Large Numbers Of Lymphocytes Research Articles

Succinate dehydrogenase A deficient renal cell carcinoma: A rare renal tumor distinct from typical Succinate dehydrogenase deficient renal cell carcinoma

Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is a rare subtype of RCC classified as a molecularly defined RCC in the fifth edition of the WHO. Most gene alterations in patients with SDH-deficient RCC involve the SDHB subunit, with less involvement of the SDHC, SDHA, and SDHD subunits. Four cases of SDHA-deficient RCC have been reported in the literature, of which one case was associated with an NF2 gene mutation. Herein, we report six novel SDHA-deficient RCC cases, including two cases with NF2 gene mutations. In contrast to the typical morphology of SDH-deficient RCC, the six tumors mainly displayed glandular, sheet-like, or papillary growth patterns with prominent nucleoli (Grades 2–3), among which two cases with NF2 mutations had prominent nucleoli (Grade 3), large transparent vacuoles in the cytoplasm, and a large number of lymphocytes in the stroma. Six tumors showed negative immunohistochemical staining for SDHA and SDHB, and three cases presented with high expression of PD-L1. Second-generation sequencing revealed novel pathogenic somatic SDHA gene mutation and NF2 gene mutations in six and two tumors, respectively. Follow-up data were collected for the six patients with a follow-up time ranging from 7 to 268 months, and all six patients have survived to date. One patient received targeted therapy for tumor metastasis to the lungs after seven months, and another patient with an NF2 gene mutation received immunotherapy for lymph node metastasis revealed during surgery. SDHA-deficient RCCs with NF2 gene mutations have the ability to metastasize but might respond well to immunotherapy. For the first time, we report the largest number of SDHA-deficient RCC cases and comprehensively investigate their clinicopathological and molecular features to provide important guidance for diagnosis and clinical immunotherapy.

THE EFFECT OF THE EXPERIMENTAL INVASION OF T. PSEUDOSPIRALIS ON THE MORPHOLOGY OF THE SPLEEN OF LAYING HENS (GALLUS DOMESTICUS)

Background. Еhe study of the reaction of the organs of the immune system of birds with nematodes is relevant for the development of treatment regimens. Numerous models have been developed for laboratory animals (mice and rats), carnivores (hori, etc.) and birds (quails, chickens). In the latter, a capsule-free type of trichinella parasitizes, which has a number of reproduction features. In this study, a model of experimental invasion of T. pseudospiralis was used. The role of the spleen in the formation of anti-nematodosis immunity and its reaction to the introduction of the parasite in chicken (Gallus domesticus) has been studied. The purpose of this study was to investigate morphological changes in the structure of the spleen in trichinellosis caused by T. pseudospiralis in chickens in the muscular stage of the invasive process. Materials and methods. By the method of analogues, 2 groups of 6 heads were formed. The birds of the experimental group were weighed and T. pseudospiralis larvae isolate was injected into the goiter at a dose of 2 lich. / g of body weight (3200-3600 thousand larvae per bird). T. pseudospiralis larvae used for experimental infection of poultry were previously isolated from the muscles of birds, and were maintained on laboratory animals. All chickens were kept and fed under identical conditions. In order to determine the distribution of larvae in the muscles of T. pseudospiralis poultry, 6 chickens of the experimental group were euthanized 3.5 months after experimental infection. The birds were removed from the experiment in accordance with the "Rules for carrying out work using experimental animals" and in accordance with the principles of the Declaration of Helsinki, and approved by the Institutional Review Board. The intensity of invasion (AI, lich./g) for each chicken and the average for the group and AI by the distribution of larvae in the slice were determined. Histological preparations of the spleen were prepared according to the classical method and stained with hematoxylin – eosin. Results. After digestion of muscle mass in artificial gastric juice, the number of larvae was 2570+640 l./g of muscles (average AI from muscle samples of the studied groups), no trichinella larvae were found in the control group. By CT, the largest AI was found in the muscles of the head (5.5+1.5 larvae in the section). The parenchyma of the organ of the spleen is represented by red and white pulp, in healthy birds the area of the red pulp was 10 + 5% of the area of the organ, and the white pulp 76.5 + 5% of the mass of the organ. In chickens infected with trichinella larvae, the area of the white pulp increased dramatically to 90% of the organ area and more. Conclusion. The chicken spleen is actively involved in the pathogenesis of helminthiasis of birds. The follicles of the white pulp, as in the trichinosis of white mice, grow, merging into large conglomerates. In birds, as well as in mammals, the number of large lymphocytes and plasmocytes increases, which indicates the similarity of intercellular interactions and the reaction of immunocompetent cells to the introduction of the parasite.

Cross‑talk between lymphangiogenesis and malignant melanoma cells: New opinions on tumour drainage and immunization (Review).

Malignant melanoma (MM) is a highly aggressive tumour that can easily metastasize through the lymphatic system at the early stages. Lymph node (LN) involvement and lymphatic vessel (LV) density (LVD) represent a harbinger of an adverse prognosis, indicating a strong link between the state of the lymphatic system and the advancement of MM. Permeable capillary lymphatic vessels are the optimal conduits for melanoma cell (MMC) invasion, and lymphatic endothelial cells (LECs) can also release a variety of chemokines that actively attract MMCs expressing chemokine ligands through a gradient orientation. Moreover, due to the lower oxidative stress environment in the lymph compared with the blood circulation, MMCs are more likely to survive and colonize. The number of LVs surrounding MM is associated with tumour-infiltrating lymphocytes (TILs), which is crucial for the effectiveness of immunotherapy. On the other hand, MMCs can release various endothelial growth factors such as VEGF-C/D-VEGFR3 to mediate LN education and promote lymphangiogenesis. Tumour-derived extracellular vesicles are also used to promote lymphangiogenesis and create a microenvironment that is more conducive to tumour progression. MM is surrounded by a large number of lymphocytes. However, both LECs and MMCs are highly plastic, playing multiple roles in evading immune surveillance. They achieve this by expressing inhibitory ligands or reducing antigen recognition. In recent years, tertiary lymphoid structures have been shown to be associated with response to anti-immune checkpoint therapy, which is often a positive prognostic feature in MM. The present review discusses the interaction between lymphangiogenesis and MM metastasis, and it was concluded that the relationship between LVD and TILs and patient prognosis is analogous to a dynamically tilted scale.

The need of radiotherapy optimization for glioblastomas considering immune responses.

Glioblastoma is the most common of malignant primary brain tumors and one of the tumors with the poorest prognosis for which the overall survival rate has not significantly improved despite recent advances in treatment techniques and therapeutic drugs. Since the emergence of immune checkpoint inhibitors, the immune response to tumors has attracted increasing attention. Treatments affecting the immune system have been attempted for various tumors, including glioblastomas, but little has been shown to be effective. It has been found that the reason for this is that glioblastomas have a high ability to evade attacks from the immune system, and that the lymphocyte depletion associated with treatment can reduce its immune function. Currently, research to elucidate the resistance of glioblastomas to the immune system and development of new immunotherapies are being vigorously carried out. Targeting of radiation therapy for glioblastomas varies among guidelines and clinical trials. Based on early reports, target definitions with wide margins are common, but there are also reports that narrowing the margins does not make a significant difference in treatment outcome. It has also been suggested that a large number of lymphocytes in the blood are irradiated by the irradiation treatment to a wide area in a large number of fractionations, which may reduce the immune function, and the blood is being recognized as an organ at risk. Recently, a randomized phase II trial comparing two types of target definition in radiotherapy for glioblastomas was conducted, and it was reported that the overall survival and progression-free survival were significantly better in a small irradiation field group. We review recent findings on the immune response and the immunotherapy to glioblastomas and the novel role of radiotherapy and propose the need to develop an optimal radiotherapy that takes radiation effects on the immune function into account.

Inflammatory pseudotumor-like follicular dendritic cell sarcoma with first clinical manifestation of thrombocytopenia: A case report.

Inflammatory pseudotumor-like follicular dendritic cell sarcoma (IPT-like FDCS) is often associated with Epstein-Barr (EB) virus infection. The tumor is commonly found in the spleen and liver, and it has been reported in the literature that it can be associated with paraneoplastic pemphigus, myasthenia gravis, and other diseases. A case of IPT-like FDCS with clinical features of thrombocytopenia has not been reported. A 59-year-old male patient visited our hospital in September 2020 due to bleeding gums and epistaxis. Splenic lymphoma with marked thrombocytopenia was initially diagnosed. The patient underwent pathological examination after splenectomy. Microscopic examination showed spindle-shaped or oval cells arranged in loose bundles, a large number of lymphocytes and plasma cells infiltrating the interstitium, and fibrin-like changes in the blood vessel wall. Immunohistochemical detection of tumor cells was positive for CD21, CD35, and Epstein-Barr virus in situ hybridization, and the patient was diagnosed with IPT-like FDCS. The patient underwent a splenectomy. The patient received platelet-raising therapy postoperatively. No tumor recurrence or metastasis was found during the 17-month follow-up period, and the platelet count returned to normal. IPT-like FDCS is an uncommon tumor, and its first presentation with marked thrombocytopenia is even rarer. The tumor was clinically and radiographically nonspecific. Definitive diagnosis relies on histopathological and immunohistochemical staining. IPT-like FDCS is biologically indolent and has a favorable prognosis.

Inflammatory pseudotumor-like follicular dendritic cell sarcoma with first clinical manifestation of thrombocytopenia: a case report

Inflammatory pseudotumor-like follicular dendritic cell sarcoma (IPT-like FDCS) is often associated with Epsrein-Barr (EB) virus infection. A male patient visited our hospital in September 2020 due to bleeding gums and epistaxis. The initial diagnosis was splenic lymphoma with marked thrombocytopenia. The patient was sent for pathological examination after splenectomy. Microscopic examination showed spindle-shaped or oval cells arranged in loose bundles, a large number of lymphocytes and plasma cells infiltrated in the interstitium, and fibrin-like changes in the blood vessel wall. Immunohistochemical detection of tumor cells was positive for CD21, CD35 and EBER, and we diagnosed IPT-like FDCS. The patient received platelet-raising therapy after operation. No tumor recurrence or metastasis was found during the 17-month follow-up, and the platelets returned to normal.IPT-like FDCS is an uncommon tumor, and the first presentation with marked thrombocytopenia is even rarer. The tumor was clinically and radiographically nonspecific. Its definitive diagnosis needs to rely on histopathological and immunohistochemical staining. IPT-like FDCS is biologically indolent and has a good prognosis.

Social Isolation Influences Endocrine and Metabolic Parameters in Female Mice Depending on Estrous State

Social distancing is a critical public health strategy employed to reduce the transmission of respiratory illnesses, such as COVID‐19. Studies conducted throughout the pandemic suggest that social distancing measures, including staying at home, simultaneously lead to an increased experience of isolation and loneliness. Social isolation is of potential concern because previous research in both humans and non‐human animals demonstrates that reduced social interaction has detrimental effects on mental and physical wellness, including an increase in mortality rate. Despite this background, less is known about how social isolation affects physiological parameters in a comprehensive manner, especially in females. We therefore conducted this study to investigate the extent to which social isolation simultaneously impacts multiple physiological and behavioral variables related to stress, metabolism, and reproduction. To do this, we housed three‐week‐old female Swiss‐Webster mice individually or in groups of three for five weeks. We measured body weight and food consumption each week of the experiment. During the last two weeks of treatment, we tracked the estrous cycle, using vaginal cytology to determine estrous states. After four weeks of housing treatment, we used closed system respirometry to measure oxygen consumption rate as an approximation of whole‐body metabolic rate. At the conclusion of the study, we collected blood in order to measure leukocyte counts, blood glucose concentration, and serum estrogen and progesterone concentrations. Individually housed females consistently consumed more food compared to group‐housed females. While there was no effect of social isolation on the length or proportion of time spent in the different estrous phases, the effects of isolation on other physiological variables depended on estrous state. Our preliminary results suggest that body weight, oxygen consumption rate, number of large lymphocytes, blood glucose concentration, and serum progesterone concentration were higher in individually housed females in diestrus, compared to group‐housed females in diestrus. In contrast, serum estrogen concentration was lower in individually housed females in diestrus, compared to group‐housed females in diestrus. Taken together, these findings suggest that social isolation has a substantial body‐wide effect on physiology and health in females, potentially mediated through a direct effect on ovarian hormone secretion. Furthermore, these findings highlight the importance of studying how stressors impact female physiology in naturally cycling animals.

CHANGES IN THE STRUCTURAL ORGANIZATION OF THE SPLEEN UNDER THE INFLUENCE OF MONOSODIUM GLUTAMATE AND AFTER ITS ABOLITION

Актуальність. Глутамат натрію є однією з найпоширеніших харчових добавок в світі. В статті наведено та проаналізовано дані експериментального дослідження, яке проводено на 52 білих щурах самцях та самках репродуктивного віку.
 Мета дослідження – вивчити морфометричні, гістологічні та електронно-мікроскопічні зміни паренхіми селезінки щурів за умов впливу глутамату натрію та після його відміни.
 Методи. Мікроанатомію компонентів селезінки білих щурів за умов фізіологічної норми дослідили на 10 інтактних тваринах. Експериментальні тварини поділені на 3 групи. Статистичну обробку цифрових даних проводили за допомогою програмного забезпечення «Excel» та «STATISTICA» 6.0 з використанням параметричного методу.
 Результати. Через вісім тижнів дії глутамату натрію виявлено достовірне зменшення відносної площі білої пульпи в паренхімі селезінки білих щурів самців та самок, збільшення кількості вторинних лімфоїдних вузликів, зростання кількості моноцитів, макрофагів, плазматичних клітин та клітин мієлоїдного ряду, зростання частки ретикулярної сполучної тканини в складі селезінкових тяжів червоної пульпи. Еритроцити та тромбоцити заповнюють не лише просвіт пазух селезінки, але й накопичуються в пульпарних тяжах, велика кількість лімфоцитів на різних стадіях апоптозу. Венозні пазухи червоної пульпи повнокровні, їхні просвіти розширені та дещо деформовані. Навколо судин та венозних пазух наявні ознаки набряку. Збільшення кількості плазматичних клітин свідчить про пришвидшення проліферації активованих лімфоцитів, яке є ознакою iмуноіндукуючого ефекту. Через чотири тижні після відміни глутамату натрію гістологічна та електронно-мікроскопічна будова органа майже не відрізняється від попередньої групи тварин. Зростає повнокрів’я судин паренхіми селезінки, щільність клітин зменшується. Збільшується кількість апоптично змінених клітин.
 Підсумок. Через вісім тижнів після відміни глутамату натрію зворотніх змін у структурі паренхіми селезінки не виявлено. Отже, відміна введення глутамату натрію після його тривалого впливу не «покращує» морфометричних показників паренхіми селезінки щурів та не призводить до відновлення структурної організації органа.

Neurobrucellosis due to Brucella ceti ST26 in Three Sowerby's Beaked Whales (Mesoplodon bidens)

Fatal meningoencephalitis due to Brucella ceti infection has been described in striped dolphins (Stenella coeruleoalba), Atlantic white-sided dolphins (Lagenorhynchus acutus), short-beaked common dolphins (Delphinus delphis) and long-finned pilot whales (Globicephala melas), which are all within the family Delphinidae. We report B. ceti-associated neurobrucellosis in three juvenile male Sowerby's beaked whales (Mesoplodon bidens) that all had typical lesions of lymphocytic meningoencephalitis, which increased in severity from rostral to caudal regions of the brain. In two cases there was loss of ependymal cells lining the cerebral ventricular system, with large numbers of lymphocytes in the underlying neuropil. This finding suggests that B. ceti gains access to, and multiplies in, the cerebrospinal fluid, and confirms that this is the sample of choice for bacteriological recovery of the causative organism. These findings expand the increasing range of cetaceans susceptible to neurobrucellosis to members of the family Ziphiidae.

Circadian Variations in Cellular Composition of Lymphoid Organs in Rats with Experimental Endomyometritis.

Circadian variations in the cellular composition of the lymphoid organs were studied in female Wistar rats under normal conditions and in experimental endomyometritis. The fractions of CD8+ cells (effector killers), CD25+ cells (activated/immature lymphocytes), as well as large, medium, small lymphocytes and monocytes/macrophages were assessed at 10.00 and 20.00 h. In the thymus and spleen of rats with endomyometritis, the number of parameters demonstrating significant circadian variations was lower than in intact animals. In the lymph nodes, morning/evening differences appeared for the number of CD8+ and CD25+ cells and monocytes/macrophages in the para-aortic lymph nodes, the number of large and small lymphocytes and CD8+ cells in inguinal lymph nodes, and in the number of large lymphocytes, CD8+ cells, and monocytes/macrophages in the ileal lymph nodes. Thus, the development of chronic inflammation in the uterine and vaginal mucosa was accompanied by desynchronosis in the immune system. Hence, circadian rhythms should be taken into consideration in the diagnosis and treatment of the disease.

Neuroimmunomodulation in the mucosa of the alimentary tract

Neuropeptides synthetised in the enteric nervous system can change the function of the immunocells and play a role in inflammatory processes. In our review the effects of inflammation on the neuropeptide content of nerves and immune cells were compared. Inflamed tissue samples (human gastritis and animal models with experimental colitis and streptozotocin-induced diabetes mellitus) were examined. The number and contacts of neuropeptide-containing nerves and immune cells were studied using immunohistochemistry, confocal laser microscopy and electronmicroscopy. In inflammation, the number of substance P, vasoactive intestinal polypeptide and neuropeptide Y nerve fibres was increased significantly in parallel with the strongly increased number of immunocompetent cells (p<0.001). In inflammatory diseases, a large number of lymphocytes and mast cells were also positive for these neuropeptides. Very close morphological relationship between substance P and neuropeptide Y immunoreactive nerve fibres and immunocells could be demonstrated only in inflamed mucosa. Some of the substance P immunoreactive immunocells were also immunoreactive for tumor necrosis factor alpha and nuclear factor kappa B in the case of inflammation. The increased number of tumor necrosis factor alpha and nuclear factor kappa B immunoreactive immune cells correlated with the increased number of substance P-containing nerve fibres. Substance P, vasoactive intestinal polypeptide and neuropeptide Y released from nerve fibres and immunocells can play a role in inflammation. Our results suggest that using substance P antagonists or vasoactive intestinal polypeptide and neuropeptide Y peptides might be a novel therapeutic concept in the management of inflammation. Orv Hetil. 2020; 161(35): 1436-1440.

Cranioesophageal Pythiosis in a Horse

Background: Pythiosis is a chronic inflammatory disease that is caused by oomycete Pythium insidiosum. This illness affects several species including humans and horses. Equine is the most affected species, having no predisposition for breed, gender, or age. It is usually shown in cutaneous and subcutaneous forms, and the lesions, which grow quickly and are hard to treat, are located mainly in the extremities. The diagnosis is made via epidemiology, clinical signs, and macroscopic and microscopic aspects of the lesion. This study describes a case of cranioesophageal pythiosis in a horse, examining the epidemiological, clinical and pathological characteristics.Case: A 12-year-old male quarter horse, weighing 515 kg was taken to the Veterinary Hospital at the University Center of Espírito Santo (UNESC). The horse had an increase in volume in the cranioesophageal region, coughing, difficulty breathing, and a runny nose. On clinical examination, the horse showed an enlargement in the submandibular and retropharyngeal lymph nodes, subcutaneous edema in the larynx region, and a temperature of 38.2ºC. According to the owner, cough was recurrent and had lasted about 12 months even after treatment with different kinds of antimicrobials. On radiographic exam, there was a marked decrease in the tracheal lumen and increased soft tissue radiopacity in the region adjacent to the narrowing. The animal was taken to surgery to remove the mass, but he died because of complications during surgery. The animal’s owner did not allow necropsy, but a fragment of the mass in the cranioesophageal was removed and sent for histological examination. The fragment was fixed in 10% formalin and processed using routine histological analysis. Macroscopically, the mass was light yellowish and ulcerated, and it measured 7.0 × 5.0 × 5.0 cm. In the middle of the ulcerated areas, there were yellow and firm granular structures that were consistent with kunkers. Histologically, extending from the tracheal adventitia to the thyroid, there was a large number of lymphocytes, macrophages, neutrophils, eosinophils, and multinucleated cells (foreign body type) and a well-defined focus of coagulative necrosis, which was surrounded by a thin border of macrophages. Within the necrotic areas, there were negative images of tubuliform hyphae. Grocott’s silver methanamine staining showed hyphae that had irregular branches, rare septa, smooth and parallel walls, and was impregnated by silver. Histological sections of the mass were subjected to immunohistochemistry. Hyphae were positive for Pythium insidiosum.Discussion: The diagnosis of pythiosis was based on macroscopic, histological findings and positive immunostaining for Pythium insidiosum. This report shows the unusual location of the disease in the horse, which made the clinical diagnosis of the disease complex. Extracutaneous forms of pythiosis in horses are less frequent than cutaneous forms. The etiopathogenesis of these forms is still unclear, but it has been suggested that previous lesions in the intestinal mucosa caused by plant material or pathogens may be predisposing factors for the appearance of the enteric form of the disease. It was not possible to observe if the animal’s other organs were affected because a necropsy could not be performed. The agent probably penetrated the esophageal epithelium and spread throughout the trachea and thyroid, but its origin cannot be determined. The radiographic findings in this study are compatible with neoplasms. However, inflammatory processes such as those caused by pythiosis should be included in the differential diagnosis of horses with swelling in the cranial portion of the esophagus.

HTLV-1c associated bronchiolitis in an Aboriginal man from central Australia

We describe the first case of HTLV associated bronchiolitis to be associated with HTLV-1c subtype infection. An Aboriginal man with HTLV-1 infection was repeatedly admitted to Alice Springs Hospital, central Australia, with hypercapnic respiratory failure from the age of 28 years. High resolution CT chest findings were consistent with bronchiolitis and large numbers of lymphocytes were found in bronchoalveolar lavage fluid (BALF). After extensive investigations failed to find a cause, he was tested for HTLV-1 and found to have a high HTLV-1c proviral load (6.8 %) in peripheral blood leukocytes and in BALF (4.7 %). The administration of systemic corticosteroids resulted in a rapid clinical response; however, he did not continue treatment after discharge and died due to respiratory failure in the community.

Abstract 1420: Novel expansion of CD8+PD1+ spleen cells for therapeutic intent in pancreatic adenocarcinoma cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor prognosis and overall survival. In 2018 it is estimated that there will be 44,333 deaths making PDAC the 3rd cause of cancer related deaths. A distal pancreatomy for PDAC in the body/tail of the pancreas usually includes a splenectomy, with current practice to discard the spleen post-surgery. Spleens can provide a large number of lymphocytes, including CD8+ T-cells with potential to be utilized for adoptive cellular therapy. Our studies have focused on spleen from this patient population, which we posit (and show herein) provides a large number of CD8+PD1+ cells for expansion and the first clinical strategy to expand activated, tumor specific T-cells for subsequent infusion with therapeutic intent. In our studies we used Milteny magnetic bead isolation of CD8+PD1+ T-cells from the spleens of PDAC patients with disease in the distal pancreas. The purity of the cells was 98% with a yield of 79% providing 9x108 CD8+PD1+ cells from an idealized 160 gm spleen. CD8 expansion was undertaken with various growth factor cocktails incorporating combinations of three interleukins (IL); IL-7, IL-15, and IL-21 at varying concentrations. IL-7 supports T-cell survival and proliferation, IL-15 is a potent T-cell growth factor and promotes naïve and memory T-cell survival, and IL-21 limits T-cell exhaustion in response to chronic stimulation. The optimized cocktail incorporated IL-7, IL-15, and IL-21 at 40 ng/mL, which demonstrated maximum T-cell expansion, based on cellularity and cell viability. The predominant T-cell memory phenotype of the CD8+PD1+ cells following expansion was transitional memory (TTM) T-cells that increased from 35.6 ± 4.3 to 52 ± 3%. This memory T-cell phenotype has a high proliferative potential while retaining effector function. Following six days of culture with the three interleukins we observed a 10 fold increase in CD8+PD1+ cells such that 9x109 cells are obtained from the 160 gm spleen. These cells, based on ELISPOT analysis with autologous tumor lysate pulsed dendritic cells retained tumor specificity. In conclusion, CD8+PD1+ cells can be isolated from resected spleen, expanded with retention of tumor specificity and potentially used for adoptive cellular therapy. Citation Format: Kathryn Cole, Quan P. Ly, Jesse L. Cox, Michael A. Hollingsworth, James C. Padussis, Jason M. Foster, Luciano M. Vargas, James E. Talmadge. Novel expansion of CD8+PD1+ spleen cells for therapeutic intent in pancreatic adenocarcinoma cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1420.

Abstract 4049: Cellular phenotypes of spleen cells in cancer patients targeted for adoptive cellular therapy

Abstract The spleen is a rich resource of large numbers of lymphocytes, with potential for use in adoptive cellular therapy (ACT). This is of particular relevance to patients with a distal pancreatic ductal adenocarcinoma (PDAC) who frequently undergo a pancreatectomy that required a splenectomy to clear the nodal basin. In this study we compared the phenotypes of eight paired sets of peripheral blood (PB) and spleen cell populations to assess the frequency of myeloid derived suppressor cells (MDSC) and lymphocyte subpopulations. Because a positive clinical response to ACT requires a low frequency of T-regs and MDSC’s, both systemically and in the tumor microenvironment these cells were one of the foci for our studies. A high frequency of these cells negatively correlate with survival and positively with tumor burden. Indeed, in this study we observed a significant decrease in the frequency of granulocytic, monocytic and immature MDSC’s in the spleen vs PB (4.8±1.6 vs. 54.4±6.1; 0.2±0.1 vs. 0.9±0.4; and 0.6±0.1 vs. 2.3±0.8 percent respectively) but not T-regulatory (T-reg) cells (0.8+0.5 vs. 0.1+0.04 percent) supporting the potential superiority of spleen cells relative to PB as a cellular source for ACT. In addition to a significantly higher number of spleen cells as compared to the PB for expansion/infusion, spleens have a higher frequency of T-cells as compared to the PB including CD3+ (35+5 vs. 16+4%), CD4+ (19+2 vs. 10+2%) and CD8+ (10+1 vs. 5+2%) T-cells. The frequency of transitional memory (Ttm) T-cells, which have a high proliferative potential were also significantly increased in the spleen vs. PB (37.5±6 vs. 26±3.0%) as was the frequency of PD1+CD8+ T-cells (8+2 vs 1+0.5%), which have been shown to have tumor specific cytotoxicity in cancer patients. In summary the increased frequency of PD-1+CD8+ cells, a Ttm memory phenotype and low levels of an exhaustion phenotype (TIM3 and Lag3 expression) in spleen cells vs the PB is supportive of the potential utility of these cells for expansion and therapeutic utility for these cells. Citation Format: Kathryn Cole, Quan Ly, Jesse L. Cox, Michael A. Hollingsworth, James C. Padussis, Jason M. Foster, Luciano M. Vargas, James E. Talmadge. Cellular phenotypes of spleen cells in cancer patients targeted for adoptive cellular therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4049.

Advances in IgG4-related sinonasal diseases

IgG4 related disease (IgG4-RD) is an independent clinical pathological entity which is different from common chronic inflammation and other autoimmune diseases in recent years. It often appears in the form of tumor like tissue-destructive lesions and may be accompanied by the increase of concentration of serum IgG4. Histopathology is characterized by a large number of lymphocytes and plasma cells infiltration, storiform fibrosis and occlusive phlebitis. The characteristics of IgG4-RD in nose and sinuses have not been widely investigated. The aim of the present study is to review the advances in IgG4 related sinonasal diseases from four aspects including pathogenesis, clinical features, treatment and future research directions.

Expression of the apoptosis-releated genes in patients with newly diagnosed chronic lymphocytic leukemia in clinical data context

Introduction.The given data of fundamental studies of apoptosis processes in B-cell lymphocytic leukemia (B-CLL) testifies about the complexity and variety of mechanisms affecting the kinetics of normal cells and tumor lymphocytes in this disease. It is important to study the severity of clinical manifestations of the disease depending on the expression of the genes that modulate apoptosis.The purposeof the study is to compare the activity of genes encoding apoptosis modulators, the cell cycle and cancer-testicular PRAME protein with clinical manifestations of the disease in primary patients with B-CLL.Materials and methods.The level of expression of the proapoptotic genes FAS, TRAIL, TNFR2, DR4/5 and DR3, as well as the HSP27, XIAP genes, blocking apoptosis was determined in 23 patients with newly diagnosed chronic B-CLL. In addition, expression of genes TP53 and P21 and cancer-testis gene PRAME are tested.Results.According to the multivariate regression analysis, the FAS gene expression in the onset of the disease had the greatest impact on the clinical characteristics of the disease. In this connection, the patients were divided into groups with normal (group) and low gene level (group II). A low level of FAS expression (Me 387 %) was associated with stage II disease (p = 0.03), a large number of lympho cytes (p = 0.001), fewer erythrocytes (p = 0.08), and a lower level of TNFR2 gene expression (p = 0.08), high level of expression of XIAP, HSP27, P21. Overall, the anti-apoptotic potential in Group II patients was higher, which was accompanied by more pronounced clinical manifestations of the disease.Conclusions.The increased anti-apoptotic potential of tumor lymphocytes in newly diagnosed B-CLL is accompanied by a larger tumor mass and greater clinical and hematological manifestation of the disease.

THE ROLE OF ADHESION MOLECULES IN THE MIGRATION OF LEUKOCYTES FROM THE BLOOD TO THE CAPILLARIES OF PAPULES IN PATIENTS WITH PSORIASIS

The processes of leukocytes' migration to the psoriatic papule are important mechanisms in the development of immune reactive changes. The research relevance is determined by search for clinically significant targets for anti-inflammatory therapy (for ex. adhesion molecules). The aim of the study was to investigate the role of adhesion molecules in the mechanisms of blood leukocytes migration to papule capillaries in patients with psoriasis. Methods: Clinical immunological examination of 82 patients suffering from psoriasis vulgaris and exudative and 50 practically healthy people (a control group) was carried out. The content of neutrophils, monocytes, and lymphocytes was determined on the smears of venous blood and blood obtained as a phenomenon of pinpoint bleeding of the psoriatic triad localized on forearm. Their morphological differentiation was performed. The number of neutrophils, monocytes and lymphocytes of venous blood containing molecules of L-selectin (CD62L), LFA-1 (CD11a), LFA-3 (CD58), ICAM-1 (CD54), PECAM-1- (CD31) was determined on a flow cytometer FC-500, BeckmanCoulter (USA). Results: It was stated that the capillary blood of psoriatic papules was characterized by a lower content of neutrophils with a predominance of 2-segmental forms; the content of monocytes was 3 times higher than the level of venous blood due to an increase in the level of polymorphonuclear forms; as well as an increase in the number of large lymphocytes. At the stage of "rolling" an increasing tendency to the concentration of neutrophils carrying the l-selectin molecule were observed in patients with psoriasis. A decrease in the expression of ICAM-1 and LFA-3 molecules on neutrophils involved in the "stabile adhesion" stage was revealed. A statistically significant decrease in the concentration of PECAM-1 molecule on neutrophils was stated at the "transmigration" stage. Conclusions: The mechanisms of adhesion molecule expression in different leukocyte populations differ, which ensures accurate adjustment of migration through the endothelium. These reactions lead to the progression of immune inflammation, each stage of which has its own markers, such as cellular adhesion molecules.

Clinicopathological analysis of 22 cases of cutaneous epithelioid hemangioma

Objective To investigate clinical and histopathological features of cutaneous epithelioid hemangioma (EH) . Methods Clinical and histological data were collected from 22 patients with EH and analyzed. Results Of the 22 EH patients, 10 were male, and 12 were female. The age at onset ranged from 16 to 62 years, with an average age of 45.91 years. The duration of disease varied from 1 month to 20 years, with an average disease duration of 37 months. Skin lesions most frequently occurred on the scalp in 14 cases (63.6%) , followed by the ear in 6 cases (27.3%) , the forehead in 2 cases (9.1%) , and the thigh in 1 case (4.5%) . Lesions affected both the scalp and forehead in 1 case. Histopathological examination of the 22 cases revealed vascular proliferation. The blood vessels were lined with epithelioid endothelial cells, and a large number of lymphocytes and eosinophils infiltrated around the vessels. The dermis were involved in all cases, and subcutaneous tissues were involved in 8 cases (36.4%) . Immunohistochemical examination of 6 cases showed positive staining for CD31, CD34 and factor Ⅷ in blood vessel walls. Conclusion EH is an uncommon disease characterized by vascular proliferation and inflammatory infiltration, and clinical manifestations in combination with histopathological examination facilitate its diagnosis. Key words: Angiolymphoid hyperplasia with eosinophilia; Epithelioid hemangioma; Kimura disease

CHANGES IN THE CELL SQUAD OF ILIAC LYMPH NODES OF WHITE RATS IN CASE OF LONGTERM INFLUENCE OF NALBUFIN

The article presents data on the change in the cellular composition of the lymph nodes of the white rats, males of reproductive age, who received intramuscular opioid analgesics - nalbuphine every day for six weeks. The weekly dose of nalbuphine was gradually increased, creating a model of physical opioid dependence according to the patent of Ukraine No. 76564 U. All experimental animals were divided into 8 groups. Morphometric method was used to determine the relative number of cells of the lymphoid series - small, medium and large lymphocytes, blasts and plasmocytes in the cloak zone and the embryonic center of the secondary lymphoid nodes and brain strands of the lymph nodes. Morphometric studies were performed using a system of visual analysis of histological preparations. It was established that nalbuphine in the lymph nodes causes reactive and destructive changes: the number of large lymphocytes increases in all structural components of the lymph node with a maximum after 4 weeks, respectively, the relative number of small lymphocytes decreases in the nucleus centers and brain tracts, the relative number of plasmocytes in the brain strains increases sharply . In all structural components of the lymph nodes hemocapillaries and venules are dilated and full-blooded, around vascular edema and partial damage to the walls of the microvessels. One week after the discontinuation of nalbuphine, the relative number of lymphoid cells in the structural components of the lymph nodes does not return to the indicators of intact animals, no reversible changes are noted.