Tumour-infiltrating cytotoxic T lymphocytes in somatotroph pituitary neuroendocrine tumours

Abstract Introduction Somatotroph pituitary tumours are often resistant to first-generation somatostatin analogues and can invade the surrounding structures, limiting the chances of curative surgery. Recent studies suggested that the immune microenvironment and pro-angiogenic factors can influence neuroendocrine tumour prognosis. In this study, we aimed to investigate the prognostic role of immune cell-specific markers and endocan, a proteoglycan involved in neoangiogenesis and cell adhesion, in a cohort of acromegaly patients who underwent pituitary surgery as first-line treatment. Subjects and methods Sixty four eligible subjects were identified. CD4+, CD8+ and CD68+ cells and endocan expression were evaluated by immunohistochemistry and results correlated with clinical and neuroradiological findings. Responsiveness to somatostatin analogues was assessed in patients with persistent disease following surgery. Results The number of CD8+ lymphocytes was significantly lower in tumours with cavernous sinus invasion (median 0.2/HPF, IQR: 2.2) compared with those without cavernous sinus invasion (median 2.4/HPF, IQR: 2.3; P = 0.04). Tumours resistant to first-generation somatostatin analogues had lower CD8+ lymphocytes (median 1/HPF, IQR: 2.4) compared with responders (median 2.4/HPF, IQR: 2.9; P = 0.005). CD4+ lymphocytes were observed sporadically. The number of CD68+ macrophages and the endothelial or tumour cell endocan expression did not differ based on tumour size, cavernous sinus invasion or treatment responsiveness. Conclusions Our study suggests that a lower number of CD8+ lymphocytes is associated with cavernous sinus invasion and resistance to treatment with first-generation somatostatin analogues in acromegaly patients. These results highlight a potential role of the tumour immune microenvironment in determining the prognosis of somatotroph pituitary tumours.

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Extradural anterior clinoidectomy in surgical management of clinoidal meningiomas

The Egyptian Journal of Neurology Psychiatry and Neurosurgery ◽

10.1186/s41983-021-00336-x ◽

2021 ◽

Vol 57 (1) ◽

Author(s):

K. El-Bahy ◽

Ashraf M. Ibrahim ◽

Ibrahim Abdelmohsen ◽

Hatem A. Sabry

Keyword(s):

Cavernous Sinus ◽

Tumor Resection ◽

Visual Outcome ◽

Extent Of Resection ◽

Optic Canal ◽

Falciform Ligament ◽

Cavernous Sinus Invasion ◽

Anterior Clinoidectomy ◽

Microsurgical Techniques

Abstract Background Despite the recent advances in skull base surgery, microsurgical techniques, and neuroimaging, yet surgical resection of clinoidal meningiomas is still a major challenge. In this study, we present our institution experience in the surgical treatment of anterior clinoidal meningiomas highlighting the role of extradural anterior clinoidectomy in improving the visual outcome and the extent of tumor resection. This is a prospective observational study conducted on 33 consecutive patients with clinoidal meningiomas. The surgical approach utilized consisted of extradural anterior clinoidectomy, optic canal deroofing with falciform ligament opening in all patients. The primary outcome assessment was visual improvement and secondary outcomes were extent of tumor resection, recurrence, and postoperative complications. Results The study included 5 males and 28 females with mean age 49.48 ± 11.41 years. Preoperative visual deficit was present in 30 (90.9%) patients. Optic canal involvement was present in 24 (72.7%) patients, ICA encasement was in 16 (48.5%), and cavernous sinus invasion in 8 (24.2%). Vision improved in 21 patients (70%), while 6 patients (20%) had stationary course and 1 patient (3%) suffered postoperative new visual deterioration. Gross total resection was achieved in 24 patients (72.7%). The main factors precluding total removal were cavernous sinus involvement and ICA encasement. Mortality rate was 6.1%; mean follow-up period was 27 ± 13 months. Conclusions In this series, the use of extradural anterior clinoidectomy provided a favorable visual outcome and improved the extent of resection in clinoidal meningioma patients.

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Association of different pathologic subtypes of growth hormone producing pituitary adenoma and remission in acromegaly patients: a retrospective cohort study

BMC Endocrine Disorders ◽

10.1186/s12902-021-00850-2 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Maryam Dehghani ◽

Zahra Davoodi ◽

Farahnaz Bidari ◽

Amin Momeni Moghaddam ◽

Davood Khalili ◽

...

Keyword(s):

Growth Hormone ◽

Cohort Study ◽

Cavernous Sinus ◽

Retrospective Cohort Study ◽

Pituitary Adenomas ◽

Retrospective Cohort ◽

Remission Rate ◽

Cavernous Sinus Invasion ◽

Dual Staining

Abstract Background Regarding the inconclusive results of previous investigations, this study aimed to determine the association between pathology, as a possible predictor, with remission outcomes, to know the role of pathology in the personalized decision making in acromegaly patients. Methods A retrospective cohort study was performed on the consecutive surgeries for growth hormone (GH) producing pituitary adenomas from February 2015 to January 2021. Seventy-one patients were assessed for granulation patterns and prolactin co-expression as dual staining adenomas. The role of pathology and some other predictors on surgical remission was evaluated using logistic regression models. Results Among 71 included patients, 34 (47.9%) patients had densely granulated (DG), 14 (19.7%) had sparsely granulated (SG), 23 (32.4%) had dual staining pituitary adenomas. The remission rate was about 62.5% in the patients with SG and DG adenomas named single staining and 52.2% in dual staining groups. Postoperative remission was 1.53-folds higher in the single staining adenomas than dual staining-one (non-significant). The remission rate was doubled in DG group compared to two other groups (non-significant). By adjusting different predictors, cavernous sinus invasion and one-day postoperative GH levels decreased remission rate by 91% (95% CI: 0.01–0.67; p = 0.015) and 64% (95% CI: 0.19–0.69; p < 0.001), respectively. Responses to the medications were not significantly different among three groups. Conclusion Various pathological subtypes of pituitary adenomas do not appear to have a predictive role in estimating remission outcomes. Cavernous sinus invasion followed by one-day postoperative GH is the strongest parameter to predict biochemical remission.

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Safety and efficacy of mini doppler in recurrent pituitary tumours

Romanian Neurosurgery ◽

10.33962/roneuro-2020-051 ◽

2020 ◽

pp. 336-342

Author(s):

Moshiur Rahman ◽

Ezequiel Garcia-Ballestas ◽

Luis Rafael Moscote-Salazar

Keyword(s):

Cavernous Sinus ◽

Surgical Excision ◽

Pituitary Surgery ◽

Pituitary Tumour ◽

Csf Leak ◽

Surgical Removal ◽

Pituitary Tumours ◽

Female Ratio ◽

Cavernous Sinus Invasion ◽

Number Of Patients

Background: Pituitary surgery is the most common surgery used to remove pituitary tumours. The use of mini doppler in surgical removal of an endonasal pituitary tumour has shown good short-term clinical outcomes and few complications in patients. Cavernous sinus invasion limits the surgical excision and still a challenge of gross total resection. Objective: The main objective of this study is to evaluate the outcome of surgical removal of an endonasal pituitary tumour using mini doppler. Method: A total of 12 patients were studied retrospectively from 2012 to 2018 in a single institution (Private hospital) in Dhaka, Bangladesh. The male and female ratio was 7:5. Results: 92% of cases of the total number of patients had satisfactory removal/ neurological improvement/hormonal improvement. Among 12 cases, 8 cases had transient diabetes insipidus and one patient had CSF leak. Conclusion: The intraoperative Doppler is a useful tool to localize the carotids, which provides safer resection of endonasal pituitary tumours. Thus, it is very safe and effective for laterosellar resection of recurrent pituitary tumours and for cavernous sinus invasions.

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The Role of T Cells and Macrophages in Asthma Pathogenesis: A New Perspective on Mutual Crosstalk

Mediators of Inflammation ◽

10.1155/2020/7835284 ◽

2020 ◽

Vol 2020 ◽

pp. 1-14

Author(s):

Xueyi Zhu ◽

Jie Cui ◽

La Yi ◽

Jingjing Qin ◽

Wuniqiemu Tulake ◽

...

Keyword(s):

T Cells ◽

Cell Activation ◽

Immune Cell ◽

Immune Microenvironment ◽

Innate And Adaptive Immunity ◽

Immune Cell Activation ◽

Inflammatory Signals ◽

Macrophage Dysfunction ◽

New Perspective

Asthma is associated with innate and adaptive immunity mediated by immune cells. T cell or macrophage dysfunction plays a particularly significant role in asthma pathogenesis. Furthermore, crosstalk between them continuously transmits proinflammatory or anti-inflammatory signals, causing the immune cell activation or repression in the immune response. Consequently, the imbalanced immune microenvironment is the major cause of the exacerbation of asthma. Here, we discuss the role of T cells, macrophages, and their interactions in asthma pathogenesis.

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The Cutaneous Wound Innate Immunological Microenvironment

International Journal of Molecular Sciences ◽

10.3390/ijms21228748 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8748

Author(s):

Stephen Kirchner ◽

Vivian Lei ◽

Amanda S. MacLeod

Keyword(s):

Immune Response ◽

Wound Repair ◽

Immune Cell ◽

Skin Barrier ◽

Innate Immune ◽

Immune Microenvironment ◽

Cell Recruitment ◽

Adaptive Processes ◽

Immune Cell Recruitment

The skin represents the first line of defense and innate immune protection against pathogens. Skin normally provides a physical barrier to prevent infection by pathogens; however, wounds, microinjuries, and minor barrier impediments can present open avenues for invasion through the skin. Accordingly, wound repair and protection from invading pathogens are essential processes in successful skin barrier regeneration. To repair and protect wounds, skin promotes the development of a specific and complex immunological microenvironment within and surrounding the disrupted tissue. This immune microenvironment includes both innate and adaptive processes, including immune cell recruitment to the wound and secretion of extracellular factors that can act directly to promote wound closure and wound antimicrobial defense. Recent work has shown that this immune microenvironment also varies according to the specific context of the wound: the microbiome, neuroimmune signaling, environmental effects, and age play roles in altering the innate immune response to wounding. This review will focus on the role of these factors in shaping the cutaneous microenvironment and how this ultimately impacts the immune response to wounding.

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AIP and the somatostatin system in pituitary tumours

Journal of Endocrinology ◽

10.1530/joe-17-0254 ◽

2017 ◽

Vol 235 (3) ◽

pp. R101-R116 ◽

Cited By ~ 9

Author(s):

Alejandro Ibáñez-Costa ◽

Márta Korbonits

Keyword(s):

Zinc Finger Protein ◽

Tumour Size ◽

Somatostatin Receptor ◽

Hormone Secretion ◽

Somatostatin Analogues ◽

Pharmacological Therapy ◽

Interacting Protein ◽

Aryl Hydrocarbon

Classic somatostatin analogues aimed at somatostatin receptor type 2, such as octreotide and lanreotide, represent the mainstay of medical treatment for acromegaly. These agents have the potential to decrease hormone secretion and reduce tumour size. Patients with a germline mutation in the aryl hydrocarbon receptor-interacting protein gene, AIP, develop young-onset acromegaly, poorly responsive to pharmacological therapy. In this review, we summarise the most recent studies on AIP-related pituitary adenomas, paying special attention to the causes of somatostatin resistance; the somatostatin receptor profile including type 2, type 5 and truncated variants; the role of G proteins in this pathology; the use of first and second generation somatostatin analogues; and the role of ZAC1, a zinc-finger protein with expression linked to AIP in somatotrophinoma models and acting as a key mediator of octreotide response.

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Serum and Glucocorticoid-Inducible Kinase 1 (SGK1) in NSCLC Therapy

Pharmaceuticals ◽

10.3390/ph13110413 ◽

2020 ◽

Vol 13 (11) ◽

pp. 413

Author(s):

Ilaria Guerriero ◽

Gianni Monaco ◽

Vincenzo Coppola ◽

Arturo Orlacchio

Keyword(s):

Small Molecules ◽

First Generation ◽

Immune Cell ◽

Therapeutic Window ◽

Immune Microenvironment ◽

Oncogenic Signaling ◽

Future Studies ◽

Normal Tissues ◽

Recent Success ◽

Single Modality

Non-small cell lung cancer (NSCLC) remains the most prevalent and one of the deadliest cancers worldwide. Despite recent success, there is still an urgent need for new therapeutic strategies. It is also becoming increasingly evident that combinatorial approaches are more effective than single modality treatments. This review proposes that the serum and glucocorticoid-inducible kinase 1 (SGK1) may represent an attractive target for therapy of NSCLC. Although ubiquitously expressed, SGK1 deletion in mice causes only mild defects of ion physiology. The frequent overexpression of SGK1 in tumors is likely stress-induced and provides a therapeutic window to spare normal tissues. SGK1 appears to promote oncogenic signaling aimed at preserving the survival and fitness of cancer cells. Most importantly, recent investigations have revealed the ability of SGK1 to skew immune-cell differentiation toward pro-tumorigenic phenotypes. Future studies are needed to fully evaluate the potential of SGK1 as a therapeutic target in combinatorial treatments of NSCLC. However, based on what is currently known, SGK1 inactivation can result in anti-oncogenic effects both on tumor cells and on the immune microenvironment. A first generation of small molecules to inactivate SGK1 has already been already produced.

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GENE-27. MENINGIOMA RECURRENCE: ROLE OF M1/M2 TUMOUR-ASSOCIATED MACROPHAGE INFILTRATION

Neuro-Oncology ◽

10.1093/neuonc/noz175.429 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi103-vi103

Author(s):

Dustin Proctor ◽

Jordan Huang ◽

Sanju Lama ◽

Abdulrahman Albakr ◽

Guido Van Marle ◽

...

Keyword(s):

Immune Cell ◽

Phenotypic Diversity ◽

Tumour Size ◽

High Rate ◽

Potential Contribution ◽

Who Grade ◽

Patient Demographics ◽

Meningioma Recurrence ◽

Tumour Characteristics

Abstract BACKGROUND Meningioma, a most common brain tumour, has a high rate of recurrence. Tumour-associated macrophages (TAMs) are the most abundant immune cell type in meningioma. TAMs display functional phenotypic diversity and may establish either an inflammatory and anti-tumoural or an immunosuppressive and pro-tumoural microenvironment. TAM subtypes present in meningioma and potential contribution to growth and recurrence is unknown. METHODS Fluorescence immunohistochemistry was used to evaluate the distribution and quantify M1 and M2 TAM populations in 30 meningioma tissues. Association between quantified M1 and M2 cells and M1/M2 ratio to tumour characteristics including WHO grade, tumour recurrence, size, location, peri-tumoural edema and patient demographics such as age and sex was examined. RESULTS TAM cells accounted for ~17% of all cells in tumour tissues. Importantly, greater than 80% of infiltrating TAMs were discovered to be of a polarized pro-tumoural M2 phenotype which positively associated with tumour size. TAM subtype profiles differed significantly between non-recurrent (n=18) and recurrent meningioma (n=12) (P=0.044). Specifically, the M1/M2 cell ratio was decreased by ~250% in recurrent tumours. CONCLUSION This study is the first to confirm existence of pro-tumoural M2 TAMs in the meningioma microenvironment and a potential role in tumour growth and recurrence.

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Pasireotide: successful treatment of a sparsely granulated tumour in a resistant case of acromegaly

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-17-0067 ◽

2017 ◽

Vol 2017 ◽

Author(s):

W K M G Amarawardena ◽

K D Liyanarachchi ◽

J D C Newell-Price ◽

R J M Ross ◽

D Iacovazzo ◽

...

Keyword(s):

Cavernous Sinus ◽

First Generation ◽

Somatostatin Receptor ◽

Oral Glucose ◽

List Type ◽

Residual Tumour ◽

Receptor Ligands ◽

Cavernous Sinus Invasion ◽

Somatostatin Receptor Ligands ◽

Eosinophilic Cytoplasm

Summary The granulation pattern of somatotroph adenomas is well known to be associated with differing clinical and biochemical characteristics, and it has been shown that sparsely granulated tumours respond poorly to commonly used somatostatin receptor ligands (SRLs). We report a challenging case of acromegaly with a sparsely granulated tumour resistant to multiple modalities of treatment, ultimately achieving biochemical control with pasireotide. A 26-year-old lady presented with classical features of acromegaly, which was confirmed by an oral glucose tolerance test. Insulin-like growth factor 1 (IGF1) was 1710 µg/L (103–310 µg/L) and mean growth hormone (GH) was >600 U/L. MRI scan showed a 4 cm pituitary macroadenoma with suprasellar extension and right-sided cavernous sinus invasion. She underwent trans-sphenoidal pituitary surgery. Histology displayed moderate amounts of sparsely granular eosinophilic cytoplasm, staining only for GH. Postoperative investigations showed uncontrolled disease (IGF1:1474 µg/L, mean GH:228 U/L) and residual tumour in the cavernous sinus. She received external beam fractionated radiation. Over the years, she received octreotide LAR (up to 30 mg), lanreotide (up to 120 mg) two weekly, cabergoline, pegvisomant and stereotactic radiosurgery to no avail. Only pegvisomant resulted in an element of disease control; however, this had to be stopped due to abnormal liver function tests. Fifteen years after the diagnosis, she was started on pasireotide 40 mg monthly. Within a month, her IGF1 dropped and has remained within the normal range (103–310 µg/L). Pasireotide has been well tolerated, and there has been significant clinical improvement. Somatostatin receptor subtyping revealed a positivity score of two for both sst5 and sst2a subtypes. Learning points: Age, size of the tumour, GH levels on presentation, histopathological type and the somatostatin receptor status of the tumour in acromegaly should be reviewed in patients who poorly respond to first-generation somatostatin receptor ligands. Tumours that respond poorly to first-generation somatostatin receptor ligands, especially sparsely granulated somatotroph adenomas, can respond to pasireotide and treatment should be considered early in the management of resistant tumours. Patients with membranous expression of sst5 are likely to be more responsive to pasireotide.

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Identification and Validation of a Prognostic Immune-Related Alternative Splicing Events Signature for Glioma

Frontiers in Oncology ◽

10.3389/fonc.2021.650153 ◽

2021 ◽

Vol 11 ◽

Author(s):

Minjie Wang ◽

Zijie Zhou ◽

Jianglin Zheng ◽

Wenxuan Xiao ◽

Jiameng Zhu ◽

...

Keyword(s):

Alternative Splicing ◽

Immune Cells ◽

Prognostic Value ◽

Immune Cell ◽

Cox Regression ◽

Functional Enrichment ◽

Transcriptome Data ◽

Immune Microenvironment ◽

Cox Regression Analysis

BackgroundGlioma is the most common malignant brain tumor in adults, with its tumor-promoting immune microenvironment always being intricate to handle with. Amounts of evidence has accumulated to suggest that alternative splicing (AS) is related to tumor immune microenvironment. However, comprehensive analysis of immune-related AS events and their clinical significance are still lacking in glioma.MethodsAS events and transcriptome data of 653 glioma patients were downloaded online. ssGSEA was performed on transcriptome data of 653 patients to divided them into low, medium and high immune cell infiltration groups. Immune-related AS events were filtrated based on this grouping. Then lasso Cox regression analysis and multivariate Cox regression analysis were done to achieve an immune-related AS events prognostic signature for glioma. Kaplan-Meier analysis, ROC analyses, univariate Cox regression and multivariate Cox regression were performed to reveal the independent prognostic role of this signature. Meanwhile, a nomogram was constructed to achieved better prognostic value for glioma patients. Besides, functional enrichment analyses and correlation analyses with immune cells infiltration were used to validated the immune-related characteristic of this signature.Results36 immune-related AS events were achieved based on the grouping mentioned above. A nine-immune-related alternative splicing event signature was built for glioma patients. This signature showed an independent prognostic value and a nomogram containing gender, age, Karnofsky performance score, grade, IDH status, MGMT promoter status and risk score derived from the signature was constructed with a higher predictive ability for overall survival. Association with the infiltration of immune cell subtypes was validated and functional enrichment analysis found that the signature was mainly enriched in immune-related and pro-tumor functions.ConclusionOur research presented all immune-related AS events in glioma, identified an immune-related prognostic AS events risk model and a nomogram was constructed to predict the prognosis individually and more precisely. Tight connection was verified between this signature and clinical characteristics. Also, immune cells infiltration and immune checkpoints expression level were proved to link to risk scores, which enhanced the understanding of relationship between AS events and glioma immune microenvironment, firstly revealing the potential role of AS in immunotherapy of glioma.

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