Upregulation of MAPKAPK5-AS1, PXN-AS1 and URB1-AS1 lncRNAs in non-functioning pituitary adenoma.

Long non-coding RNAs (lncRNAs) have been shown to be dysregulated in a variety of malignant and non-malignant lesions including non-functioning pituitary adenomas (NFPAs). In the current experimental study, we have selected six lncRNAs, namely MAPKAPK5-AS1, NUTM2B-AS1, ST7-AS1, LIFR-AS1, PXN-AS1 and URB1-AS1 to assess their expression in a cohort of Iranian patients with NFPA. MAPKAPK5-AS1, PXN-AS1 and URB1-AS1 were shown to be over-expressed in NFPA tissues compared with control samples (Expression ratios (95% CI) = 10 (3.94-25.36), 11.22 (4.3-28.8) and 9.33 (4.12-21.12); p values < 0.0001, respectively). The depicted ROC curves showed the AUC values of 0.73, 0.80 and 0.73 for MAPKAPK5-AS1, PXN-AS1 and URB1-AS1, respectively. Relative expression level of PXN-AS1 was associated with tumour subtype (p value = 0.49). Besides, relative expression levels of MAPKAPK5-AS1 and LIFR-AS1 were associated with gender of patients (p values = 0.043 and 0.01, respectively). Cumulatively, the current study indicates the possible role of MAPKAPK5-AS1, PXN-AS1 and URB1-AS1 lncRNAs in the pathogenesis of NFPAs.

Surgical anatomic findings of sphenoid sinus in 1009 Iranian patients with pituitary adenoma undergoing endoscopic transsphenoidal surgery.

OBJECTIVE: The most common surgical technique for the management of pituitary adenomas is the endoscopic endonasal transsphenoidal approach (EEA). preoperative neuroimaging along with detecting surgical landmarks of the sphenoid sinus during surgery is important for making a successful operation. METHOD: This study includes 1009 patients with pituitary adenomas who underwent EEA between 2013 and 2020. We evaluated the anatomical features of the sphenoid sinus through a panel of items obtained from imaging and intra-operative findings. RESULTS: Our result includes 57.38% nonfunctional, 8.42% cushing, 12.39% prolactinoma, and 21.8% acromegaly patients who had undergone endoscopic endonasal transsphenoidal surgery. The mean age of the patients was 45 with a male to female ratio of 1.2:1. Sellar sphenoid type was the most common (91.8%) with only 12% symmetrical inter sphenoid septa, Internal carotid artery dehiscence was found in 1.7% of the cases. Apoplexy was present in 6.3% of patients, which was found more prevalent in nonfunctional adenomas (9.67%, Odds ratio: 4.85, 95% CI 2.24-11.79) and further investigation revealed a significant association between apoplexy and sphenoid mucosal edema and hemorrhage (Odds ratio: 43.0, 95% CI 22.50-84.26), and between apoplexy and cystic lesions (OR = 4.14, 95% CI 1.87-8.45, P-value < 0.0001). Acromegaly is associated with the increased number of lateral recces (Odds ratio: 11.41, 95% CI 7.54-17.52), septation of the sphenoid sinus (Marginal mean: 3.92, 95% CI 3.69-4.14), edematous sinonasal mucosa (Odds ratio: 6.7; 95% CI 4.46-10.08), and higher bony (OR: 4.81, 95% CI 2.60-8.97, P-value < 0.001) and cavernous (OR: 1.7, 95% CI 1.13-2.46, P-value < 0.01) invasion. CONCLUSION: The present study provides anatomical data about the sphenoid sinus and its adjacent vital structures with adenomal specific changes that are necessary to prevent complications during endoscopic advanced transsphenoidal surgery.

A review on the role of cyclin dependent kinases in cancers.

The Cyclin-dependent kinase (CDK) class of serine/threonine kinases has crucial roles in the regulation of cell cycle transition and is mainly involved in the pathogenesis of cancers. The expression of CDKs is controlled by a complex regulatory network comprised of genetic and epigenetic mechanisms, which are dysregulated during the progression of cancer. The abnormal activation of CDKs results in uncontrolled cancer cell proliferation and the induction of cancer stem cell characteristics. The levels of CDKs can be utilized to predict the prognosis and treatment response of cancer patients, and further understanding of the function and underlying mechanisms of CDKs in human tumors would pave the way for future cancer therapies that effectively target CDKs. Defects in the regulation of cell cycle and mutations in the genes coding cell-cycle regulatory proteins lead to unrestrained proliferation of cells leading to formation of tumors. A number of treatment modalities have been designed to combat dysregulation of cell cycle through affecting expression or activity of CDKs. However, effective application of these methods in the clinical settings requires recognition of the role of CDKs in the progression of each type of cancer, their partners, their interactions with signaling pathways and the effects of suppression of these kinases on malignant features. Thus, we designed this literature search to summarize these findings at cellular level, as well as in vivo and clinical levels.

MRI-negative Cushing's Disease: Management Strategy and Outcomes in 15 Cases Utilizing a Pure Endoscopic Endonasal Approach.

BACKGROUND: Cushing's disease (CD) is among the most common etiologies of hypercortisolism. Magnetic resonance imaging (MRI) is often utilized in the diagnosis of CD, however, up to 64% of adrenocorticotropic hormone (ACTH)-producing pituitary microadenomas are undetectable on MRI. We report 15 cases of MRI negative CD who underwent surgical resection utilizing a purely endoscopic endonasal approach. METHODS: Endoscopic endonasal transsphenoidal surgery (EETS) was performed on 134 CD cases by a single surgeon. Fifteen cases met inclusion criteria: no conclusive MRI studies and no previous surgical treatment. Data collected included signs/symptoms, pre- and post-operative hormone levels, and complications resulting from surgical or medical management. Data regarding tumor diameter, location, and tumor residue/recurrence was obtained from both pre- and post-operative MRI. Immunohistochemistry was performed to assess for tumor hormone secretion. RESULTS: Aside from a statistically significant difference (P = 0.001) in histopathological results between patients with negative and positive MRI, there were no statistically significant difference between these two groups in any other demographic or clinical data point. Inferior petrosal sinus sampling (IPSS) with desmopressin (DDAVP®) administration was performed on the 15 patients with inconclusive MRIs to identify the origin of ACTH hypersecretion via a central/peripheral (C/P) ratio. IPSS in seven, five and three patients showed right, left, and central side lateralization, respectively. With a mean follow-up of 5.5 years, among MRI-negative patients, 14 (93%) and 12 patients (80%) achieved early and long-term remission, respectively. In the MRI-positive cohort, over a mean follow-up of 4.8 years, 113 patients (94.9%) and 102 patients (85.7%) achieved initial and long-term remission, respectively. CONCLUSIONS: Surgical management of MRI-negative/inconclusive Cushing's disease is challenging scenario requiring a multidisciplinary approach. An experienced neurosurgeon, in collaboration with a dedicated endocrinologist, should identify the most likely location of the adenoma utilizing IPSS findings, followed by careful surgical exploration of the pituitary to identify the adenoma.

Expression analysis of necroptosis related genes and lncRNAs in patients with pituitary neuroendocrine tumors.

Necroptosis can either be the cause of tumorigenesis or it can impede its process. Recently, it has been proved that long non-coding RNAs (lncRNAs) have different crucial roles at cellular level, especially on cell death. Regarding the important role of necroptosis and lncRNAs in the pathogenesis of different cancers, especially pituitary adenomas (PAs), we assessed expression levels of two necroptosis related genes, namely TRADD and BIRC2, in addition to three related lncRNAs, namely FLVCR1-DT, MAGI2-AS3, and NEAT1 in PAs compared with adjacent normal tissues (ANTs). TRADD had no significant difference between two groups; however, BIRC2, FLVCR1-DT, MAGI2-AS3, and NEAT1 were upregulated in PAs compared to ANTs (Expression ratios [95% CI] = 2.3 [1.47-3.6], 2.13 [1.02-4.44], 3.01 [1.76-5.16] and 2.47 [1.37-4.45], respectively). When taking into account different types of PAs, significant upregulation of BIRC2, MAGI2-AS3 and NEAT1 was recorded in non-functioning PAs compared with corresponding ANTs (Expression ratios [95% CI] =1.9 [1.04-3.43], 2.69 [1.26-5.72] and 2.22 [0.98-5.01], respectively). Additionally, higher levels of BIRC2 were associated with higher flow of CSF (P value=0.048). Moreover, higher Knosp classified tumors had lower levels of BIRC2 (P value=0.001). Finally, lower levels of MAGI2-AS3 were associated with larger tumor size (P value=0.006). NEAT1 expression was correlated with FLVCR1-DT and TRADD. TRADD expression was correlated with FLVCR1-DT. Additional correlation was observed between expression of BIRC2 and MAGI2-AS3. In sum, this study provides evidence that dysregulated levels of studied genes could contribute to the pathogenesis of pituitary tumors.

Differential expression of cancer-related lncRNAs in different subtypes of pituitary adenomas.

Recent investigations have demonstrated abnormal expression of non-coding RNAs in pituitary adenomas. Cntribution of many lncRNAs to the pathogenesis of these tumors has not been evaluated yet. HOTTIP, ANRIL, PANDAR, PCGEM1 and HOTAIR are among lncRNAs with established roles in the pathogenesis of human cancers, particularly those originated from endocrine organs. The current study aims at assessment of expression of these lncRNAs in pituitary adenomas in comparison with the adjacent non-cancerous pituitary tissues. HOTAIR expression was absent from the majority of adenoma and non-tumoral samples. Expression of HOTTIP was significantly higher in non-functioning pituitary adenoma (NFPA) samples compared with paired normal samples (expression ratio (95 % CI)= 2.1 (1.13-2.1), P value=0.03). Expression of PANDAR was higher in total adenoma samples compared with paired normal samples (expression ratio (95 % CI)= 1.91 (1.16-3.13), P value=0.02). Expression of ANRIL was higher in NFPA samples compared with paired normal samples (expression ratio (95 % CI)= 1.94 (1.05-3.6), P value=0.048) and in total adenoma samples compared with paired normal samples (expression ratio (95 % CI)= 1.82 (1.11-2.98), P value=0.025). The current study raises the possibility of contribution of lncRNAs in the pathogenesis of at least some subtypes of pituitary adenomas and warrant further functional studies in this field.

Expression pattern of lncRNAs in pituitary adenomas.

Non-functioning pituitary adenomas (NFPAs) are a group of pituitary tumors lacking manifestations linked to high hormone production, such as acromegaly and Cushing's syndrome. NFPA carcinogenesis depends on several molecular players. Long non-coding RNAs (lncRNAs) are a class of molecular players whose role in tumorigenesis has just recently been recognized. In the current study, we appraised expressions of 5 lncRNAs, namely FGD5-AS1, ATP6V0E2-AS1, ARHGAP5-AS1, WWC2-AS2 and EPB41L4A-AS1 in NFPAs versus their corresponding non-tumoral samples. Expressions of ATP6V0E2-AS1, EPB41L4A-AS1, FGD5-AS1 and WWC2-AS2 were significantly increased in NFPA samples compared with adjacent non-tumoral samples (P values = 0.037, 0.007, 0.008 and 0.03, respectively). However, expression of ARHGAP5-AS1 was not different between NFPA samples and controls (P value = 0.62). EPB41L4A-AS1 and FGD5-AS1 could discriminate between NFPA samples and adjacent non-tumoral samples (P values = 0.03 and 0.04, respectively). However, the AUC values were not appropriate. There was a significant positive association between age of NFPA patients and invasiveness of NFPA (χ2 = 4.24, P value = 0.039). Moreover, there was a significant positive association between diseases duration and CSF leak (χ2 = 11.4, p value = 0.023). Finally, there was a significant positive association between tumor size and Knosp classification (χ2 = 11.5, p value = 0.02) and invasiveness of NFPA (χ2 = 6.12, p value = 0.04). The current study provides information about dysregulation of lncRNAs in NFPAs and warrants additional studies in this field.

Mucormycosis, New Causative Agents, and New Susceptible Populations: Review of Cases in a Tertiary Care Hospital in Iran (2007-2021).

Background: Mucormycosis is an aggressive opportunistic fungal infection that afflicts patients with severe underlying immunosuppression, uncontrolled hyperglycemia and/or ketoacidosis, iron overload, and occasionally healthy patients who are inoculated with fungal spores through traumatic injuries. The epidemiology of mucormycosis has changed after the COVID-19 pandemic, with mucormycosis becoming the most common and the fatal coinfection. Methods: In a retrospective, cross-sectional study, 82 hospitalized patients with a definite diagnosis of mucormycosis were reported from 2007 to 2021 in a referral, tertiary care center in Tehran, Iran. Results: The number of post-COVID cases increased 4.6 times per year, with 41.5% of patients admitted during the two years of the pandemic. Mucormycosis was more common in women (57.3%), and the most common underlying diseases were diabetes (43.7%), both COVID-19 and diabetes (23.2%), cancer (11%), rheumatic diseases (7.3%), COVID-19 without other underlying diseases (6.1%), and transplantation (4.9%). Rhino-orbito-cerebral Mucormycosis (54.9%) followed by Sino-orbital infection (23.2%) was the most common presentation. There was a significant relationship between the use of immunosuppressive agents and the development of Mucormycosis (P<0.005) The average mortality was 41.5%, but this ratio decreased to 35% during the pandemic era. Conclusion: The COVID-19 pandemic caused a 4.6-fold increase in the number of mucormycosis patients, and there was a significant relationship between hyperglycemia, corticosteroid use, and mucormycosis. The death rate during the COVID-19 pandemic has decreased by 6.5%, and during the COVID period, the interval between the arrival of a patient with mucormycosis and the start of the correct treatment was significantly decreased.

Manifestations of Mucormycosis and Its Complications in COVID-19 Patients: A Case Series Study.

OBJECTIVE: Mucormycosis is an opportunistic fungal disease that affects immunocompromised patients. With the advent of SARS-CoV-2, this opportunistic disease has increased. METHODS: A case series of 47 patients with COVID-19 associated mucormycosis have been analyzed. Demographic information, signs, symptoms, laboratory investigations, imaging studies, and their association with ICU admission and 30-day mortality were assessed. RESULTS: Total number of 47 consecutive rhino-orbital cerebral mucormycosis (ROCM) cases were analyzed. Periorbital swelling was the most common sign among patients. Majority of cases had diabetes. All patients received liposomal Amphotericin B. Debridement was performed for all cases. CONCLUSIONS: SARS-CoV-2 increases the susceptibility to mucormycosis infection in various ways. Uncontrolled level of HbA1c in all patients, even non-diabetic individuals, indicates hyperglycemia over the past three months. Diabetes, orbital exenteration, ptosis, periorbital swelling, DKA, LOC, brain involvement, and mechanical ventilation all correlated with a higher rate of ICU admission and 30-day mortality. In addition, a higher white blood cell count is related to the higher probability of ICU admission. While considering all of the inflammatory laboratory data and HbA1c could help predict 30-day mortality.

COVID-19-related rhino-orbital-cerebral mucormycosis: Neurological manifestation and related risk factors in two cases.

Mucormycosis is an opportunistic infection that has become a serious concern as a result of the immunosuppressive drugs used during COVID-19. In this report, we describe two cases of rhino-orbital-cerebral mucormycosis with neurological presentation and ophthalmologic problems accompanied by a history of COVID-19 and diabetes.

Expression pattern of non-coding RNAs in non-functioning pituitary adenoma.

Non-functioning pituitary adenoma (NFPA) is a benign tumor arising from the adenohypophyseal cells. They can be associated with symptoms arising from mass effect. Although these tumors are regarded to be benign tumors, they are associated with increased comorbidity and mortality. Several studies have indicated abnormal expression of genes in these tumors. In the current study, we have used existing methods to identify differentially expressed genes (DEGs) including DE long non-coding RNAs (DElncRNAs) and DE microRNAs (DEmiRNAs) in NFPAs compared with normal samples. Then, we have assessed the relation between these genes and important signaling pathways. Our analyses led to identification of 3131 DEGs, including 189 downregulated DEGs (such as RPS4Y1 and DDX3Y) and 2898 upregulated DEGs (such as ASB3 and DRD4), and 44 DElncRNAs, including 8 downregulated DElncRNAs (such as NUTM2B-AS1 and MALAT1) and 36 upregulated DElncRNAs (such as BCAR4 and SRD5A3-AS1). GnRH signaling pathway, Tight junction, Gap junction, Melanogenesis, DNA replication, Nucleotide excision repair, Mismatch repair and N-Glycan biosynthesis have been among dysregulated pathways in NFPAs. Taken together, our study has revealed differential expression of several genes and signaling pathways in this type of tumors.

Rathke's cleft cysts: A single-center case series.

Background: Rathke's cleft cysts (RCCs) are common benign sellar or suprasellar lesions. The aim of this study is to report our experience on the management of 27 RCC cases. Methods: We retrospectively analyzed a series of 27 patients with symptomatic RCC who were referred to our department between January 2016 and January 2020. Data regarding patients' demographics, clinical evaluations, laboratory and neuroimaging findings, pathologic records, surgical treatment, and complications were extracted from our electronic database. All patients underwent RCC removal through a direct endoscopic endonasal transsphenoidal (EETS) approach, except for two cases. Results: Data of 27 patients (3 men and 24 women; mean age: 38 years) with symptomatic RCC were reviewed. The most common presenting symptom was headache, occurring in 20 (74.0%) patients. In 16 (59.2%) cases, the tumor was primarily located in the sella turcica. Nine (33.3%) cases exhibited a secondary suprasellar extension. Conclusion: Our experience with RCC patients showed that EETS is a safe method of treatment, with minimal recurrence.

Garcin syndrome in a case of acquired immunodeficiency syndrome.

In this study, we report a parapharyngeal diffuse large B-cell lymphoma in a human immunodeficiency virus (HIV) infected patient which had caused the patient to suffer from Garcin syndrome.

Non-coding RNA Activated by DNA Damage: Review of Its Roles in the Carcinogenesis.

Long intergenic non-coding RNA 00657 (LINC00657) or "non-coding RNA activated by DNA damage" (NORAD) is an extremely conserved and copious long non-coding RNA (lncRNA). This transcript has pivotal role in the preservation of genome integrity. Several researches have appraised the role of NORAD in the evolution of human cancers with most of them indicating an oncogenic role for this lncRNA. Several miRNAs such as miR-199a-3p, miR-608, miR-155-5p, miR-590-3p, miR-495-3p, miR-608, miR-202-5p, miR-125a-3p, miR-144-3p, miR-202-5p, and miR-30a-5p have been recognized as targets of NORAD in different cancer cell lines. In addition, NORAD has interactions with cancer-related pathways, particularly STAT, TGF-ß, Akt/mTOR, and PI3K/AKT pathway. Over-expression of NORAD has been related with poor clinical outcome of patients with diverse types of neoplasms. Collectively, NORAD is a prospective marker and target for combating cancer.

Patterns of extrasellar invasive growth of pituitary adenomas with normal sellar cavity size.

BACKGROUND: Pituitary adenomas (PAs) are among the most common brain tumors which characteristically become symptomatic due to the mass effect on surrounding structures and/or hormonal imbalances. This study describes 28 cases of PAs with an extrasellar invasive growth (EIG) at the early stage of tumor growth with normal sellar cavity size. METHODS: 1200 cases of PAs either treated medically or via Endoscopic transsphenoidal surgery were reviewed during a 10-year period. Pre-operative imaging was analyzed to evaluate the tumor expansion pattern, tumor invasion sites and other relevant tumor properties. A comprehensive preoperative endocrinological along with postoperative histopathological studies were conducted to evaluate the subjects' homeostasis and further identify the lesions characteristics. RESULTS: Of the 28 patients, patients 19, 2, 1 and 6 had a growth hormone (GH)-secreting PA, an adrenocorticotropic hormone (ACTH)-secreting PA, a nonfunctional PA (NFPA) and a mix-hormones secreting PA, respectively. There was a statistically significant difference between patients with and without EIG regarding types of PAs (P = 0.000). Post-hoc tests demonstrated that GH-secreting PAs (P = 0.0003) and mix-hormones secreting PAs (P = 0.0000) are significantly more invasive, while NFPAs (P = 0.0000) are less invasive. There was not a statistically significant difference between the invasion sites and different types of PAs (P = 0.122). CONCLUSION: Among different histological subtypes of PAs, GH-secreting PAs revealed a remarkable tendency for EIG with normal sellar cavity size. The extra-sellar tumor extension with a normal sella did not correlate with atypical histology. Considering EIG patterns, surgeons should be vigilant to investigate and follow the tumor spreading to its enclosing boundary during surgery, the clival part of sphenoid bone should be more exposed, and both inferomedial and lateral borders of the sphenoid sinus should be carefully explored in order to remove the tumor.