Aggressive Course Research Articles

TNF-α Inhibitor-Induced Psoriasis and Psoriatic Alopecia in Adolescent with Ulcerative Colitis: Clinical Case

Background. Genetically engineered biological therapy has revolutionized the treatment of many chronic inflammatory diseases. It often allows to achieve significant clinical effect and improve the patient's quality of life. However, sometimes it leads to adverse events, and physicians encounter them more often. One of such side effects is paradoxical psoriasis (PP) that can be revealed during the therapy with tumor necrosis factor alpha (TNF-α) inhibitors. PP is the debut or exacerbation of pre-existing psoriasis.Clinical case description. Patient A., 17 years old, has suffered from ulcerative colitis since 2020; biological therapy with infliximab has been initiated in March 2022. Numerous rashes were revealed, as well as development of confluent alopecia foci on the background of scalp psoriatic damage, during the next hospitalization in December 2022. The patient was examined by dermatologist; diagnosis of PP was established according to the clinical picture and medical history. Skin rashes progressed and ulcerative colitis worsened (diarrheal syndrome, fecal calprotectin levels increased up to 526 μg/g) after cessation of infliximab therapy. Biological therapy with the inhibitor IL-12/23 (ustekinumab) was initiated due to the aggressive cutaneous pathological process and the aggravation of inflammatory bowel disease (IBD) symptoms. The gradual regression of rashes with the restoration of scalp hair growth and ulcerative colitis clinical and laboratory remission were noted during the treatment.Conclusion. PP is a rare complication that develops during therapy with TNF-α inhibitors, and it is most often observed in patients with IBD. In our case there was aggressive course of psoriasis with severe scalp lesion and hair loss (it is specific type of lesion in such patients). The ustekinumab, inhibitor IL-12/23, treatment efficacy correlates with the literature data on this drug successful use in both nosologies. Ustekinumab can be a first-line therapy in such pediatric patients. This clinical case is the first case in the Russian literature on effective management of PP and ulcerative colitis with ustekinumab in children.

STAT5-Feedback Controls Distinct Metabolic States for Dynamic Transitions between Cellular Activation and Quiescence in Acute Lymphoblastic Leukemia

Background and significance: B-cell acute lymphoblastic leukemia (B-ALL) is characterized by dynamic shifts between activation and quiescence. These cycles are predicated by fluctuations in oncogenic signaling, which mimic pre-BCR and cytokine receptor signaling, e.g. IL7 receptor signaling and phosphorylation of STAT5. These fluctuations in cytokine receptor and STAT5 signaling are mitigated by powerful feedback regulators, including CISH and SOCS (suppressors of cytokine signaling) family members. While B-ALL cells depend on oncogenic STAT5 signaling, CISH and SOCS2 negative feedback regulators of STAT5 are highly expressed in aggressive B-ALL and high expression levels are strongly linked to poor clinical outcome, positive MRD and increased likelihood of bone marrow relapse in children (COG P9906) and adults (ECOG E2993). To determine whether high levels of CISH and SOCS2 are biomarkers of high oncogenic STAT5 signaling or mechanistically contribute to clonal fitness and adaptability of B-ALL, we performed genetic experiments in mouse models for B-ALL. Here we examined the mechanisms and consequences of active and inactive states of STAT5 by studying constitutively active (CA) and non-phosphorylatable Y694F (YF) mutations of STAT5. Results: Consistent with a central role of STAT5-feedback control in B-ALL survival, inducible ablation of Cishfl/fl resulted in rapid depletion of B-ALL cells. Socs2-/- B-ALL cells rapidly underwent cellular senescence, lacked colony forming and leukemia-initiating capacity in serial transplantation experiments. Likewise direct interference with STAT5-function, by mutations resulting in constitutive activation (STAT5-CA) or an inactive state (STAT5-YF). Consistent with a requirement of adaptive STAT5-feedback control in B-ALL, both Stat5-CA and Stat5-YF resulted in rapid cell death. Induction of Stat5-CA caused accumulation of biomass indicated by their increased cell size, whereas Stat5-YF caused rapid cell shrinkage ( Figure A). To determine whether the mTOR cell growth pathway was responsible for cell death induced by Stat5-CA, we tested whether the genetic deletion of Mtor or pharmacological inhibition of protein synthesis were sufficient to rescue B-ALL cell death. As expected, B-ALL cells retaining intact Mtor rapidly underwent energy crisis and cell death, while genetic deletion of Mtor reversed the toxic effects of Stat5-CA, suggesting that Stat5-CA is associated with excessive protein synthesis and defective ER turnover. Indeed, Stat5-CA increased protein synthesis rate and ER content compared to EV control, and these effects were opposed by Stat5-YF. To compare the metabolic outcomes of Stat5-CA and Stat5-YF, we performed mass spectrometry-based metabolomic analyses ( Figure B). Consistent with the role of mTOR in promoting glycolysis, Stat5-CA increased the content of glycolytic intermediates in B-ALL cells. In contrast, Stat5-YF increased phospholipid intermediates and phosphatidylethanolamine (PtdEtn). Opposed by Myc, Stat5-YF increased the expression levels of Bcl6 and autophagic genes, suggesting that Bcl6-dependent programs promote PtdEtn-LC3B conjugation, thereby autophagosome formation. As expected, microscopic validation with LC3B-GFP reporter revealed that Stat5-YF increased the number of LC3B-GFP puncta, upon pharmacological inhibition of autophagosome-lysosome fusion ( Figure A). Consistent with STAT5-CA promoting Myc- as opposed to STAT5-YF driving Bcl6-dependent programs, a flow cytometry analysis of Myc-eGFP/Bcl6-mCherry dual reporter expression in murine B-ALL cells demonstrated that changes between glycolytic Myc+ and autophagic Bcl6+ states were the direct consequence of Stat5-CA and Stat5-YF induction, respectively. Conclusions: Our results demonstrate feedback regulators of STAT5, including SOCS2 and CISH are not only biomarkers of increased oncogenic STAT5 activity and a more aggressive course of disease linked to poor overall outcomes. Importantly, negative STAT5 feedback control mechanisms are essential to enable nimble adaptations of B-ALL cells in response to fluctuations of oncogenic signaling strength and availability of nutrients during distinct metabolic states of cellular activation (MYC) and quiescence (BCL6).

Provisional Prognostic Score for Blastic Plasmacytoid Dendritic Cell Neoplasm

Background BPDCN is an aggressive hematologic malignancy which often involves the skin. This disorder has gone through many iterations over the years, being classified initially as a blastic NK-cell lymphoma, then a subset of AML, and finally recognized as a unique myeloid neoplasm. While BPDCN often follows an aggressive course, its outcomes vary considerably. We conducted this study to develop a provisional BPDCN prognostic score (BPS) for this rare disease. Methods We used our constructed BPDCN database, which contains retrospective data on 273 cases. Such data included demographics such as sex, age, and race. It also included disease presentation symptoms, duration of symptoms before diagnosis, site(s) of the disease, blood counts, coexisting comorbidities, disease immunohistochemical and molecular phenotype, types of treatment, and survival outcomes. Of the 273 cases, only 218 had complete survival and outcomes data, the sample chosen for this study. Cox proportional-hazards model and Log-rank tests were used to assess the influence of clinicopathologic factors on overall survival (OS). We included factors that statistically impacted OS and scored them by the impact of their hazard ratios. Results The median OS of the cohort was 16 months. The following dichotomous variables were identified as impactful prognostic factors in this cohort: Age>60 (10 vs. 30 months), lymphadenopathy (14 vs. 42 months), bone marrow involvement (14 vs. NR months), splenomegaly (10 vs. 16 months), and disseminated skin disease (13 vs. NR months). A prognostic model was devised using these variables to identify different levels of risk. Each variable was assigned a score of 1 when present, except for age>60, splenomegaly, and disseminated skin disease, that were assigned 2 points each as they had the highest hazard ratios of all the other variables. In this exploratory cohort, low risk was assigned a score of 0-2, intermediate risk a score of 3-4, and high risk a score of 5-8. This prognostic score system led to our cohort's most optimal risk discriminatory model, where low, intermediate, and high risk had a median OS of NR, 24, and 10 months, respectively (p<0.0001). Conclusion This BPS is a promising new tool for risk-stratifying patients with BPDCN. However, it still requires prospective validation.

Arsenic Trioxide Combine with G-CSF Triggers Distinct TP53 Mutations Acute Myeloid Leukemia Cells Ferroptosis through TP53-SLC7A11-GPX4 Pathway

Abstract ： Background ： Acute myeloid leukemia (AML) is a complex disease with diverse molecular subtypes. Approximately 8% of AML patients carry the TP53 mutation, which is associated with an aggressive disease course and dismal survival rates. Arsenic trioxide (ATO) has been remarkably effective in treating acute promyelocytic leukemia (APL), but its clinical activity in other AML subtypes remains limited. Recent evidence indicates that ATO demonstrates potential in rescuing multiple TP53 mutations effectively, offering promise as an individualized therapeutic strategy targeting mutant TP53 in leukemic cells. Our previous study showed that the upregulation of AQP9 by G-CSF enhanced the effect of ATO in non-APL AML cells. This demonstrates that ATO holds therapeutic promise in AML cases harboring distinct TP53 mutations. Methods ： We conducted a comprehensive analysis of TP53 mutations in the Analysis of Whole Genomes cohort, encompassing patients from the TCGA and OHSU databases. The frequency and distribution of TP53 mutations were determined. Median overall survival (OS) was calculated using the Kaplan-Meier method. To functionally assess the effect of TP53 mutation on AML phenotype, various cell lines harboring distinct TP53 mutation types were used for this study, including KASUMI-1 TP53 R248Q THP-1 TP53frameshift_delHL-60 TP53 deletionMOLM13 TP53 wild-type. The cellular lipid oxidation levels were measured by a C11 BODIPY flow cytometry assay and it was also observed by fluorescence microscopy. Additionally, the RNA and protein expressions of GPX4 and SLC7A11 were analyzed by real-time quantitative Polymerase Chain Reaction (QRT-PCR) and Western Blot. Results ： In the OHSU cohort and TCGALAML database, including 1005 newly diagnosed patients with 120 TP53 mutations, we found that missense mutations are the most common TP53 mutations and R248Q has the highest mutation frequency. Furthermore, TP53 mutationwas significantly associated with lower survival ( P <0.001). ATO potently induced cell death in each cell line. The KASUMI-1 R248Q cell line was the most sensitive to ATO (IC50=0.3607) and showed the most pronounced change in the IC50 of ATO with the addition of ferrostatin-1(Fer-1, ferroptosis inhibitor). ATO induced cell death was prevented by the addition of lipophilic antioxidant ferrostatin-1, supporting the hypothesis that ATO induced cell death occurred by ferroptosis. In KASUMI-1 R248Q cell line, ATO increases the lipid oxidation levels (observed by C11 BODIPY flow cytometry assay and fluorescence microscopy), MDA levels and decreases the expression of GPX4 and SLC7A11 (including RNA level and protein level). Whereas, in MOLM13 TP53 wildtype cell line, ATO increases the lipid oxidation levels but cannot prevented by Fer-1. THP-1 TP53 frameshift_del and HL-60 TP53 deletion only decrease the RNA expression of GPX4 and SLC7A11, nothing else changed in ferroptosis. These suggest that ATO has a more pronounced effect on missense mutations such as TP53 R248Q. In KASUMI-1 R248Q cell line, associated with G-CSF can further promote lipid oxidation levels (observed by C11 BODIPY flow cytometry assay and fluorescence microscopy) and further reduce the expression of GPX4 and SLC7A11. These results suggest that G-CSF promotes ATO-induced ferroptosis in KASUMI-1 R248Q cell line. Conclusion: We have demonstrated that ATO induces AML with distinct TP53 mutation cell death by ferroptosis resulting from depletion of GPX4 and SLC7A11. ATO associated with G-CSF may be able to be a new therapeutic strategy for the treatment of AML with distinct TP53 mutation.

A prognostic model for tumor recurrence and progression after meningioma surgery: preselection for further molecular work-up.

The selection of patients for further therapy after meningioma surgery remains a challenge. Progress has been made in this setting in selecting patients that are more likely to have an aggressive disease course by using molecular tests such as gene panel sequencing and DNA methylation profiling. The aim of this study was to create a preselection tool warranting further molecular work-up. All patients undergoing surgery for resection or biopsy of a cranial meningioma from January 2013 until December 2018 at the University Hospital Zurich with available tumor histology were included. Various prospectively collected clinical, radiological, histological and immunohistochemical variables were analyzed and used to train a logistic regression model to predict tumor recurrence or progression. Regression coefficients were used to generate a scoring system grading every patient into low, intermediate, and high-risk group for tumor progression or recurrence. Out of a total of 13 variables preselected for this study, previous meningioma surgery, Simpson grade, progesterone receptor staining as well as presence of necrosis and patternless growth on histopathological analysis of 378 patients were included into the final model. Discrimination showed an AUC of 0.81 (95% CI 0.73 - 0.88), the model was well-calibrated. Recurrence-free survival was significantly decreased in patients in intermediate and high-risk score groups (p-value < 0.001). The proposed prediction model showed good discrimination and calibration. This prediction model is based on easily obtainable information and can be used as an adjunct for patient selection for further molecular work-up in a tertiary hospital setting.

Potentiometric Examination of Patients with Chronic Odontogenic Maxillary Sinusitis in the Presence of Galvanic Pathology

Purpose: To determine the values of potentiometric parameters in the oral cavity present between metal inclusions, as well as between metal inclusions and the mucous membrane of the alveolar process in patients with chronic odontogenic maxillary sinusitis with galvanic pathology. Methods: 56 patients with chronic odontogenic maxillary sinusitis were divided into two observation groups, which were subjected to potentiometric and general clinical examination methods. Results: In 30 patients with chronic odontogenic maxillary sinusitis with the presence of galvanism (compensated and decompensated forms) in the oral cavity, chronic inflammation in the maxillary sinus occurred without pronounced clinical symptoms, and in 26 patients with oral galvanosis (atypical and typical forms), the clinical symptoms of inflammation in the maxillary sinus were severe with an aggressive course and complications. Conclusions: Based on an examination of 56 patients with chronic odontogenic maxillary sinusitis in the presence of galvanic pathology in the oral cavity, we found that in some types of this pathology, i.e., galvanosis, inflammatory disease in the maxillary sinus is aggressive, with pronounced clinical symptoms, frequent exacerbations of the inflammatory process, the presence of many postoperative inflammatory complications and recurrence of the disease.

Myelomatous Pleural Effusion – A Case Series

Background: The extramedullary disease usually occurs in the advanced stages of multiple myeloma and predicts poor survival. Commonly involved extramedullary sites in multiple myeloma include the nasal cavity, lymph nodes, lung, central nervous system, liver, spleen, skin, and orbit. Pleural effusion in multiple myeloma is unusual and rarely due to multiple myeloma itself. Myelomatous pleural effusions occur in less than 1% of cases of multiple myeloma. Material and methods: Eight patients were diagnosed with myelomatous pleural effusion in the Department of Medical Oncology at a tertiary cancer care center in India, during the 7-year period (2012 to 2018). Clinical presentation, diagnosis, treatment, and survival details were abstracted from medical records. Results: We report eight patients with myelomatous pleural effusion, constituting 0.45 % of all multiple myeloma cases treated during the study period. Five out of the eight patients were females with a median age of 58 years. Three patients had myelomatous pleural effusion at the time of initial diagnosis and five developed pleural effusion at disease progression. IgG was the common immunoglobulin subtype. The International staging system stage was stage I in one patient and stage III in seven patients. After the diagnosis of multiple myeloma, all patients developed myelomatous pleural effusion at a median of 7 months and all patients died within 2 weeks.Conclusion: Pleural effusions in multiple myeloma should be investigated to rule out myelomatous pleural effusion. Myelomatous pleural effusion is rare, having a poor prognostic outlook and an aggressive natural course.

Real-world assessment of treatment multiple myeloma patients on the example of one hematology center

Relevance. Despite significant improvements in therapeutic options, patients with multiple myeloma (MM) experience a series of remissions and relapses requiring further lines of therapy, which requires the prescription of new lines of therapy. Methods. We analyzed the types and outcomes of treatment, attrition rates (AR) — the proportion of patients who dropped out of program therapy, and refractoriness to different lines of therapy (LOT) in 447 patients with MM between 2010 and 2022. Resalts. The AR was 17% between LOT-1 and LOT-2, 15% between LOT-2 and LOT-3, and 25% between LOT-3 and LOT- 4. In multivariate regression analysis, only high MM risk significantly increased AR risk. Each new progression of MM increased the number of patients with refractory to bortezomib, lenalidomide, or daratumumab. After LOT-1, LOT-2, and LOT-6%, 26%, and 53% of patients were double-refractory, respectively, and 54% were triple-refractory. Bortezomib- or lenalidomide-refractory patients had a 2.6-fold lower chance of achieving a very good partial response or better (VGPR+). From LOT-1 to LOT-4, the overall response rate and VGPR+ decreased from 74% and 53% to 25% and 15%, respectively. Overall survival (OS) in the entire population was 7.6 years, with an actuarial 5-year OS of 67% and a 10-year OS of 44%. The median of progression-free survival (PFS) was 20 months on LOT-1, 19 months on LOT-2, and 7 months on LOT-3, and the actuarial 5-year PFS was 25%, 18%, and 10%, respectively. Conclusions: In this regard, we observe a continuing trend in the use of cisplatin-containing "rescue" chemotherapy regimens, especially in patients with an aggressive course, including extramedullary forms of MM. These patients could be candidates for bispecific antibody therapy and CAR T-cell therapy, but these options are not yet available in Russia.

Biphenotypic Sinonasal Sarcoma With High-Grade Features: A Diagnostic Challenge.

Biphenotypic sinonasal sarcoma (BSNS) is a rare neoplasm of the sinonasal tract. These tumors show neural and myogenic differentiation and are characterized by PAX3 translocations. The immunophenotypic features reflect their dual differentiation. They are low-grade sarcomas that show monomorphic spindle cells in sheets, fascicles, and herringbone patterns and are positive for S100 and smooth muscle actin. These tumors are common in elderly female patients and have a locally aggressive course. High-grade presentation or transformation was not documented until recently. Total 3 BSNSs have now been documented in the literature and we report a fourth tumor with high-grade transformation 8 years after the initial presentation. We identify the morphologic and immunohistochemical features of the high-grade areas and we highlight the stark differences with the low-grade areas based on literature and our specimen. We also discuss the diagnostic challenges that may come up with such a presentation.

Oligo-metastatic neoPlasms from the gastro-intestinal tract: iDentIfiCaTIon of cliNical and molecular drivers: the PREDICTION study

BackgroundMetastatic disease in tumors originating from the gastrointestinal tract can exhibit varying degrees of tumor burden at presentation. Some patients follow a less aggressive disease course, characterized by a limited number of metastatic sites, referred to as “oligo-metastatic disease” (OMD). The precise biological characteristics that define the oligometastatic behavior remain uncertain. In this study, we present a protocol designed to prospectively identify OMD, with the aim of proposing novel therapeutic approaches and monitoring strategies.MethodsThe PREDICTION study is a monocentric, prospective, observational investigation. Enrolled patients will receive standard treatment, while translational activities will involve analysis of the tumor microenvironment and genomic profiling using immunohistochemistry and next-generation sequencing, respectively. The first primary objective (descriptive) is to determine the prevalence of biological characteristics in OMD derived from gastrointestinal tract neoplasms, including high genetic concordance between primary tumors and metastases, a significant infiltration of T lymphocytes, and the absence of clonal evolution favoring specific driver genes (KRAS and PIK3CA). The second co-primary objective (analytic) is to identify a prognostic score for true OMD, with a primary focus on metastatic colorectal cancer. The score will comprise genetic concordance (> 80%), high T-lymphocyte infiltration, and the absence of clonal evolution favoring driver genes. It is hypothesized that patients with true OMD (score 3+) will have a lower rate of progression/recurrence within one year (20%) compared to those with false OMD (80%). The endpoint of the co-primary objective is the rate of recurrence/progression at one year. Considering a reasonable probability (60%) of the three factors occurring simultaneously in true OMD (score 3+), using a significance level of α = 0.05 and a test power of 90%, the study requires a minimum enrollment of 32 patients.DiscussionFew studies have explored the precise genetic and biological features of OMD thus far. In clinical settings, the diagnosis of OMD is typically made retrospectively, as some patients who undergo intensive treatment for oligometastases develop polymetastatic diseases within a year, while others do not experience disease progression (true OMD). In the coming years, the identification of true OMD will allow us to employ more personalized and comprehensive strategies in cancer treatment.Trial registrationClinicalTrials.gov ID NCT05806151.

Transcriptomic subtyping of malignant peripheral nerve sheath tumours highlights immune signatures, genomic profiles, patient survival and therapeutic targets

Malignant peripheral nerve sheath tumour (MPNST) is an aggressive orphan disease commonly affecting adolescents or young adults. Current knowledge of molecular tumour biology has been insufficient for development of rational treatment strategies. We aimed to discover molecular subtypes of potential clinical relevance. Fresh frozen samples of MPNSTs (n=94) and benign neurofibromas (n=28) from 115 patients in a European multicentre study were analysed by DNA copy number and/or transcriptomic profiling. Unsupervised transcriptomic subtyping was performed and the subtypes characterized for genomic aberrations, clinicopathological associations and patient survival. MPNSTs were classified into two transcriptomic subtypes defined primarily by immune signatures and proliferative processes. "Immune active" MPNSTs (44%) had sustained immune signals relative to neurofibromas, were more frequently low-grade (P=0.01) and had favourable prognostic associations in a multivariable model of disease-specific survival with clinicopathological factors (hazard ratio 0.25, P=0.003). "Immune deficient" MPNSTs were more aggressive and characterized by proliferative signatures, high genomic complexity, aberrant TP53 and PRC2 loss, as well as high relative expression of several potential actionable targets (EGFR, ERBB2, EZH2, KIF11, PLK1, RRM2). Integrated gene-wise analyses suggested a DNA copy number-basis for proliferative transcriptomic signatures in particular, and the tumour copy number burden further stratified the transcriptomic subtypes according to patient prognosis (P<0.01). Approximately half of MPNSTs belong to an "immune deficient" transcriptomic subtype associated with an aggressive disease course, PRC2 loss and expression of several potential therapeutic targets, providing a rationale for molecularly-guided intervention trials. Research grants from non-profit organizations, as stated in the Acknowledgements.

Possibilities of differential diagnosis of uterine leiomyosarcoma

Uterine leiomyosarcoma is a rare malignant neoplasm consisting of smooth muscle cells, characterized by an aggressive course and poor prognosis.&#x0D; Differential diagnosis of uterine leiomyosarcoma is challenging due to the nonspecificity and low severity of symptoms, particularly in the early stages. Patients with uterine leiomyosarcoma commonly present with complaints in of pelvic pain, abnormal uterine bleeding, and symptoms of compression of nearby organs. The same clinical symptoms are characteristics of patients with uterine leiomyomas.&#x0D; Leiomyosarcoma is often detected after histologic examination of material obtained during surgery for uterine myoma. At the same time, preoperative verification of the malignant nature of the neoplasm is crucial in determining the optimal tactics of surgical treatment. For instance, the use of organ-preserving techniques and morcellation in the treatment of presumed uterine leiomyoma may result in the dissemination of tumor cells and significantly worsen the prognosis in patients with undiagnosed leiomyosarcoma.&#x0D; This review discusses existing methods of preoperative diagnosis of uterine leiomyosarcoma, their efficacy, as well as the possibilities of application in clinical practice.

A - 27 Early-Onset Alzheimer's Disease: Indications of Psychosis Severity and Disease Progression.

Early-onset Alzheimer's disease (EOAD) comprises about 5% of ad cases and is associated with delays in diagnosis and aggressive course. Psychotic symptoms are frequent in ad and often include delusions of infidelity and hallucinations. When present, ad with psychosis is accompanied by elevated levels of depression and greater functional impairment. This case expands upon the existing literature on EOAD through the timeline of a complex psychosis presentation accompanied by rapid cognitive decline. 63-year-old, Hispanic, woman with progressive cognitive changes (e.g., confusion, forgetfulness, word-finding difficulties, disorganization) that emerged 5years prior to seeking neurological consultation. Psychosis symptoms (i.e., auditory/visual hallucinations, delusions), in the context of real events (i.e., husband's previous infidelity), developed simultaneously. These pervasive symptoms have contributed to social withdrawal, persistent suicidal tendencies, and impaired IADLs. Neuroimaging suggested hypometabolism in the parietotemporal regions with precuneus and posterior cingulate gyri involvement. The evaluation revealed fairly generalized cognitive decline. Basic attention, working memory, visual abstract reasoning, and phonemic fluency were intact. Visual integration/visuoconstruction were reduced. Impairments emerged in processing speed, rapid cognitive flexibility, cognitive inhibition, conceptualization, visuospatial orientation, semantic fluency, confrontation naming, and visual and verbal encoding and retention (with rapid forgetting). She endorsed moderately elevated symptoms of depression and anxiety. The pattern of cognitive and functional deficits are all suggestive of an ad process. Her age, sex, significant neuroimaging findings, report of earliest cognitive symptoms, and family history reinforce an EOAD etiology. Significant behavioral changes are often associated with increased cognitive impairment and in turn, may mark the progression/stage of the disease.

Legg–Calvé–Perthes disease presenting with osteoarthritis: Mechanisms of the development and prospects of conservative therapy using bisphosphonates

BACKGROUND: Aseptic necrosis of the femoral head in children remains a subject of great interest among specialists, despite its long history of study. The LeggCalvPerthes disease is the most common form of aseptic necrosis of the femoral head in children. The necrotic lesion in the femoral head results from the blockage of the arterial blood supply to the epiphysis, leading to its infarction. Some children experience a more aggressive disease course, with signs of osteoarthritis, which can result in the early development of coxarthrosis. Numerous publications have demonstrated the successful use of bisphosphonates in adult patients with aseptic necrosis of the femoral head.&#x0D; AIM: To generalize data on the use of bisphosphonates in children with the LeggCalvPerthes disease presenting with signs of osteoarthritis through the analysis of contemporary global literature.&#x0D; MATERIALS AND METHODS: A literature search was conducted in the open databases of PubMed, Science Direct, and Google Scholar, and the analysis depth spanned 20 years. The search terms used included LeggCalvPerthes disease, aseptic (avascular) necrosis of the femoral head, and bisphosphonates. The review encompassed the literature on bisphosphonates, their biological action, effectiveness of their use in patients with aseptic necrosis of the femoral head, and results of our research.&#x0D; RESULTS: Studies on the efficacy of bisphosphonates in children with LeggCalvPerthes disease are limited. Currently, the effect of bisphosphonates on disease course and outcome is unknown. Despite this, mechanisms of chronic inflammation are increasingly mentioned in the literature, which may directly or indirectly influence the clinical course and outcome of the disease. The key is the hyperactivity of osteoclasts in osteonecrosis. The experience of using bisphosphonates in adult patients with aseptic necrosis of the femoral head had positive results in preventing the progression of the deformity of femoral head deformity.&#x0D; CONCLUSIONS: Bisphosphonates are specific inhibitors of osteoclast activity, which has been used in many diseases. The results and inferences of using bisphosphonates in children with LeggCalvPerthes disease will lead to the formulation of a new treatment algorithm.

SAT563 Follicular Thyroid Cancer Masquerading as Chest Wall Mass With an Aggressive Course

Abstract Disclosure: I. Goyal: None. E. Punni: None. L. Adhikari: None. Introduction:Follicular thyroid cancers (FTC) are more aggressive than papillary thyroid cancer and usually have more advanced tumor stage at the time of presentation. Musculoskeletal metastases are rare though, but when present can cause various complications like pathological fractures and nerve compression. Clinical case:A 75-year-old female was seen in orthopedics clinic for a left infraclavicular chest wall mass. MRI chest showed a large destructive mass invading the manubrium. Biopsy showed follicular cells consistent with ectopic thyroid tissue. CT neck/chest showed 2x1.8 cm right thyroid lobe nodule and left sternoclavicular joint metastasis. She underwent total thyroidectomy and resection of portions of manubrium, left clavicle and left 1st and 2nd rib. Pathology showed FTC in right thyroid lobe, measuring 2.6 cm in greatest dimension with angioinvasion, and FTC of manubrium, adjacent connective tissue and sternoclavicular joint and ribs, measuring 6.3 cm in greatest dimension. Pathological TNM staging was pT2N0M1. Her 6-week post-op thyroglobulin (Tg) level was 28.7 ng/mL (Beckman Coulter Immunometric Assay, reference value &amp;lt;0.1 athyrotic). She was started on levothyroxine supplementation to achieve a TSH &amp;lt;0.01 uIu/mL. She was subsequently treated with 200 mCi of radio-active iodine (RAI) as adjuvant therapy. Post-therapy whole body scan showed increased activity in the right strap muscle and iodine-avid osseous metastasis in right hemisacrum. She further received radiation therapy to neck and sternal regions, and the right sacroiliac joint. Following this, patient was monitored with serial Tg panel and neck ultrasound (US). Her initial post-op US neck showed a soft tissue fullness in right thyroidectomy bed, concerning for residual disease but this was no longer seen after 3 months. Her Tg level downtrended from 28.7 ng/mL to 12.6 ng/mL and further to 1.8 ng/mL at 1-year follow-up. However, her course was complicated by development of several oral ulcers resulting from high-dose RAI therapy which were treated symptomatically with hydration, topical analgesics and Listerine mouth washes. The patient reported ongoing bowel incontinence since her initial cancer diagnosis. MRI pelvis showed rim-enhancing 4.5cm lesion centered at right sacral ala and extending into adjacent S1/S2 neural foramina. She was re-referred for palliative radiation therapy.Conclusion:This case of FTC is unique due to its uncommon initial presentation. Skeletal metastases to sacrum resulted in bowel incontinence in our patient. When present, skeletal metastases need treatment with high-dose (200 mCi) RAI. RAI therapy can cause xerostomia, hypogeusia and sialadenitis due to reductions in salivary flow. Clinicians should be aware of the early and late-onset complications of RAI therapy, discuss these with the patient before therapy and manage the complications adequately if these occur. Presentation Date: Saturday, June 17, 2023

Стрес і гіпертензія за умов війни та COVID-19

Common mechanisms of the development of the body’s stress response under the conditions of war and the COVID-19 pandemic relate to its acute and chronic course, post-traumatic stress disorder, the role of the hypothalamus-pituitaryadrenal gland, the sympathetic nervous system, and the renin-angiotensin-aldosterone system, and deficiency of α-1- antitrypsin. The development of stress-induced hypertensive changes is characterized by the activity of enzymes independent of the angiotensin-converting enzyme pathway of the renin-angiotensin system, expression of miRNA, damage to the endothelial cells of blood vessels, changes in the content of neutrophils and lymphocytes, and the soluble receptor for glycosylation end products. The considered stress-induced hypertensive changes under the conditions of the COVID-19 pandemic relate to chronic hyperinflammation, emotional response, effects of catecholamines, chymase activity, redox imbalance, DNA damage, endoplasmic reticulum stress. The interaction between ACE/ACE2 and miRNA may increase the probability of SARS-CoV-2 infection in patients with hypertension. A factor in the severity of COVID-19 is considered to be clinical depression and low immunity, and the possibility of a negative effect of antidepressants is highlighted. A more aggressive course of COVID-19 in hypertensive patients is associated with low levels of nitric oxide (NO). Stress-induced hypertensive changes under the conditions of war are associated with adaptation disorders, increased randomness of heart rate changes, post-traumatic stress disorder, the development of hypertension partly of psychological origin against the background of changes in the central nervous system, immunity, and the polymorphism of the ACEI/D gene as an indicator of endurance.

FRI308 A Rare Case Of Plurimorphous Plurihormonal Pituitary Neuroendocrine Tumor With LH Hypersecretion

Abstract Disclosure: A. Jeevananthan: None. L. Gratian: None. Background: Plurimorphous plurihormonal pituitary neuroendocrine tumors (PitNETs) are very rare pituitary tumors that are composed of multiple adenohypophyseal lineages and are associated with high risk of recurrence. Further, gonadotropin excess is exceptionally rare. Here we report a rare case of a plurimorphous plurihormonal PitNET with functional hypersecretion of LH. Clinical Case: A 48-year-old male was incidentally found to have a 13x12x14mm pituitary tumor without evidence of cavernous sinus invasion or mass effect during sinus imaging for workup of chronic sinusitis with polyps. Clinical symptoms at the time were notable for night sweats, hot flashes and 1 year history of erectile dysfunction. Functional testing showed normal prolactin, GH, cortisol, and thyroid hormone production. However, LH was elevated at 10.2 mIU/mL (normal range 1.4-7.77 mIU/mL) and FSH was low at 1.3 mIU/mL (normal range 2.5-17.7 mIU/mL) with normal total testosterone of 565 ng/dL (normal range 240-950 ng/dL) but elevated free testosterone of 22 ng/dL (normal range 4.26-16.4 ng/dL). Interval imaging 17 months later showed an increase in size to 16x16x13mm with deviation of the infundibulum to the left and mild mass effect on the optic chiasm. Thereafter, the patient underwent transsphenoidal surgery with subsequent normalization of FSH to 6.2 mIU/mL and LH to 7.9 mIU/mL. Initial post-operative total testosterone level was low at 29 ng/dL but improved spontaneously to 170 ng/dL six weeks following surgery. Pathology was notable for immunohistochemistry (IHC) that showed SF1 lineage (IHC positive for LH, negative for FSH) and PIT1 lineage (IHC positive for prolactin, rare GH). To our knowledge, this is the first reported case of functional LH hypersecretion due to a plurimorphous plurihormonal PitNET. Conclusion: This case aims to shed light on the first noted case of LH only secreting plurimorphous plurihormonal PitNET. Plurihomonal PitNETs are associated with aggressive course and recurrence. Particularly, this case highlights the need for routine use of immunohistochemical staining for accurate diagnosis of PitNETs to ensure rigorous follow-up. Presentation: Friday, June 16, 2023

Regos nervo glioma

Optic nerve glioma (ONG) is usually a low-grade tumor of the optic nerve. ONG can affect not only the optic nerve, but also the optic nerve chiasma and optic nerve tract. ONG can be classified as associated with neurofibromatosis type 1 (NF1) or sporadic ONG. Sporadic gliomas are more commonly diagnosed in adults, have an aggressive course, and are known to have a poor outcome. The disease can be asymptomatic. ONG often causes visual disturbances such as reduced visual acuity, visual field defects, and impaired color vision; due to the tumor mass effect, proptosis, strabismus, and diplopia are possible. As the disease progresses, various neurological symptoms can appear, including headache, hemiplegia, and endocrine disorders such as early maturation, growth hormone hypersecretion, or deficiency. A presumed diagnosis is based on clinical presentation and neuroimaging findings. Meanwhile, biopsy should be avoided due to the high probability of optic nerve damage. Treatment is individual for each patient, but remains controversial to this day. Thus, in this article, we review the prevalence, clinic, diagnostic and treatment options of ONG.

Investigation of Clinical Histopathologic Features and Metabolic Parameters of 18F-FDG PET/CT in Invasive Breast Carcinoma with a Micropapillary Component.

The aim of this study was to evaluate the correlation between clinical histopathologic features and micropapillary (MP) ratio with the maximum standardized uptake value (SUVmax) derived from 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in treatment naïve breast cancer. Twenty-nine patients diagnosed with breast cancer with a MP component who underwent PET/CT imaging before any local and/or systemic treatment were included in this retrospective study. All clinical histopathological features were recorded. SUVmax values were measured from 18F-FDG PET images for primary tumors and metastatic axillary lymph nodes. MP component percentage did not correlate with any clinical histopathological features except age. At early ages, the MP component ratio was significantly higher. Our results showed that there is no significant correlation between the SUVmax value and MP component percentage. A high SUVmax value is generally expected in aggressive malignancies. However, this assumption may not be valid for the MP subgroup, which has an aggressive course compared to other subgroups in breast cancer.

Hairy cell leukemia with an aggressive outcome: A case report with a review of the literature

Abstract Hairy cell leukemia (HCL), an uncommon cancer affecting B-lymphocytes primarily in the bone marrow and spleen, is identified by abnormal projections on malignant B cells, which give the illness its name. This condition is less frequently observed in Asian populations compared with individuals from American and European backgrounds and tends to be diagnosed around the age of 55 years. The leading genetic association of this ailment is linked to the BRAFV600 mutation. Diagnosing HCL poses challenges due to its similarity to other conditions involving excessive lymphocyte growth. Here, we present a distinctive case of an aggressive disease course in a 46-year-old male.