Thymic Origin Research Articles

A linear ontogeny accounts for the development of naive, memory and tumour-infiltrating regulatory T cells in mice.

Foxp3 + Regulatory T cells (Treg) are a subset of CD4 + T cells that play critical functions in maintaining tolerance to self antigens and suppressing autoimmunity, regulating immune responses to pathogens and have a role in the pathophysiology of anti-tumoural immunity. Treg ontogeny is complex since they are generated following recognition of self antigens in the thymus during normal T cell development (thymic Treg), but are also induced from mature conventional T cells when activated by foreign antigen with appropriate additional cues (inducible Treg). How these distinct ontogenic pathways contribute to the maintenance and function of the mature Treg compartment in health and disease remains unclear. Here, we use a combination of fate mapping approaches in mice to map the ontogeny of Treg subsets throughout life and estimate rates of production, loss and self-renewal. We find that naive and effector/memory (EM) Treg subsets exhibit distinct dynamics but are both continuously replenished by de novo generation throughout life. Using an inducible Foxp3-dependent Cre fate reporter system, we show that naive Treg and not conventional T cells, are the predominant precursors of EM Treg in adults. Tonic development of new EM Treg is not influenced by foreign antigens from commensals, rather suggesting a role for self recognition. To investigate the ontogeny of Treg development in malignant disease, we used the same fate reporter systems to characterise the Treg infiltrate of three different model tumours. In all three cases, we found that Treg derived from pre-existing, EM Treg. Together, these results reveal a predominantly linear pathway of Treg development from thymic origin to EM Treg associated with pathophysiology of malignant disease, that is driven by self antigen recognition throughout.

The Application of 68Ga-Somatostatin Analog and 18F-FDG PET/CT for Bone Metastasis from Neuroendocrine Tumors

Introduction: Aims of the study were to assess the differences in the diagnostic efficacy of 68Ga-somatostatin receptor analogs (68Ga-SSAs) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for detecting bone metastases in neuroendocrine neoplasm (NEN) and to analyze the correlation between imaging features and clinical features of BMs. Methods: We retrospectively analyzed the clinical and imaging data of 213 NEN patients who underwent 68Ga-SSA PET/CT and were finally diagnosed as BMs by pathology or follow-up. Of those, 103 patients underwent 18F-FDG PET/CT within 7 days after 68Ga-SSA PET/CT. Result: The BM detection rate of 68Ga-SSA PET/CT was higher than 18F-FDG PET/CT (86.4% vs. 66.0%, p = 0.02) in 103 patients with dual scanning. Meanwhile, the number of positive lesions in 68Ga-SSA PET/CT was significantly more than in 18F-FDG PET/CT (3.37 ± 1.95 vs. 2.23 ± 2.16, t = 4.137, p < 0.001). Most bone metastasis lesions presented as osteogenic change in CT (55.4%, 118/213). Concerning the primary tumor, the most frequent were of pancreatic origin (26.3%, 56/213), followed by rectal origin (22.5%, 48/213), thymic origin in 33 cases (15.5%), pulmonary origin in 29 cases (13.6%), paraganglioma in 20 cases (9.4%). The efficiency of 68Ga-SSA PET/CT to detect BMs was significantly correlated with the primary site (p = 0.02), with thymic carcinoid BMs being the most difficult to detect, and the positive rate was only 60.6% (20/33). However, 18F-FDG PET/CT positive rate was 76.92% (10/13) in thymic carcinoid BMs. In addition, the BMs of 7 patients in this study were detected by 68Ga-SSA PET earlier than CT for 4.57 months (range: 2–10 months). Conclusion: 68Ga-SSA PET/CT has higher sensitivity for detecting the BMs of NEN than 18F-FDG and detects the BM earlier than CT. Moreover, 18F-FDG PET/CT should be a complement for diagnosing the BMs of thymic carcinoids.

177Lu-edotreotide versus everolimus in patients with advanced neuroendocrine tumors of lung or thymic origin: The phase 3 randomized LEVEL, GETNE-T2217 trial.

TPS3177 Background: Everolimus is the only approved drug for the treatment of patients with neuroendocrine tumors (NETs) of lung and thymic origin, showing a median progression-free survival (PFS) of 11 months. Retrospective data for peptide receptor radionuclide therapy (PRRT) have demonstrated promising activity in somatostatin receptor (SSTR)-positive lung NETs. This study aims to compare the efficacy, safety, and patient-reported outcomes of 177Lu-edotreotide versus the standard of care everolimus in patients with advanced lung and thymic NETs. Methods: The LEVEL trial is a randomized, open-label, phase 3 international trial of 177Lu-edotreotide versus everolimus in patients with progressive, advanced, and well/moderately differentiated NETs of lung (typical/atypical) or thymic origin. Patients could be treatment naïve or have progressed (PD) on somatostatin analogues or ≤2 additional systemic treatments. Prior PRRT or mTOR inhibitors are not permitted. Eligible patients are randomly assigned 3:2 to 6 cycles of 177Lu-edotreotide (7.5±0.7 GBq / cycle) or to oral everolimus 10 mg once daily until PD or unacceptable toxicity. Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) scans are performed every 12 weeks until PD. Blood samples are analyzed at baseline, at 1st tumor assessment, and at PD for pharmacodynamic endpoints. Archival tumor tissue samples will be analyzed for ancillary studies. The primary endpoint is PFS according to RECIST v1.1. Secondary endpoints include overall response rate, duration of response, overall survival, safety, and quality of life (assessed through EORTC QLQ-C30). The expected sample size is 120 patients using a two-sided group sequential Lan-DeMets with O’Brien-Fleming-like boundaries test to demonstrate statistically significant risk reduction of 46.4% (HR= 0.536) in PFS between arms (α=0.05, β=0.2). The study has received institutional review board/ethics committee approval. Recruitment started in Oct 2023. Thirteen patients are already included. Clinical trial information: NCT05918302 .

Selective ablation of thymic and peripheral Foxp3+ regulatory T cell development.

Foxp3+ regulatory T (Treg) cells of thymic (tTreg) and peripheral (pTreg) developmental origin are thought to synergistically act to ensure immune homeostasis, with self-reactive tTreg cells primarily constraining autoimmune responses. Here we exploited a Foxp3-dependent reporter with thymus-specific GFP/Cre activity to selectively ablate either tTreg (ΔtTreg) or pTreg (ΔpTreg) cell development, while sparing the respective sister populations. We found that, in contrast to the tTreg cell behavior in ΔpTreg mice, pTreg cells acquired a highly activated suppressor phenotype and replenished the Treg cell pool of ΔtTreg mice on a non-autoimmune C57BL/6 background. Despite the absence of tTreg cells, pTreg cells prevented early mortality and fatal autoimmunity commonly observed in Foxp3-deficient models of complete Treg cell deficiency, and largely maintained immune tolerance even as the ΔtTreg mice aged. However, only two generations of backcrossing to the autoimmune-prone non-obese diabetic (NOD) background were sufficient to cause severe disease lethality associated with different, partially overlapping patterns of organ-specific autoimmunity. This included a particularly severe form of autoimmune diabetes characterized by an early onset and abrogation of the sex bias usually observed in the NOD mouse model of human type 1 diabetes. Genetic association studies further allowed us to define a small set of autoimmune risk loci sufficient to promote β cell autoimmunity, including genes known to impinge on Treg cell biology. Overall, these studies show an unexpectedly high functional adaptability of pTreg cells, emphasizing their important role as mediators of bystander effects to ensure self-tolerance.

Phase 3 LEVEL trial of 177Lu-edotreotide vs everolimus in patients with advanced neuroendocrine tumors of lung or thymic origin (GETNE-T2217)

Phase 3 LEVEL trial of 177Lu-edotreotide vs everolimus in patients with advanced neuroendocrine tumors of lung or thymic origin (GETNE-T2217)

Anti-PD-1 Antibody (Tislelizumab) Combined with R-CHOP for the Treatment of Previously Untreated Primary Mediastinal B-Cell Lymphoma: A Prospective Phase II Study

Background: Primary mediastinal B-cell lymphoma (PMBCL) is a rare aggressive B-cell lymphoma of thymic origin. Due to the low incidence rate of PMBCL, there is currently no internationally accepted standard first-line treatment regimen. Dose-adjusted (DA) EPOCH-R which is the more commonly used first-line therapy plan is not so effective because patients usually cannot tolerate it. The R-CHOP regimen is comparable to the R-DA-EPOCH for the first-line treatment of PMBCL in terms of survival and has a better safety profile (Bhatt, V.R. et al, Cancer Treat Rev 2015; Iwanicka el al., Curr Hematol Malig Rep 2014). Meanwhile, patients with PMBCL usually have alterations of 9p24.1, leading to overexpression of PDL-1/2. Previous studies have found that PD-1 monoclonal antibody shows good efficacy in recurrent and refractory PMBCL (Steidl et al., Blood 2011; Zinzani et al., Blood 2017). Tislelizumab, a humanized IgG4 antibody that binds PD-1 with high affinity, minimizes binding to Fcγ receptor 1 (FcγRI) on macrophages by the genetic engineering of Fc segment, abrogating antibody-dependent phagocytosis (ADCP)-induced T-cell clearance. The efficacy and safety of its combination with R-CHOP in previously untreated PMBCL is not yet clear. We speculate that the combination of both may be a new option for the first-line therapy for PMBCL patients with good efficacy and low toxicity. Methods: This is a single-arm, multi-center, phase II clinical study (ChiCTR2100044313). Patients aged 18 years or older with a diagnosis of PMBCL and previously untreated were eligible. Eligible patients received 6 cycles of Tislelizumab (200 mg D1), Rituximab (375 mg/m 2 D1), Cyclophosphamide (750 mg/m 2 D2), Pirarubicin (50 mg/m 2 D2), Vincristine (1.4 mg/m 2, maximum dose 2 mg, D2), Prednisone (100 mg/d D2-6), every 21 days for 1 cycle. Disease response assessments were performed by positron emission tomography and computed tomography (PET-CT) or enhanced CT every two cycles, meanwhile peripheral blood ctDNA was monitored, and treatment-related adverse effects were assessed and recorded. The primary endpoint was objective remission rate (ORR). The secondary endpoints included treatment safety, progression-free survival (PFS) and overall survival (OS), and the exploratory analyses of the correlation between PD-L1 expression in tumor tissues, tumor-associated macrophages (TAM) phenotype in tumor microenvironment and efficacy. Results: From June 2020 to June 2023, 12 patients were enrolled and 9 patients had evaluable efficacy with the median age of 34 years, 3 males and 6 females, all patients had large mediastinal mass at initial diagnosis. 7 patients had PD-L1 expression (VENTANA SP263) above 80% and 2 cases could not be further tested due to insufficient tissue specimens. The ORR was 100%, and the CR rate was 77.8% (7/9) after 6 cycles of treatment. The 5 th and 9 th patient reached PR after 6 cycles of treatment due to irregular hospitalization. And CR was achieved after 2 cycles of regular treatment for the 5 th patient. NGS from formalin-fixed paraffin-embedded (FFPE) and circulating tumor DNA (ctDNA) evaluation from blood were performed across all patients before treatment. 5 patients underwent end of treatment-ctDNA test. Median follow-up 15m (6.8m-26.3m), the third patient was lost to follow-up at 9m. The other patients who achieved CR are still at complete remission. Moreover, we found SOCS1, TNFAIP3 are the most frequently mutated genes in biopsies of PMBCL and only the 5th patient had RHOA mutation which is highly related to PMBCL. The PET-CT and ctDNA assessments were negative in three patients at the end of 6 cycles with 60% concordance, and the 5 th and 9 th patient achieved PR on PET-CT, but the ctDNA assessments were negative. The most common adverse events (AEs) were gastrointestinal reactions, 2 patients experienced grade IV myelosuppression and 1 patient had grade I hyperthyroidism. No treatment-related deaths occurred. Conclusion: Tislelizumab combined with R-CHOP for the treatment of previously untreated PMBCL had good efficacy and sustained response with low toxicity. Longer follow-up is required to access the survival benefit of this regimen. Figure 1: Disease Remission in the Included Patients

Targeted Protein Degradation for c-MYC Overcomes Therapy Resistance in T-Cell Acute Lymphoblastic Leukemias

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy characterized by diffuse infiltration of the bone marrow by immature lymphoblasts of thymic origin expressing T-cell surface markers. Early T cell precursor (ETP)-ALL is a distinct subtype of T-ALL characterized by a lack of CD1a and CD8; low expression of CD5 and the presence of myeloid or stem cell markers, and recent studies have shown resistance to conventional chemotherapies and poor outcome in ETP-ALL compared to thymic or mature T-ALL. A recent study revealed distinct gene expression profiles in adult compared to pediatric-adolescent ETP-ALL, representing higher expression levels of BCL2 and CD34 (Dai et al. Proc Natl Acad Sci 2022), however, detailed proteomic profiling in ETA-ALL has yet to be determined. Amplification of overexpression of MYC oncogene or stabilization of c-MYC protein occurs up to 70% in human cancers. Multifaceted activities of MYC include rapid proliferation of malignant cells supported by increased mitochondrial and ribosome biogenesis, dysregulated protein translation, and altered metabolism. NOTCH1-MYC signaling axis activation is one of the hallmarks that drives T-ALL leukemogenesis (Weng et al, Science 2004; Sanchez-Martin and Ferrando, Blood 2017). We have reported that targeting of BRD4 proteins induces suppression of leukemia initiating cells (LICs) in T-ALL by inhibiting the NOTCH1-MYC-CD44 axis, providing rationale to target MYC in therapy-resistant T-ALL (Piya et al. Leukemia 2022). We recently reported targeted protein degradation of c-MYC utilizing GT19715, the first-in-class cereblon modulator (CELMoD) for c-MYC exhibited promising anti-leukemia efficacy in acute myeloid leukemias (Nishida et al. ASH 2022). Here we employ GT19715 to investigate efficacy of targeting protein degradation of c-MYC in T-ALL. GT19715 induced dose-dependent apoptosis and cytoreduction in T-ALL cell lines with IC50 values below 10 nM except HPB-ALL cells. We found substantial decrease of c-MYC protein levels in sensitive but not in resistant cells (HPB-ALL). GT19715 induced apoptosis and ³ 90% cytoreduction at nanomolar concentrations in primary, therapy-resistant T-ALL. GT19715 also enhanced cell death induced by dexamethasone. In a xenograft model of CCRF-CEM cells carrying NOTCH1, PTEN, FBXW7, KRAS and TP53 mutations, GT19715 (3 mg/kg, three IP injections per week, two weeks on and one week off) reduced &amp;gt; 99% circulating human CD45+ leukemia cells compared to vehicle on day 16 after engraftment ( Fig. A), suggesting promising anti-leukemia efficacy in T-ALL in vivo. ETP-ALL cells from an adult patient exhibited distinct clustering compared to those from an adolescent patient as determined by single-cell mass cytometry (CyTOF) (N = 2). Adult ETP-ALL cells were characterized by increased protein levels of BCL2, CD34, CD44 and p-S6 compared to adolescent ETP-ALL cells, suggesting more stem-like properties. On the other hand, adolescent ETP-ALL cells showed higher CD7, CD33 and CD38 levels compared to the adult sample ( Fig. B). Interestingly, GT19715 treatment predominantly reduced p-S6 high clusters in adult ETP-ALL cells, potentially suggesting c-MYC degradation-induced suppression of the AKT-mTOR pathway. Conclusion: Targeted protein degradation of c-MYC induces promising anti-leukemia efficacy in T-ALL cells in vitro and in vivo. Further mechanistic and in vivo studies are ongoing.

Spindle cell thymoma and its histological mimickers.

Spindle cell thymomas are the most common spindle cell neoplasms of the anterior mediastinum. These tumors belong to the group of thymic epithelial neoplasms and are known for their wide histomorphologic spectrum. This histological heterogeneity is the reason why unequivocal diagnosis can be challenging, especially when dealing with small biopsy material. Conversely, less conventional patterns of the tumor may also pose significant diagnostic problems in resected material and the differential diagnosis often includes other spindle cell neoplasms that are known to arise in the mediastinal cavity. These can be of variable origin and may share overlapping pathological features with spindle cell thymoma. Since spindle cell thymomas are tumors that primarily affect the adult population and predominantly arise from the thymic gland in the anterior mediastinum, this review will focus on the differential diagnosis with other spindle cell neoplasms that share similar demographic characteristics and, for the most part, originate from the anterior mediastinal compartment. These include other epithelial spindle cell tumors of thymic origin (sarcomatoid thymic carcinoma and spindle cell carcinoid tumor), mesenchymal neoplasms [solitary fibrous tumor (SFT), synovial sarcoma, and dedifferentiated liposarcoma] and various other tumors with spindle cell morphology, that may occasionally involve the anterior mediastinum. The clinical, pathological, immunohistochemical and molecular hallmarks of these lesions will be discussed and useful tips for the differential diagnosis with spindle cell thymoma will be provided.

P129 RARE CASE OF A GIANT THYMIC CYST: A CHALLENGING DIFFERENTIAL DIAGNOSIS OF A PARACARDIAC CYSTIC LESION

Abstract Background Benign thymic cysts are a rare clinical entity, representing approximately 3% of all mediastinal masses and can be congenital or acquired. We report a case of a 58–year–old female with a giant benign thymic cyst which entered in differential diagnosis with pericardial cyst and pericardial effusion. Case presentation: A 58–year–old female was brought to our hospital due to new onset dyspnoea and fatigue. She had a history of a mediastinal liquid mass incidentally discovered 9 years before which was interpreted at that time as a loculated pericardial effusion (Fig. 1). An echocardiogram was performed and it revealed increased size of the known lesion without any signs of hemodynamic compromise (Fig. 2). A magnetic resonance showed a voluminous liquid lesion that originated from the anterior mediastinum, extending caudally to the diaphragm with maximum dimension on the right hemithorax of 16 x 12 x 9 cm and on the left hemithorax of 10 x 5 x 13 cm (antero–posteriorly, transversely and cranio–caudally respectively) (Fig. 3). It was initially interpreted as a pericardial cyst. All the findings were then collegially reviewed and it was suspected of being a giant thymic cyst especially due to its rapid growth and spatial evolution over time. The cyst was surgically removed using a thoracoscopic approach. Histological examination confirmed the thymic origin of the cyst and excluded malignancy. At three month follow up, the patient presented no symptoms, and the echocardiogram was normal. Discussion The echocardiographic features of mediastinal cysts are not specific for the type of cystic lesion, so the origin and location of the cyst can be used for differential diagnosis. Computed tomography has the best spatial resolution, while the magnetic resonance has better capacity to differentiate the content of the cyst, especially when it is not a homogeneous liquid lesion. In our case, the growth over nine years was a crucial hint to suspect the thymic origin of the lesion. On the other hand, the sole evaluation of the last imaging exam would have made the diagnosis more challenging because of its huge dimensions, which made the exact site of origin almost impossible to identify. Conclusion Our case is a rare example of a giant thymic cyst which was extremely difficult to differentiate from other paracardiac cystic lesions and required integrated imaging and discussion by a team of experts of different specialties to make the correct diagnosis.

Beklenmedik bir lokalizasyonda ortaya çıkan primer mediastinal büyük B hücreli lenfoma

Primary mediastinal large B-cell lymphoma (PMLBCL) is a mature aggressive large B-cell lymphoma of putative thymic B-cell origin arising in the mediastinum, with distinctive clinical, immunophenotypic, genotypic, and molecular features. Cases that arise outside the mediastinum are very uncommon. A 27-year-old woman presented with mass which had an extramedullary, extradural component at the right T5-6 foramina indenting to the spinal canal, extending craniocaudally from the middle mediastinum to the level of the aortic hiatus. Pathological examination of the mass revealed atypical lymphoid cells with medium-large size, eosinophilic and clear cytoplasm In our case CD23 and MAL expression with morphological findings supported PMLBCL. PMLBCL may be seen with abnormal localization and clinical presentation. Immunohistochemical profile including MAL is helpful to detect these cases.

186 RARE CASE OF A GIANT THYMIC CYST: A CHALLENGING DIFFERENTIAL DIAGNOSIS OF A PARACARDIAC CYSTIC LESION

Abstract Background Benign thymic cysts are a rare clinical entity, representing approximately 3% of all mediastinal masses. Thymic cysts can be congenital or acquired. We describe a case of a 58-year-old female with a giant benign thymic cyst which entered in differential diagnosis with a pericardial cyst and pericardial effusion. Case presentation A 58-year-old female was brought to our hospital due to new onset dyspnoea and fatigue. She had a history of a liquid mediastinal mass accidentally discovered 9 years before which was interpreted at that time as a loculated pericardial effusion (Fig. 1). An echocardiogram was performed which showed increased size of the known lesion without any signs of hemodynamic compromise (Fig. 2). A magnetic resonance showed a voluminous liquid lesion that originated from the anterior mediastinum, extending caudally to the diaphragm with maximum dimensions on the right hemithorax of 16×12×9 cm (antero-posteriorly, transversely and cranio-caudally respectively) and of 10×5×13 cm on the left hemithorax (Fig. 3). It was initially interpreted as a pericardial cyst. All the findings were then collegially reviewed and for the first time it was suspected of being a giant thymic cyst, especially due to its spatial distibution and growth over time; in particular the cranio-caudal growth in both the hemithoraxes suggested that it might have originated from the thymus gland and then, by force of gravity, extended downword bilaterally. The cyst was surgically removed using a unilateral thoracoscopic approach. Histological examination confirmed the thymic origin of the cyst and excluded malignancy. At the three month follow up, the patient presented no symptoms, and the echocardiogram was normal. Discussion The echocardiographic features of mediastinal cysts are not lesion-specific, so the origin and location of the cyst can be used for differential diagnosis. Computed tomography has the best spatial resolution, while the magnetic resonance has better capacity to differentiate the content of the cyst, especially when it is not a homogeneous liquid lesion. In our case, spatial distribution and, in particular, growth over nine years were crucial hints to suspect the thymic origin of the lesion. Indeed, the sole evaluation of the last imaging exam would have made the diagnosis more problematic because of its huge dimensions, which made the exact site of origin very challenging to identify. Conclusion Our case is a rare example of a giant thymic cyst which was extremely difficult to differentiate from other paracardiac cystic lesions and required integrated imaging and discussion by a team of experts of different specialties to make the correct diagnosis.

SUPERIOR VENA CAVA SYNDROME DUE TO A MEDIASTINAL MASS WITH RIGHT ATRIAL INVOLVEMENT

SUPERIOR VENA CAVA SYNDROME DUE TO A MEDIASTINAL MASS WITH RIGHT ATRIAL INVOLVEMENT

ATYPICAL PRESENTATION OF CARDIAC TAMPONADE SECONDARY TO MALIGNANT THYMIC NEUROENDOCRINE TUMOR MASKED BY OPIOID OVERDOSE

ATYPICAL PRESENTATION OF CARDIAC TAMPONADE SECONDARY TO MALIGNANT THYMIC NEUROENDOCRINE TUMOR MASKED BY OPIOID OVERDOSE

Combined Thymic Epithelial Neoplasms - a Review.

Thymic epithelial neoplasms are the most common tumors of thymic origin but are overall rare in the general population. Their morphologic diversity, ranging from low grade to overtly malignant lesions, along with various histologic growth patterns make them a diagnostically challenging group of tumors. Very occasionally, thymomas and thymic carcinomas may develop in combination with other benign or malignant lesions of thymic origin, further complicating the diagnostic process. The focus of this review lies on the spectrum of thymic epithelial tumors that present with other thymic lesions in the same tumor mass, such as multilocular thymic cysts, neuroendocrine neoplasms, lymphomas, and germ cell tumors among others. Awareness of the existence of such unusual tumors may not only aid in their diagnosis but may also have implications for prognostic and therapeutic purposes.

Glutor, a Glucose Transporter Inhibitor, Exerts Antineoplastic Action on Tumor Cells of Thymic Origin: Implication of Modulated Metabolism, Survival, Oxidative Stress, Mitochondrial Membrane Potential, pH Homeostasis, and Chemosensitivity.

Neoplastic cells overexpress glucose transporters (GLUT), particularly GLUT1 and GLUT3, to support altered metabolism. Hence, novel strategies are being explored to effectively inhibit GLUTs for a daunting interference of glucose uptake. Glutor, a piperazine-2-one derivative, is a newly reported pan-GLUT inhibitor with a promising antineoplastic potential. However, several aspects of the underlying mechanisms remain obscure. To understand this better, tumor cells of thymic origin designated as Dalton’s lymphoma (DL) were treated with glutor and analyzed for survival and metabolism regulatory molecular events. Treatment of tumor cells with glutor caused a decrease in cell survival with augmented induction of apoptosis. It also caused a decrease in glucose uptake associated with altered expression of GLUT1 and GLUT3. HIF-1α, HK-2, LDH-A, and MCT1 also decreased with diminished lactate production and deregulated pH homeostasis. Moreover, glutor treatment modulated the expression of cell survival regulatory molecules p53, Hsp70, IL-2 receptor CD25, and C-myc along with mitochondrial membrane depolarization, increased intracellular ROS expression, and altered Bcl-2/BAX ratio. Glutor also enhanced the chemosensitivity of tumor cells to cisplatin, accompanied by decreased MDR1 expression. Adding fructose to the culture medium containing glutor reversed the latter’s inhibitory action on tumor cell survival. These results demonstrate that in addition to inhibited glucose uptake, modulated tumor growth regulatory molecular pathways are also implicated in the manifestation of the antineoplastic action of glutor. Thus, the novel findings of this study will have a long-lasting clinical significance in evaluating and optimizing the use of glutor in anticancer therapeutic strategies.

European Neuroendocrine Tumor Society (ENETS) 2022 Guidance Paper for Carcinoid Syndrome and Carcinoid Heart Disease

European Neuroendocrine Tumor Society (<scp>ENETS</scp>) 2022 Guidance Paper for Carcinoid Syndrome and Carcinoid Heart Disease

Rho-GTPase dependent leukocyte interaction generates pro-inflammatory thymic Tregs and causes arthritis

Conditional mutation of protein geranylgeranyltransferase type I (GGTase-I) in macrophages (GLC) activates Rho-GTPases and causes arthritis in mice. Knocking out Rag1 in GLC mice alleviates arthritis which indicates that lymphocytes are required for arthritis development in those mice. To study GLC dependent changes in the adaptive immunity, we isolated CD4+ T cells from GLC mice (CD4+GLCs). Spleen and joint draining lymph nodes (dLN) CD4+GLCs exhibited high expression of Cdc42 and Rac1, which repressed the caudal HOXA proteins and activated the mechanosensory complex to facilitate migration. These CDC42/RAC1 rich CD4+GLCs presented a complete signature of GARP+NRP1+IKZF2+FOXP3+ regulatory T cells (Tregs) of thymic origin. Activation of the β-catenin/Lef1 axis promoted a pro-inflammatory Th1 phenotype of Tregs, which was strongly associated with arthritis severity. Knockout of Cdc42 in macrophages of GLC mice affected CD4+ cell biology and triggered development of non-thymic Tregs. Knockout of Rac1 and RhoA had no such effects on CD4+ cells although it alleviated arthritis in GLC mice. Disrupting macrophage and T cell interaction with CTLA4 fusion protein reduced the Th1-driven inflammation and enrichment of thymic Tregs into dLNs. Antigen challenge reinforced the CD4+GLC phenotype in non-arthritic heterozygote GLC mice and increased accumulation of Rho-GTPase expressing thymic Tregs in dLNs. Our study demonstrates an unexpected role of macrophages in stimulating the development of pro-inflammatory thymic Tregs and reveal activation of Rho-GTPases behind their arthritogenic phenotype.

Possibilities of immunotropic drugs of thymic origin in cancer patients

Introduction. At present, in the light of impressive scientific achievements in tumor immunology, the question of the need for immunotherapeutic support in the treatment of cancer patients is especially relevant. Increasing attention is paid to the quality of life of patients receiving immunosuppressive therapy. However, the standards of immunotropic therapy in the complex and combined treatment of an oncological patient have not yet been developed. In the Russian Federation, more than 30 years ago, Timalin, a complex of peptides of thymic origin, was registered and approved for use in cancer patients.The aim of the study was to evaluate the potential of Timalin to improve the quality of life of cancer patients during standard therapy.Materials and methods. The study included 20 cancer patients, mostly with III–IV stages of the disease. All patients underwent a study of immunological status indicators before the start of therapy. The main indicators of cellular and humoral immunity were assessed: T-cells, B-cells, NKT-cells, activation markers, NK-cells, immunoregulatory index. All patients received Timalin. To assess the quality of life of patients, a questionnaire was used: EQ-5D before the start of Timalin immunotherapy, then once a week for one course lasting 1 month.Results. After 1 month 9 patients responded that their health status increased by 20 points (on a 100‑point scale), 3 patients by 15 points, and 8 patients by 10 points. Against the background of immunotherapeutic support, all patients noted a decrease in the level of side effects in the process of special treatment for the underlying disease.Conclusion. The article shows that before treatment, the indicators of the immune status and the condition of patients required immunocorrective therapy. Substantiated conclusions were made about the need to consider the inclusion of thymic peptides in the standards of care for cancer patients.

Thymic Carcinoma: A Review.

The diagnosis of thymic carcinoma may pose significant problems not necessarily in the histopathological diagnosis but rather in assigning the thymus as specific origin. Often the tissue available for interpretation is obtained via a mediastinocopic biopsy, which raises two different issues -minimal tissue and lack of specific features to make a carcinoma of thymic origin. In addition, if to that conundrum we add that there is no magic immunohistochemical stain that will unequivocally lead to the interpretation of thymic carcinoma, then we are left with a true clinical-radiological-pathological correlation. In this review, we will highlight some of those challenges that diagnostic surgical pathologists may encounter in the histopathological assessment of thymic carcinoma as well as in the staging of these tumors.

Can the Ratio SUVmax of the Lesion/SUVmax of Mediastinal Tissues Guide the Choice of Surgical Access for the Resection of Thymic Epithelial Tumors?

BackgroundThere are studies showing the utility of the 18-fluorodeoxyglucose positron emission tomography (18FDG PET) scan in the management of patients with thymic epithelial tumors. It seems to be a correlation between the standard uptake value (SUVmax) of thymic epithelial tumors and the histological type and the stage. This study aims to use the ratio of the SUVmax of the lesion to the SUVmax of the adjacent mediastinal tissues in order to guide the choice of the surgical access.MethodsAll patients who presented an anterior mediastinal lesion with a high suspicion of being of thymic origin were included in a prospective database. A ratio inferior to 1 could predict a benign nature and less aggressive behavior, and a minimally invasive approach was performed. A ratio superior to 1 suggested a malignant and aggressive behavior, and a median sternotomy (or a thoracotomy) was performed.ResultsThere were 15 male (mean age 44.6 ± 16.26 years, range 25–73) and 15 female patients (mean age 50.1 ± 16.94 years, range 25–76). When the ratio is inferior to 1, it predicts benign disease in 80% of cases. When it is superior to 1, it predicts in half of cases advanced histological types (high risk thymomas and thymic carcinomas). On the contrary, it can quite accurately predict advanced Masaoka–Koga stages.ConclusionsThe protocol of this study is in accordance with the current literature showing the utility of 18FDG PET scan in the treatment of thymic epithelial tumors. This study goes one step further since the choice of surgical access is based on the SUVmax values. The ratio SUVmax of the lesion/SUVmax of the mediastinal tissues could be a new marker, more pertinent than absolute SUVmax values.