Bing Xing

Inhibition of PI3K/AKT/mTOR Pathway Enhances Temozolomide-Induced Cytotoxicity in Pituitary Adenoma Cell Lines in Vitro and Xenografted Pituitary Adenoma in Female Nude Mice

Invasive pituitary adenomas (PAs) are often refractory to standard therapy and salvage treatment with temozolomide (TMZ). Hyperactivation of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway contributes to chemotherapy resistance in many cancers. XL765, a novel dual-PI3K/mTOR inhibitor, has recently shown its efficacy as a monotherapy and in combination with conventional therapeutics in many cancers. The hyperactive PI3K/AKT/mTOR pathway frequently occurs in invasive PAs. In this study, we investigated whether XL765 sensitizes PA cells to TMZ in vitro and in vivo. Experiments were carried out to evaluate the effect of XL765 and TMZ alone or in combination on cell proliferation and apoptosis of PA cell lines (αT3-1, GH3, and MMQ) in vitro as well as the tumor growth and serum GH and prolactin secretions in a GH3 xenograft tumor model of female nude mice. XL765 and TMZ synergistically inhibited the growth of PA cell lines and induced apoptosis. Combination of XL765 and TMZ synergistically inhibited tumor growth, decreased serum GH and prolactin levels, and reduced the sacrifice rate of GH3 xenograft tumor models without increased systemic side effects. In addition, XL765 in combination with TMZ dramatically decreased phosphorylation of AKT and mTOR as well as the expression of Bcl-2. The increased expression of cleaved poly (ADP-ribose) polymerase and Bcl-2-associated X protein along with elevated caspase-3/7 activity were also observed in the combination group. Therefore, dual inhibitors of PI3K and mTOR may enhance alkylating agent-mediated cytotoxicity and provide a novel regimen in the treatment of invasive PAs.

Application of 68Ga-PRGD2 PET/CT for αvβ3-integrin Imaging of Myocardial Infarction and Stroke

Purpose: Ischemic vascular diseases, including myocardial infarction (MI) and stroke, have been found to be associated with elevated expression of αvβ3-integrin, which provides a promising target for semi-quantitative monitoring of the disease. For the first time, we employed 68Ga-S-2-(isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid-PEG3-E[c(RGDyK)]2 (68Ga-PRGD2) to evaluate the αvβ3-integrin-related repair in post-MI and post-stroke patients via positron emission tomography/computed tomography (PET/CT). Methods: With Institutional Review Board approval, 23 MI patients (3 days-2 years post-MI) and 16 stroke patients (3 days-13 years post-stroke) were recruited. After giving informed consent, each patient underwent a cardiac or brain PET/CT scan 30 min after the intravenous injection of 68Ga-PRGD2 in a dose of approximately 1.85 MBq (0.05 mCi) per kilogram body weight. Two stroke patients underwent repeat scans three months after the event. Results: Patchy 68Ga-PRGD2 uptake occurred in or around the ischemic regions in 20/23 MI patients and punctate multifocal uptake occurred in 8/16 stroke patients. The peak standardized uptake values (pSUVs) in MI were 1.94 ± 0.48 (mean ± SD; range, 0.62-2.69), significantly higher than those in stroke (mean ± SD, 0.46 ± 0.29; range, 0.15-0.93; P < 0.001). Higher 68Ga-PRGD2 uptake was observed in the patients 1-3 weeks after the initial onset of the MI/stroke event. The uptake levels were significantly correlated with the diameter of the diseases (r = 0.748, P = 0.001 for MI and r = 0.835, P = 0.003 for stroke). Smaller or older lesions displayed no uptake. Conclusions: 68Ga-PRGD2 uptake was observed around the ischemic region in both MI and stroke patients, which was correlated with the disease phase and severity. The different image patterns and uptake levels in MI and stroke patients warrant further investigations.

Overview of the health care system in Hong Kong and its referential significance to mainland China

Abstract Hong Kongs health system was established within the framework of a perfect market‐oriented economic matrix, where there are wide‐ranging social security and medical service systems. There are many differences in the economic foundations, social systems, and ideologies between Hong Kong and mainland China, therefore, it would probably be entirely impossible to copy Hong Kongs health care system mode. However, under the framework of one country, two systems, the referential significance of relevant concepts of Hong Kongs medical service system to mainland China cannot be ignored, and merits further study.

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.

Screening for AIP gene mutations in a Han Chinese pituitary adenoma cohort followed by LOH analysis

OBJECTIVE The aryl hydrocarbon receptor interacting protein gene (AIP) is associated with pituitary adenoma (PA). AIP has not been sequenced in East Asian PA populations, so we performed this study in a Han Chinese cohort. DESIGN Our study included six familial PA pedigrees comprising 16 patients and 27 unaffected relatives, as well as 216 sporadic PA (SPA) patients and 100 unrelated healthy controls. METHODS AIP sequencing was carried out on genomic DNA isolated from blood samples. Multiplex ligation-dependent probe amplification and microsatellite marker analyses on DNA from the paired tumor tissues were performed for loss of heterozygosity analysis. RESULTS We identified three common and four rare single nucleotide polymorphisms (SNPs), one intron insertion, one novel synonymous variant, four novel missense variants, and a reported nonsense mutation in three familial isolated PA (FIPA) cases from the same family. Large genetic deletions were not observed in the germline but were seen in the sporadic tumor DNA from three missense variant carriers. The prevalence of AIP pathogenic variants in PA patients here was low (3.88%), but was higher in somatotropinoma patients (9.30%), especially in young adults (≤30 years) and pediatric (≥18 years) paients (17.24% and 25.00% respectively). All AIP variant patients suffered from macroadenomas. However, the AIP mutation rate in FIPA families was low in this cohort (16.67%, 1/6 families). CONCLUSION AIP gene mutation may not be frequent in FIPA or SPA from the Han Chinese population. AIP sequencing and long-term follow-up investigations should be performed for young patients with large PAs and their families with PA predisposition.

Study on the Expression Levels of CXCR4, CXCL12, CD44, and CD147 and Their Potential Correlation with Invasive Behaviors of Pituitary Adenomas

OBJECTIVE To evaluate the factors of CXCR4, CXCL12, CD44, and CD147 as early potential diagnostic biomarkers by determining their expression levels in invasive and non-invasive pituitary adenomas. METHODS Fresh pituitary adenoma specimens were collected from 35 pituitary adenoma (21 invasive and 14 non-invasive) patients who underwent surgical treatment in our Neurosurgery Department between January and April of 2009. The expression levels of CXCR4, CXCL12, CD44, and CD147 were evaluated firstly by flow cytometry, fluorescence microscopy in single cell suspensions, and then by immunohistochemical staining of paraffin tissue sections. RESULTS Flow cytometric analyses showed that the percentage of CXCR4- and CXCL12-positive cells from invasive pituitary adenomas (IPA) was significantly higher in the single cell suspensions than that from non-invasive pituitary adenomas (nIPA) (P<0.05). Immunohistochemical staining revealed that CXCR4 and CXCL12 staining index scores of the invasive pituitary adenomas were significantly higher than those of the non-invasive pituitary adenomas (P<0.05). In contrast, neither flow cytometry nor immunohistochemical staining demonstrated significant difference between CD44 and CD147 expression levels, respectively. CONCLUSION Expression levels of CXCR4 and CXCL12 are correlated with the invasiveness of pituitary adenomas. Therefore, rather than CD44 and CD147, CXCR4 and CXCL12 may potentially serve as biomarkers for early detection of pituitary adenomas.

Primary malignant peripheral nerve sheath tumor of the cauda equina with metastasis to the brain in a child: case report and literature review

BACKGROUND CONTEXT Primary intradural malignant peripheral nerve sheath tumors (MPNSTs) are extremely rare; only 23 cases have been reported in the English-language literature till now. No gold standard for treating primary intradural MPNSTs has yet been established. PURPOSE To report a rare case of primary intradural MPNSTs in a child and review the literature pertaining to this rare disease. STUDY DESIGN/SETTING Case report and literature review. METHODS We report our experience with one new case. An 8-year-old boy diagnosed with primary intradural MPNSTs underwent three surgical excisions and two rounds of radiotherapy; however, metastasis to the brain was found, and the boy died 16 months after the first surgery. We also review the literature pertaining to both MPNSTs in general and primary intradural MPNSTs. RESULTS Surgery is currently the mainstay of MPNST treatment. Radiotherapy and chemotherapy are of limited value in these tumors. Based on the review of the 24 cases described in the literature, including the present case, primary intradural MPNST is a very aggressive tumor with a very high recurrence rate even after gross total resection and with significant potential for leptomeningeal and systemic metastasis. The overall prognosis is very poor and seems to be worse than that of MPNSTs in general. CONCLUSIONS Primary intradural MPNST is a very rare entity with a poor prognosis. Surgical tumor removal combined with postoperative high-dose radiation may be recommended. Chemotherapy is usually reserved for patients with disseminated metastases or tumors that are unresectable at the time of diagnosis.

Comparison of (68)Ga DOTATATE to 18F-FDG uptake is useful in the differentiation of residual or recurrent pituitary adenoma from the remaining pituitary tissue after transsphenoidal adenomectomy.

Aim The evaluation of the remaining pituitary tissue and recurrent or residual tumor after the pituitary adenoma resection is difficult. However, it is essential to assess the size of the recurrent tumor and remaining pituitary reserve before resurgery. This study aimed to distinguish the remaining pituitary tissue from pituitary adenoma with 68Ga 1,4,7,10-tetraazacyclododecane-N,N′,N″,N″′-tetraacetic acid-D-Phe1,Tyr3-octreotate (DOTATATE) and 18F-FDG PET imaging in patients status post transsphenoidal adenomectomy. Methods Thirty-five patients with suspected recurrent/residual pituitary tumors were retrospectively evaluated. All of these patients underwent DOTATATE and FDG PET/CT within 1 week before additional surgery. The DOTATATE and FDG uptake levels were compared. The image findings were then compared with pathology results after the additional surgery. Results Residual or recurrent pituitary adenoma were confirmed pathologically in all 35 patients. One recurrent pituitary adenoma did not have either DOTATATE or FDG uptake. In the remaining 34 adenomas, 33 had higher FDG uptake than DOTATATE uptake. In comparison, DOTATATE had significant higher uptake than FDG in the remaining pituitary tissues in all cases. Conclusions Different degree of uptake of 68Ga DOTATATE and 18F-FDG PET/CT in the remaining pituitary tissue and recurrent/residual pituitary tumor indicated that combined analysis of 68Ga DOTATATE and 18F-FDG PET/CT might be of clinical value in differentiating recurrent/residual pituitary adenoma from the remaining pituitary tissue.

Primary Intraosseous Cavernous Hemangioma in the Skull

AbstractPrimary intraosseous cavernous hemangiomas (PICHs) are benign vascular tumors that may involve any part of the body. PICH occurs more frequently in the spine and less commonly in skull. The earliest description in the English literature was in 1845 by Toynbee, who reported a vascular tumor arising in the confines of the parietal bone. Skull PICHs do not always have typical radiologic features and should always be considered in the differential diagnosis of malignant skull lesions. We now reviewed and analyzed related literatures in detail with reporting a rare case of PICH in the left front bone that was surgically resected.