Kan Deng

Pituitary abscess following transsphenoidal surgery: The experience of 12 cases from a single institution

OBJECTIVE To explore possible reasons for the incidence of a pituitary abscess following transsphenoidal surgery and determine the most effective treatment. METHODS A series of 12 patients who had undergone transsphenoidal surgery in other hospitals before being treated at Peking Union Medical College Hospital were reviewed. The presence of a pituitary abscess was confirmed when pus was intraoperatively observed within the sella turcica. All patients were treated with debridement of the abscess, nine among whom through a transsphenoidal approach and the other three via a craniotomy, followed by antibiotic treatment and hormone replacement therapy. The mean follow-up time was 27.0 months (range from 3.0 to 79.0 months). RESULTS Headache (92%), panhypopituitarism (58%) and visual disturbance (50%) were the most common clinical indicators of a pituitary abscess. Imaging tests demonstrated a pituitary mass in all patients, with seven (58%) manifested with typical magnetic resonance features of an abscess. Ten patients (83%) were correctly diagnosed preoperatively. During surgical exploration, six presented with severe inflammation or an abscess within the sphenoidal sinus. Causative organisms were identified in five patients (42%). After surgical and antibiotic therapies, all patients fully recovered except for two presenting with severe visual impairment. Six patients (50%) required hormone replacement therapy. CONCLUSION Retrograde infection from the sphenoid sinus may be a vital mechanism underlying the formation of a pituitary abscess following transsphenoidal surgery. Debridement of the abscess through surgical approaches combined with antibiotic treatment has been found to yield positive outcomes.

Pyrimethamine sensitizes pituitary adenomas cells to temozolomide through cathepsin B-dependent and caspase-dependent apoptotic pathways.

Invasive pituitary adenomas (PAs) are generally refractory to conventional therapy and salvage treatment with temozolomide (TMZ). In addition to antiprotozoan effects, pyrimethamine (PYR) has recently shown its strong antitumor activity as an antineoplastic agent or in combination with TMZ in metastatic melanoma cells. In this study, the effects of TMZ, PYR or TMZ/PYR combination on rat/mouse PA cell lines αT3‐1, GH3, MMQ and ATt‐20 as well as GH3 xenograft tumor model were evaluated. TMZ/PYR combination synergistically inhibited proliferation, invasion and induced apoptosis of these PA cell lines in vitro. Strikingly, combination treatment with TMZ and PYR produced synergistic antitumor activity and enhanced the survival rate of GH3 xenograft tumor models without increasing systemic side effects. In addition, TMZ/PYR induced cell cycle arrest, increased DNA damage, upregulated the expression of cathepsin B, BAX, cleaved PARP and phosphorylated histone H2AX as well as elevated caspase3/7, 8 and 9 activities. The decreased expression of Bcl‐2, MMP‐2 and MMP‐9 alone with cytochrome c release from mitochondria into the cytosol was also observed in the TMZ/PYR combination group. The increase in cell apoptosis due to combination with PYR was rescued by leucovorin. These data suggest that PYR may enhance the efficacy of TMZ via triggering both cathepsin B‐dependent and caspase‐dependent apoptotic pathways. Therefore, combination of PYR and TMZ may provide a novel regimen for invasive PAs refractory to standard therapy and TMZ.

Differential expression of folate receptor alpha in pituitary adenomas and its relationship to tumor behavior.

BACKGROUND Folate receptor alpha (FRα) plays a pivotal role in the tumorigenesis of some malignant tumors, but its role and clinical significance in pituitary adenomas remain unclear. OBJECTIVE To identify a possible biomarker for the diagnosis of nonfunctional pituitary adenomas (NFAs) that could also be used to assess tumor behavior. METHODS Sporadic pituitary tumor specimens (n = 76) and normal pituitary glands (n = 7) were examined. FRα protein and mRNA expression were quantified by immunohistochemistry and quantitative reverse transcriptase polymerase chain reaction, respectively. We verified the differential expression of FRα in pituitary adenomas and evaluated the associations of FRα expression with Ki-67 labeling index (LI) and clinicopathologic characteristics of NFAs. Statistical significance was determined by using the Student t test or one-way analysis of variance. RESULTS FRα mRNA and protein was uniquely overexpressed in NF (immunohistochemically positive) and NF (immunohistochemically negative) adenomas but not in functional adenomas (adrenocorticotropic hormone, growth hormone, and prolactin) or normal adenohypophysial tissues (P < .001). The expression of FRα was positively correlated with tumor invasiveness, size and Ki-67 LI in NFAs. CONCLUSION FRα may play an important role in the development and progression of NFAs. Therefore, FRα may be useful as a molecular biomarker for the diagnosis of NFAs and assessment of tumor invasiveness.

Antiproliferative, Antiinvasive, and Proapoptotic Activity of Folate Receptor α-Targeted Liposomal Doxorubicin in Nonfunctional Pituitary Adenoma Cells

There is an urgent need for novel therapeutic strategies for the treatment of nonfunctional pituitary adenomas (NFPAs), especially those that are invasive. The folate receptor (FR)α is overexpressed in several cancers, including NFPA. The aim of this study was to determine the efficacy of FRα-targeted liposomes loaded with doxorubicin (F-L-DOX) in the treatment of NFPA. We evaluated targeting, cytotoxicity, antiinvasive, and proapoptotic activity of F-L-DOX in 25 primary cell lines derived from patients with NFPAs. We found that these liposomes effectively targeted NFPA cells through FRα and that endocytosis of the liposomes was blocked by 1mM free folic acid. F-L-DOX inhibited proliferation of NFPA cells and promoted apoptosis through activation of caspase-8, caspase-9, and caspase-3/7 more effectively than L-DOX. Furthermore, F-L-DOX also exerted greater antiinvasive ability in NFPA cells than L-DOX through suppression of the secretion of matrix metalloproteinase-2 and matrix metalloproteinase-9. Addition of 1mM free folic acid significantly reduced the pleotropic effects of F-L-DOX in NFPA cells, suggesting that FRα plays a critical role in mediating the antitumor effect of F-L-DOX. Our findings warrant further investigation of F-L-DOX as an alternative therapeutic strategy for the treatment of NFPAs that express FRα.

Correlations of Pituitary Tumor Transforming Gene Expression with Human Pituitary Adenomas: A Meta-Analysis

Objective Pituitary tumor transforming gene (PTTG) is an important paracrine growth factor involved in early lactotrope transformation and early onset of angiogenesis in pituitary hyperplasia. Emerging evidences have shown that PTTG expression may contribute to the etiology of pituitary adenomas; but individually published studies showed inconclusive results. This meta-analysis aimed to derive a more precise estimation of the correlations of PTTG expression with human pituitary adenomas. Methods A range of electronic databases were searched: MEDLINE (1966∼2013), the Cochrane Library Database (Issue 12, 2013), EMBASE (1980∼2013), CINAHL (1982∼2013), Web of Science (1945∼2013) and the Chinese Biomedical Database (CBM) (1982∼2013) without language restrictions. Meta-analysis was performed using the STATA 12.0 software. Crude odds ratio (OR) or standard mean difference (SMD) with its corresponding 95% confidence interval (95%CI) were calculated. Results Twenty-four clinical cohort studies were included with a total of 1,464 pituitary adenomas patients. The meta-analysis results revealed that patients with invasive pituitary adenomas had higher positive expression of PTTG than those of non-invasive patients (OR  = 6.68, 95%CI  = 3.72–11.99, P<0.001). We also found a significant difference in microvessel density between invasive and non-invasive patients (SMD  = 1.81, 95%CI  = 0.39–3.23, P = 0.013). However, there were no significant difference in PTTG expression between functional and non-functional patients with pituitary adenomas (OR  = 1.11, 95%CI  = 0.58–2.10, P = 0.753). No publication bias was detected in this meta-analysis (all P>0.05). Conclusion This present meta-analysis suggests that PTTG expression may be associated with tumor invasiveness and microvessel density of pituitary adenomas, while no correlations with functional status was found.

Cardiovascular System Changes and Related Risk Factors in Acromegaly Patients: A Case-Control Study

Background. Cardiovascular complications are known to be the main determinants of reduced life expectancy and decreased quality of life in acromegaly patients. Our study aimed to provide insight into the cardiovascular changes that occur in acromegaly patients and to investigate the correlative risk factors. Methods. A total of 108 patients definitively diagnosed with acromegaly and 108 controls matched for age and gender were recruited into study and control groups, respectively. Standard echocardiography was performed on all of the participants, and data were collected and analyzed. Results. All acromegaly patients presented with structural cardiac changes, including a larger heart cavity, thicker myocardial walls, and increased great vessel diameters compared with the control group. Additionally, the acromegaly patients presented with reduced diastolic function. Aging and increased body mass index (BMI) were correlated with myocardial hypertrophy and diastolic dysfunction; a longer disease duration was correlated with larger great vessel diameters. Conclusions. Ageing and increased BMI are independent risk factors for acromegalic cardiomyopathy, and a long disease duration results in the expansion of great vessels. Increased efforts should be made to diagnose acromegaly at an early stage and to advise acromegaly patients to maintain a healthy weight.

O-6-Methylguanine-DNA methyltransferase expression is associated with pituitary adenoma tumor recurrence: a systematic meta-analysis

O-6-methylguanine-DNA methyltransferase (MGMT) reportedly counteracts the cytotoxic effects of the alkylating agent temozolomide. MGMT expression is often low in aggressive pituitary adenomas (PAs) and recurrent PAs. However, because these associations are controversial, we performed this meta-analysis to clarify the involvement of MGMT in the prognosis and clinicopathology of PA. We searched for relevant studies in electronic databases (MEDLINE, the Cochrane Library Database, EMBASE, CINAHL, Web of Science and the Chinese Biomedical Database (CBD)) and calculated/pooled the odds ratios (ORs) or standard mean differences (SMDs) with 95% confidence intervals (95% CIs). Eleven case-control studies with a total of 454 PA patients were included. Our meta-analysis revealed that lower expression of MGMT was associated with PA recurrence (OR=2.09, 95% CI=1.09–4.02; p=0.026). On the other hand, MGMT expression was not associated with PA invasiveness (OR=1.112, 95% CI=0.706–1.753; p=0.646), Unexpectedly, MGMT expression could not be used to distinguish functional from non-functional PA patients (OR=1.766, 95% CI=0.938–3.324; p=0.078). The MGMT expression was not found to be related to other clinicopathological indicators of PA including age, gender or tumor size. No publication bias was detected in this meta-analysis (p>0.05). This meta-analysis suggests that MGMT expression may be associated with PA tumor recurrence, but not be related to invasiveness or other clinicopathological indicators. Thus, detection of MGMT expression may facilitate outcome prediction and guide clinical therapy for PA patients.

Refractory pituitary adenoma: a novel classification for pituitary tumors

Pituitary adenomas are classified as typical or atypical, invasive or noninvasive, and aggressive or nonaggressive based on pathological features, radiological findings, and clinical behavior. Only pituitary tumors with cerebrospinal and/or systemic metastasis are considered malignant carcinomas. However, some pituitary adenomas with high Ki-67 indexes exhibit aggressive behaviors, such as rapid growth, early and frequent recurrence, and resistance to conventional treatment, even in the absence of metastasis. Novel terminology is needed to define these tumors. Here, we propose the use of the term “refractory pituitary adenoma” to define malignant pituitary tumors exhibiting 1) a high Ki-67 index and rapid growth, 2) early and high frequency of recurrence, 3) resistance to conventional treatments and/or salvage treatment with temozolomide (TMZ), 4) poor prognosis, 5) and a lack of cerebrospinal or systemic metastases. To illustrate the utility of this refractory pituitary adenoma classification and the difficulty in managing disease in these patients, we examined twelve clinical cases. Correctly identifying refractory pituitary adenomas is crucial for improving patient prognoses. Early identification might encourage the early use of aggressive therapeutic strategies to prevent or delay recurrence.

Tumour Lateralization in Cushing's disease by Inferior Petrosal Sinus Sampling with desmopressin

Bilateral inferior petrosal sinus sampling (IPSS) with corticotropin‐releasing hormone (CRH) is currently the gold standard in the diagnosis of Cushings disease (CD) and has also been used in tumour lateralization. Our objective was to determine the diagnostic value and lateralization accuracy of IPSS with desmopressin.

Clinical characteristics and management of growth hormone excess in patients with McCune–Albright syndrome

OBJECTIVE McCune-Albright syndrome (MAS) is a sporadic, postzygotic disease presenting with fibrous dysplasia, cafe-au-lait spots and multiple endocrinopathies. Growth hormone (GH) excess is an uncommon but potentially severe complication of MAS. This study aims to describe the clinical manifestations of GH excess in the context of MAS and analyze the responses of these patients to treatments. DESIGN Retrospective clinical study. METHODS Clinical data from 52 MAS patients were analyzed. Serum GH and IGF1 levels, as well as nadir GH levels after an oral glucose tolerance test and alkaline phosphatase (ALP) levels were determined before and after the treatment. RESULTS In total, 13 MAS patients (25%) had the complication of GH excess, including 10 males (76.9%). Among them, all had FD, and 6 patients had sphenoidal bone involvement. Visual deficits were present in 8 patients, and hearing deficits were present in 5. Olfactory dysfunction was observed in 3 patients. Evident pituitary adenomas were confirmed in 9 patients by MRI. These patients underwent surgery with or without pretreatment of long-acting somatostatin analogue octreotide, and 6 achieved complete remission. The serum ALP levels decreased significantly after treatment for GH excess. CONCLUSIONS MAS with GH excess is more common in male patients. GH excess can lead to more severe skeletal lesions in MAS patients involving more of the craniofacial bones. Complete trans-sphenoidal complete tumor excision with neuronavigational guidance is effective and could lower ALP levels. LAR is recommended as a preoperative treatment and when patients fail to achieve complete remission after surgery.