTR1 mRNA levels when compared to other patients.Conclusion:AGTR1 expression was found positively correlated with plasma β2-microglobulin level and patients with increased AGTR1 expression showed increased bone marrow CD34 levels.

Dermatologic TherapyVolume 32, Issue 1 e12759 Therapeutic Hotline: Letter A case report demonstrating potential utility of topical imiquimod for cutaneous Rosai–Dorfman disease Ayse S. Karadag, Ayse S. Karadag Department of Dermatology, Istanbul Medeniyet University, Goztepe Research and Training Hospital, Istanbul, TurkeySearch for more papers by this authorBurak Tekin, Corresponding Author Burak Tekin buraktekin@hotmail.com orcid.org/0000-0002-2330-1215 Department of Dermatology, Istanbul Medeniyet University, Goztepe Research and Training Hospital, Istanbul, Turkey Correspondence Burak Tekin, Department of Dermatology, Istanbul Medeniyet University, Goztepe Research and Training Hospital, Dr.Erkin Street, 34722, Kadikoy, Istanbul, Turkey. Email: buraktekin@hotmail.comSearch for more papers by this authorOzge Hurdogan, Ozge Hurdogan Pathology Department, Istanbul University, Istanbul Medical Faculty, Istanbul, TurkeySearch for more papers by this authorDeniz Dagdelen, Deniz Dagdelen Department of Dermatology, Istanbul Medeniyet University, Goztepe Research and Training Hospital, Istanbul, TurkeySearch for more papers by this authorOner Dogan, Oner Dogan Pathology Department, Istanbul University, Istanbul Medical Faculty, Istanbul, TurkeySearch for more papers by this authorNesimi Buyukbabani, Nesimi Buyukbabani Pathology Department, Istanbul University, Istanbul Medical Faculty, Istanbul, TurkeySearch for more papers by this author Ayse S. Karadag, Ayse S. Karadag Department of Dermatology, Istanbul Medeniyet University, Goztepe Research and Training Hospital, Istanbul, TurkeySearch for more papers by this authorBurak Tekin, Corresponding Author Burak Tekin buraktekin@hotmail.com orcid.org/0000-0002-2330-1215 Department of Dermatology, Istanbul Medeniyet University, Goztepe Research and Training Hospital, Istanbul, Turkey Correspondence Burak Tekin, Department of Dermatology, Istanbul Medeniyet University, Goztepe Research and Training Hospital, Dr.Erkin Street, 34722, Kadikoy, Istanbul, Turkey. Email: buraktekin@hotmail.comSearch for more papers by this authorOzge Hurdogan, Ozge Hurdogan Pathology Department, Istanbul University, Istanbul Medical Faculty, Istanbul, TurkeySearch for more papers by this authorDeniz Dagdelen, Deniz Dagdelen Department of Dermatology, Istanbul Medeniyet University, Goztepe Research and Training Hospital, Istanbul, TurkeySearch for more papers by this authorOner Dogan, Oner Dogan Pathology Department, Istanbul University, Istanbul Medical Faculty, Istanbul, TurkeySearch for more papers by this authorNesimi Buyukbabani, Nesimi Buyukbabani Pathology Department, Istanbul University, Istanbul Medical Faculty, Istanbul, TurkeySearch for more papers by this author First published: 04 October 2018 https://doi.org/10.1111/dth.12759Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume32, Issue1January/February 2019e12759 RelatedInformation

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Fig. 1. A triphasic bone scan scintigraphy showed increased late-phase activity in the frontal and parietal bones, right hip joint, right femoral condyle, right proximal, distal epiphyses of the tibia, and right tarsal bones. BLOOD RESEARCH Volume 53ᆞNumber 3ᆞSeptember 2018

Objective: Chronic lymphocytic Leukemia (CLL) is the most common form of leukemia in adults. Clinical findings may broad range vary. Detecting some deletions using the FISH method may help us to foresee the progression of the disease and to choose a better treatment method in healing the patient. Case: In this case report, we will present you a CLL patient with t(7;14), t(14;19) and 17p deletions, which are known for bad prognosis, developing autoimmune hemolytic anemia which is refractor to the treatment. This patient unfortunately died due to a clinical form of hemophagocytic syndrome including prolymphocytic transformation.

Background Bone marrow involvement (BMI) affects the lymphoma stage, survival, and treatment. Bone marrow biopsy (BMB) and fluorodeoxyglucose (FDG) positron emission tomography- computed tomography (PET/CT) are useful techniques to detect BMI. Both have advantages and disadvantages. We aimed to identify factors that could be used to predict BMI with positive and negative results on PET/CT compare them with BMB in newly diagnosed patients with lymphoma. Methods We included 22 non-Hodgkin and 16 Hodgkin lymphoma patients in this single center study. All patients had PET/CT examination and BMB before treatment. BMI in BMB was reported as negative or positive. Bone marrow was classified into 3 types by FDG uptake on PT/CT; diffuse involvement, focal involvement, and normal bone marrow. Results PET/CT and BMB results were concordant (7 positive, 15 negative) in 22 patients (57%). We evaluated concordant and discordant patient characteristics and risk-stratified patients for BMI. Our findings suggest that patients with diffuse FDG uptake on PET/CT, especially patients with advanced age and low platelet and white blood cell counts, are likely to have BMI and could potentially forego BMB. Patients with negative PET/CT findings and no significant laboratory abnormalities are very unlikely to have BMI. Conclusion Our results suggest that BMI should not be decided solely based PET/CT or BMB findings. It is reasonable to use both diagnostic assays along with clinical and laboratory findings. PET/CT result, clinical and laboratory findings could be useful for predicting BMI in patient for whom BMB is contraindicated.

B cells may contribute to the pathogenesis of myasthenia gravis with anti-acetylcholine antibodies (AChR+ MG) by co-stimulation or selection of T cells. In this study, we investigated costimulatory molecules on B cells in the blood and in the thymus as well as by TLR9 and IL-21 stimulations in AChR+ MG patients with or without immunosuppressive treatment and controls. CD80 and CD86 expression on B cells was increased in the peripheral blood and in the thymus of untreated patients. CD86 was further amplified by IL-21. A role for activated B cells, active thymic environment and IL-21 is implicated in MG.

Overexpression of DEK oncogene is associated with increased proliferation of carcinoma cells and it is observed in several solid tumors due to the amplification of the 6p22.3 chromosomal region where DEK locates. Although the same chromosomal amplification occurs in multiple myeloma (MM), a plasma cell neoplasm, whether the expression and the copy number of the DEK gene are affected in MM remains elusive. We show that despite the increased copy number in CD138positive MM cells (4 out of 41 MM samples), DEK mRNA expression was down-regulated compared with that in CD138negative bone marrow (BM) cells of the same patients (P<0.0001). DEK protein was not detectable by immunohistochemistry (IHC) in CD138positive normal plasma cells or in malignant plasma cells of MM patients (n = 56) whereas it was widely expressed in normal and neoplastic B-cells. Stable knockdown or overexpression of DEK in CD138positive MM cell lines did not affect the proliferation and viability of the cells profoundly in the presence or absence of chemotherapeutic agent melphalan whereas knockdown of DEK moderately but significantly increased the expression level of CD138 (p<0.01). Decreased DEK expression in plasma cells suggests a potential role of this gene in plasma cell development and lack of detectable DEK protein by IHC could be used as a biomarker for normal and malignant plasma cells.

Background. Lymphomas and leukemias may rarely present as bone tumors and may mimick Ewing's Sarcoma.

Objective: It is widely known that myocardial damage is not immediately terminated after the elimination of epicardial occlusion in cases of myocardial infarction. In situ thrombosis during epicardial occlusion might contribute to poor myocardial perfusion after reperfusion of an occluded epicardial artery. In the current study, we sought to determine the effects of ischemia and reperfusion on microvascular thrombotic occlusion.Methods: Thirty male Wistar rats were included in the study. After the rats had been anesthetized and thoracotomized, the left coronary artery was occluded for 30 minutes in the first group, and it was occluded for 30 minutes and reperfused for an additional 20 minutes in the second group. Ten rats were used as a sham-operated control group. After completion of the study protocol, excised heart preparations were analyzed by immunohistochemistry and electron microscopy.Results: A significant difference was found between the infarction plus reperfusion group and the other 2 groups, with respect to microvascular fibrin and thrombocyte deposition in immunohistochemistry analysis. These results were confirmed by morphological examination with electron microscopy.Conclusion: In situ fibrin formation accompanies microvascular obstruction in acute myocardial infarction. Our results indicate that additional therapeutic approaches are needed in order to achieve better tissue perfusion in contemporary treatment of acute myocardial infarction after successful reopening of the infarct-related artery.

This study aims to investigate genetic susceptibility to early-onset and late-onset anti-acetylcholine receptor antibody positive myasthenia gravis (EOMG and LOMG) and anti-muscle specific kinase antibody positive MG (MuSK-MG) at genome-wide level in a single population. Using a custom-designed array and imputing additional variants and the classical HLA alleles in 398 patients, we detected distinct associations. In EOMG, rs113519545 in the HLA class I region (OR = 5.71 [3.77–8.66], P = 2.24 × 10− 16), HLA-B*08:01 (OR = 7.04 [3.95–12.52], P = 3.34 × 10− 11) and HLA-C*07:01 (OR = 2.74 [1.97–3.81], P = 2.07− 9), in LOMG, rs111256513 in the HLA class II region (OR = 2.22 [1.59–3.09], P = 2.48 × 10− 6) and in MuSK-MG, an intronic variant within HLA-DQB1 (rs68081734, OR = 5.86, P = 2.25 × 10− 14) and HLA-DQB1*05:02 (OR = 8.56, P = 6.88 × 10− 13) revealed the most significant associations for genome-wide significance. Differential genetic susceptibility within the HLA to EOMG, LOMG and MuSK-MG has been established in a population from Turkey.

a Department of Physiology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey b Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA c Division of Health Science and Technology, Harvard Medical School, Boston, MA, USA d Department of Neurology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey e Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA f Department of Neurology, Bakirkoy Research and Training Hospital for Psychiatric and Neurological Diseases, Istanbul, Turkey g Department of Neurology, Cerrahpaşa Medical Faculty, Istanbul University, Istanbul, Turkey h Department of Pathology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey i Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany

Premise: There may be signs of joint and bone involvement in hematologic malignancies, but it is most rare for hematologic malignancies like lymphomas to present with joint symptoms. Patient: A 49-year-old male patient was admitted with rheumatoid arthritis-like symmetrical polyarthritis, morning stiffness, cutaneous vasculitis and hypereosinophilia. Autoantibodies, like rheumatoid factor, anti-citrullinated cyclic peptide, antinuclear antibody, anti-nuclear cytoplasmic antibody, were negative. After 4 months of follow-up, the patient developed a diffuse cutaneous rash and multiple lymphadenopathies. Lymph node biopsy was compatible with peripheral T-cell lymphoma, unspecified. Result: The patient was administered, respectively, CHOP and ICE chemotherapy regimens to which he was refractory. He died from infection and respiratory failure. Conclusion: It should be borne in mind that T-cell lymphomas may have unusual presentations with arthritis and hypereosinophilia.