Neuro-ophthalmic presentation of COVID-19 disease: A case report.

COVID-19 is a respiratory virus, which has affected various organ systems as well. Here we report a neuro-ophthalmic presentation of pituitary apoplexy under the setting of COVID-19 infection in a middle-aged man who presented to ophthalmic emergency with sudden bilateral loss of vision along with a history of fever past 10 days. There was sluggishly reacting pupils and RT-PCR for COVID was positive. Imaging pointed the diagnosis as pituitary macroadenoma with apopexy. In view of pandemic situation, patient was given symptomatic treatment as per the protocols and stabilized. Vision also showed improvement to some extent and the patient is awaiting neurosurgery.

Status of Pituitary Surgery During the COVID-19 Pandemic.

Even in ideal circumstances, the performance of safe and effective endoscopic transsphenoidal pituitary surgery requires complicated orchestration of care amongst multiple medical and surgical teams in the preoperative, intraoperative, and postoperative settings. The current COVID-19 pandemic further complicates this highly orchestrated effort. Healthcare systems around the globe are working to adapt to the rapidly changing healthcare landscape as information about the SARS-CoV-2 virus is discovered and disseminated. The nature of the transsphenoidal corridor exposes the pituitary surgery team to increased risk of virus exposure.

Case reports of latent HBV hepatitis in patients after neurosurgical treatment for hypothalamic and pituitary tumors.

BACKGROUND: Hepatitis B virus (HBV) infection is a major public health problem worldwide. More than 2 billion people have been exposed to HBV, and about 257 million individuals are chronic carriers of HBV. HBV reactivation has been increasingly reported in HBV carriers who have undergone immunosuppression or chemotherapy, resulting in mortality. Treatment of hypothalamic/pituitary tumors in HBV carriers requires extensive care to avoid HBV reactivation as steroid therapy is required after surgery for hypothalamic/pituitary tumors. CASE PRESENTATION: This retrospective review identified 5 patients, who were HBV carriers positive for hepatitis B surface antigen among 1352 patients with surgically treated hypothalamic/pituitary tumor in Kohnan Hospital between February 2007 and April 2017. Transsphenoidal surgery was performed with particular attention to prevent damage to the pituitary gland, with delicate manipulation to minimize postoperative steroid coverage. All patients received nucleot(s)ide analogue to control HBV-DNA levels before the surgery. As a result, all patients had a good clinical course. Blood examinations found a transient increase of liver enzymes and HBV-DNA levels in all patients, which started to decrease within 2 weeks after surgery. No specific treatment other than nucleot(s)ide analogues was needed to maintain liver function, and all patients returned to their previous activities including reinstatement. CONCLUSION: Initiation of nucleot(s)ide analogues administration prior to the surgery for hypothalamic/pituitary tumors can be an effective strategy for preventing reactivation in HBV carriers. Appropriate screening of the patient's HBV phase, optimal timing of nucleot(s)ide analogues -administration, and administration period of nucleot(s)ide analogues need to be established.

Is the presence of HCMV components in CNS tumors a glioma-specific phenomenon?

BACKGROUND: Human cytomegalovirus (HCMV) has been associated with malignant gliomas. The purpose of the present study was to investigate the presence of HCMV in common non-glial tumors of the central nervous system (CNS) and to determine whether it is a glioma-specific phenomenon. METHODS: Using HCMV-specific immunohistochemical staining, HCMV proteins IE1-72 and pp65 were examined in 65 meningiomas (benign, atypical and malignant), 45 pituitary adenomas, 20 cavernous hemangiomas, and 30 metastatic carcinomas specimens. HCMV DNA was also measured in these tumor tissues and the peripheral blood from patients using nested PCR. RESULTS: In meningioma, IE1-72 was detected in 3.1% (2/65) and pp65 was detected in 4.6% (3/65), whereas no IE1-72 and pp65 were detected in atypical and malignant meningioma. A low level of IE1-72 immunoreactivity 6.7% (2/30) was detected in metastatic carcinoma; pp65 was not detected. No HCMV components were detected in pituitary adenoma and cavernous hemangioma. The results of immunohistochemical staining were confirmed by HCMV-specific PCR. HCMV DNA was not detected in the peripheral blood of the non-glial CNS tumors patients. CONCLUSIONS: Our results demonstrate that the presence of HCMV components is not an entirely glioma-specific phenomenon, and that HCMV is present in a low percentage in some non-glioma CNS tumors. Comparing HCMV-positive non-glial CNS tumors with HCMV-positive gliomas may cast light on the mechanism and role of HCMV in CNS tumors.

Evidence for possible role of toll-like receptor 3 mediating virus-induced progression of pituitary adenomas.

Tumor-related viruses are known to be involved in initiation and progression of certain tumors. However, the relationship between virus and pituitary adenomas (PAs) remains unknown. Here, we investigated infection status of three types of viruses (HPV16, HHV6B and HSV1) and expression level of toll-like receptor 3 (TLR3) in 60 human PA samples. We also determined the role of TLR3 signaling pathway on a PA cell line (GH3). We firstly found that positive rates of HPV16 and HHV6B infection were significantly higher in invasive PA samples than in noninvasive samples (P < 0.01). Similarly, TLR3 mRNA and protein expression also increased in invasive PA samples (P < 0.01). In vitro analysis indicated that GH3 cell proliferation and survival were enhanced by TLR3 activation, which was accompanied by NF-κB activation. Our data indicate that HPV16 and HHV6B viruses may be involved in promoting the progression of PA by activating the TLR3 signaling pathway.

Activation and regulation of endogenous retroviral genes in the human pituitary gland and related endocrine tumours.

AIMS: Adenohypophysis (AH) hormone-producing cells represent the origin of diverse groups of pituitary adenomas (PA). Deregulation of hypothalamic hormone receptors, growth factors and cAMP signalling have been implicated in the aetiology of PA. Endogenous retroviruses (ERVs) are derived from past exogenous retroviral infections and represent more than 8% of the human genome. Some ERV genes encode open reading frames and produce functional proteins, for example, the ERVW-1 envelope gene Syncytin-1, essential for placentogenesis, but also deregulated in human tumours. Data concerning ERV expression in the AH and related endocrine tumours are missing. METHODS: Syncytin-1 protein was analysed in normal AH (n = 15) and compared with five PA subtypes (n = 117) by immunohistochemistry. Absolute gene expression of 20 ERV functional envelope genes and ERVW-5 gag was measured. PA tissues were examined for Syncytin-1 and the cAMP signalling marker phospho-CREB-Ser133 using immunohistochemistry. Isolated primary human PA cells were treated with different hormones. Murine embryonic and adult pituitary gland ERV expressions were compared with human AH. RESULTS: Syncytin-1 protein colocalized with corticotropic cells of AH. In contrast, all PA demonstrated significant Syncytin-1 protein overexpression, supporting deregulation. All other ERV genes showed significant up-regulations in different PA subtypes. Phospho-CREB-Ser133 and Syncytin-1 colocalized in PA cells. Cultivated primary PA cells with ACTH or CRH induced their respective receptors and ERV genes. Syncytin-A/-B, murine orthologues to human Syncytin-1/-2, localized to embryonic and adult pituitary glands demonstrating functional mammalian conservation. CONCLUSIONS: Deregulated ERV genes may contribute to PA development via cAMP signalling.

Lentiviral vectors efficiently transduce human gonadotroph and somatotroph adenomas in vitro. Targeted expression of transgene by pituitary hormone promoters.

Despite important advances in human therapeutics, no specific treatment for both non-functioning gonadotroph and resistant somatotroph adenomas is available. Gene transfer by viral vectors can be considered as a promising way to achieve a specific and efficient treatment. Here we show the possibility of efficient gene transfer in human pituitary adenoma cells in vitro using a human immunodeficiency virus (HIV)-type 1-derived vector. Using enhanced green fluorescent protein (eGFP) gene as a marker placed under the phosphoglycerate kinase (PGK) promoter, gonadotroph and somatotroph adenomas were transduced even with moderate viral loads. The expression started at day 2, reached a peak at day 5, and it was still present at day 90. For targeting somatotroph and gonadotroph adenomas, human growth hormone (GH) promoter (GH -481, +54 bp) and two fragments of the human glycoprotein hormone alpha-subunit promoter (alpha-subunit 1 -520, +33 bp, and alpha-subunit 2 -907, +33 bp) were tested. In gonadotroph adenomas, the percentage of identified fluorescent cells and the fluorescence intensity analyzed by fluorescence-activated cell sorting indicated that the strength of the alpha-subunit 1 and alpha-subunit 2 promoters were comparable to that of the PGK promoter. Primary cultures of rat pituitary cells showed that alpha-subunit 1 is more selective to thyreotroph and gonadotroph phenotypes than alpha-subunit 2. GH promoter activity appeared weak in somatotroph adenomas. The human GH enhancer did not increase the GH promoter activity at all but the human prolactin promoter (-250 bp) allowed 4-fold more fluorescent cells to be obtained than the GH promoter. Several cell lines appeared too permissive to test cell-specificity of pituitary promoters. However, on human non-pituitary cell cultures, the tested pituitary promoters seemed clearly selective to target endocrine pituitary phenotypes. This study gives a starting point for a gene-therapy program using lentiviral vectors to transfer therapeutic genes in human pituitary adenomas.

Nasopharyngeal carcinoma metastasis to the pituitary gland: a case report and literature review.

While nasopharyngeal carcinoma (NPC) commonly invades the skull base, true central nervous system metastasis is a rare phenomenon. We report a case of NPC metastasis to the pituitary gland and review the literature for similar events. Eight months after his definitive radiation therapy, our patient presented with symptoms of optic chiasm compression and panhypopituitarism. Medical imaging revealed a pituitary mass but demonstrated no evidence of skull base erosion or direct intracranial extension. Subsequent biopsy of the pituitary lesion was confirmed as NPC in origin with Epstein-Barr virus-encoded RNA in-situ hybridization studies. The patient was treated with high dose chemotherapy followed by autologous stem cell transplant, which produced short-term symptomatic relief and at least a 7 month survival.

Pituitary neoplasia induced by expression of human neurotropic polyomavirus, JCV, early genome in transgenic mice.

In recent years, there has been mounting evidence pointing to the association of polyomaviruses with a wide range of human cancers. The human neurotropic polyomavirus, JCV, infecting greater than 75% of the human population produces a regulatory protein named T-antigen which is expressed at the early phase of viral lytic infection and plays a critical role in completion of the viral life cycle. Furthermore, this protein has the ability to transform neural cells in vitro and its expression has been detected in several human neural-origin tumors. To further investigate the oncogenic potential of the JCV early protein in vivo, transgenic mice expressing JCV T-antigen under the control of its own promoter were generated. Nearly 50% of the animals developed large, solid masses within the base of the skull by 1 year of age. Evaluation of the location as well as histological and immunohistochemical data suggest that the tumors arise from the pituitary gland. As T-antigen is known to interact with several cell cycle regulators, the neoplasms were analysed for the presence of the tumor suppressor protein, p53. Immunoprecipitation/Western blot analysis demonstrated overexpression of wild-type, but not mutant p53 within tumor tissue. In addition, co-immunoprecipitation established an interaction between p53 and T-antigen and overexpression of p53 downstream target protein, p21/WAF1. This report describes the analysis of inheritable pituitary adenomas induced by expression of the human polyomavirus, JCV T-antigen in transgenic mice where T-antigen disrupts the p53 pathway by binding to and sequestering wild-type p53. This animal model may serve as a useful tool to further evaluate mechanisms of tumorigenesis by JCV T-antigen.

Detection of polyomaviral DNA sequences in normal and adenomatous human pituitary tissues using the polymerase chain reaction.

BACKGROUND: Tumor viruses are known to have a role in the pathogenesis of many types of benign and malignant human tumors. The possible roles of these viruses in the development of human pituitary tumors have not been investigated. METHODS: The polymerase chain reaction was used to screen human pituitary tumors for human papillomaviral (HPV) and Polyomaviral DNA sequences. Sets of consensus primers, which are capable of amplifying HPV Types 16, 18, and 33 and polyomavirus BK, JC, and SV40, were used in these experiments. RESULTS: Amplification products were not detected using HPV consensus primers in 30 tumors. Twenty-six of 30 tumors demonstrated an amplification product with polyomaviral primers that hybridized to SV40 and BK internal probes and was confirmed to be SV40 in one tumor by direct sequencing. Ten normal postmortem pituitary samples then were examined similarly with Polyomaviral consensus primers; 8 of 10 normal samples demonstrated a similar amplification product that also hybridized with SV40 and BK internal probes by Southern blotting. Polyomaviral DNA sequences in normal and tumor samples were not present at levels detectable by genomic Southern blotting. Expressed viral protein (large T antigen) was not demonstrated in positive samples by Western blot analysis. CONCLUSIONS: These findings, that polyomaviral DNA sequences are detectable at low levels in certain normal tissues, are in agreement with those of other groups and, to the authors' knowledge, serve as the first report of polyomaviral latency in human pituitary tissue. A role for polyomaviruses in pituitary tumorigenesis could not be established in this analysis.