A Case of Left Carotid Artery Injury.

Invasive pituitary adenomas can infiltrate the dura mater, sphenoid sinus, or cranial bone. Endoscopic transsphenoidal sinus surgery is considered the standard of care; however, several potential complications must be noted. These complications can include cerebrospinal fluid leaks, infection, bleeding, optic nerve damage, and endocrinological complications such as diabetes insipidus. We present a case of a 69-year-old female with multiple recurrent invasive pituitary adenomas who has previously undergone 5 transsphenoidal procedures. Intraoperatively, the patient suffered from a left-sided carotid artery injury that was repaired with a muscle graft. Management of carotid artery injury during transsphenoidal surgery is optimized in a step-by-step approach which includes early recognition of the injury, briefing the surgical team, immediate control using compression, use of additional tissue graft for wound repair, and postoperative care. Through the use of the approach mentioned above, we were able to control the complication successfully.

A novel risk model based on the correlation between the expression of basement membrane genes and immune infiltration to predict the invasiveness of pituitary adenomas.

Objective: Invasive pituitary adenomas (IPAs) are common tumors of the nervous system tumors for which invasive growth can lead to difficult total resection and a high recurrence rate. The basement membrane (BM) is a special type of extracellular matrix and plays an important role in the invasion of pituitary adenomas (PAs). The aim of this study was to develop a risk model for predicting the invasiveness of PAs by analyzing the correlation between the expression of BM genes and immune infiltration. Methods: Four datasets, featuring samples IPAs and non-invasive pituitary adenomas (NIPAs), were obtained from the Gene Expression Omnibus database (GEO). R software was then used to identify differentially expressed genes (DEGs) and analyze their functional enrichment. Protein-protein interaction (PPI) network was used to screen BM genes, which were analyzed for immune infiltration; this led to the generation of a risk model based on the correlation between the expression of BM genes and immunity. A calibration curve and receiver operating characteristic (ROC) curve were used to evaluate and validate the model. Subsequently, the differential expression levels of BM genes between IPA and NIPA samples collected in surgery were verified by Quantitative Polymerase Chain Reaction (qPCR) and the prediction model was further evaluated. Finally, based on our analysis, we recommend potential drug targets for the treatment of IPAs. Results: The merged dataset identified 248 DEGs that were mainly enriching in signal transduction, the extracellular matrix and channel activity. The PPI network identified 11 BM genes from the DEGs: SPARCL1, GPC3, LAMA1, SDC4, GPC4, ADAMTS8, LAMA2, LAMC3, SMOC1, LUM and THBS2. Based on the complex correlation between these 11 genes and immune infiltration, a risk model was established to predict PAs invasiveness. Calibration curve and ROC curve analysis (area under the curve [AUC]: 0.7886194) confirmed the good predictive ability of the model. The consistency between the qPCR results and the bioinformatics results confirmed the reliability of data mining. Conclusion: Using a variety of bioinformatics methods, we developed a novel risk model to predict the probability of PAs invasion based on the correlation between 11 BM genes and immune infiltration. These findings may facilitate closer surveillance and early diagnosis to prevent or treat IPAs in patients and improve the clinical awareness of patients at high risk of IPAs.

Radiological Knosp, Revised-Knosp, and Hardy-Wilson Classifications for the Prediction of Surgical Outcomes in the Endoscopic Endonasal Surgery of Pituitary Adenomas: Study of 228 Cases.

PURPOSE: To evaluate which radiological classification, Knosp, revised-Knosp, or Hardy-Wilson classification, is better for the prediction of surgical outcomes in the endoscopic endonasal transsphenoidal (EET) surgery of pituitary adenomas (PAs). METHODS: This is a retrospective study of patients with PAs who underwent EET PA resection for the first time between January 2009 and December 2020. Radiological cavernous sinus invasiveness was defined as a Knosp or revised-Knosp grade >2 or a grade E in the Hardy-Wilson classification. RESULTS: A total of 228 patients with PAs were included. Cavernous sinus invasion was evident in 35.1% and suprasellar extension was evident in 74.6%. Overall, surgical cure was achieved in 64.3% of patients. Surgical cure was lower in invasive PAs than in non-invasive PAs (28.8% vs. 83.1%, p < 0.0001), and the risk of major complications was higher (13.8% vs. 3.4%, p = 0.003). The rate of surgical cure decreased as the grade of Knosp increased (p < 0.001), whereas the risk of complications increased (p < 0.001). Patients with Knosp 3B PAs tended to achieve surgical cure less commonly than Knosp 3A PAs (30.0% vs. 56.0%, p = 0.164). Similar results were observed based on the invasion and extension of Hardy-Wilson classification (stage A-C 83.1% vs. E 28.8% p < 0.0001, grade 0-II 81.1% vs. III-IV 59.7% p = 0.008). The Knosp classification offered the greatest diagnostic accuracy for the prediction of surgical cure (AUC 0.820), whereas the invasion Hardy-Wilson classification lacked utility for this purpose (AUC 0.654). CONCLUSION: The Knosp classifications offer a good orientation for the estimation of surgical cure and the risk of complications in patients with PAs submitted to EET surgery. However, the invasion Hardy-Wilson scale lacks utility for this purpose.

Apatinib (YN968D1) and Temozolomide in Recurrent Invasive Pituitary Adenoma: Case Report and Literature Review.

BACKGROUND: Invasive pituitary adenomas often recurred after postoperative radiotherapy and are difficult to treat. Temozolomide is an alkylating cytostaticum and has been reported to reduce pituitary tumor size and hormone hypersecretion. However, this is far from enough. Pituitary adenomas have relatively high expression of vascular endothelial growth factor. Therefore an antiangiogenic agent has been used in a small number of aggressive or malignant pituitary tumors after recurrence. Apatinib (YN968D1) is a small-molecule antiangiogenic agent that selectively inhibits VEGFR-2 and also mildly inhibits c-Kit and c-Src tyrosine kinases, abundant in invasive pituitary adenomas. CASE DESCRIPTION: We present a 41-year-old female with a growth hormone (GH)-secreting invasive pituitary adenoma causing menstrual disorder and headache symptoms. Over 3 years, she underwent 4 surgeries and a stereotactic radiosurgery, but the results were poor. Two months after the fourth operation, she started treatment with temozolomide (200 mg/m2, days 1-5, 28 days, orally) and apatinib (0.425 g, daily, orally). Her GH level dropped to normal with a >90% decrease in tumor size, after 1-year treatment. There was no evidence of recurrence by imaging or by serum GH levels over 31.5 months of follow-up. CONCLUSIONS: We successfully treated this patient with recurrent invasive pituitary adenoma with temozolomide and apatinib for 31.5 months without recurrence. Angiogenesis is an active process in the cases of invasive pituitary adenomas that cannot be controlled by conventional therapy.

Endoscopic Endonasal Surgery Treatment Strategies for Invasive Pituitary Adenoma: Analysis of Four Approaches.

OBJECTIVE: To explore the surgical methods and clinical effect of endoscopic endonasal approaches for the treatment of invasive pituitary adenomas (IPAs). METHODS: A retrospective analysis was made of the clinical data of 74 patients (75 procedures) with IPAs treated by different endoscopic endonasal approaches at the Department of Neurosurgery, The First Affiliated Hospital of Shenzhen University from May 2014 to August 2017. The data include clinical manifestation, imaging features, surgical methods and complications, resection rate, cure rate, prognosis, and complications in different Knosp classifications and Hardy stages. The transcavernous approach was used in 47 patients, the lateral-cavernous approach was used in 14 patients, the tuberculum sella planum approach was used in 8 patients, and the diaphragma sellae open or dorsum sellae cut approach was used in 6 patients. RESULTS: The gross total resection (GTR) rate was 70.7% (53 patients) and tumor residue rate was 29.3% (22 patients). GTR rate for pituitary adenoma according to Knosp classification was 89.3% in grade 3 and 28.6% in grade 4. The biology cure rate was 75.0% and 23.8%, respectively. There was significance between them (P < 0.05). In addition, the GTR rate of Hardy stage was 90.5% in stage C, 90.0% in stage D, 26.1% in stage E, and the biology cure rate was 80.1%, 75.0%, and 13.0%, respectively. There was significance among them (P < 0.05) Postoperative severe complications included 9 patients (12.0%) with cerebrospinal fluid leaks, 26 patients (34.7%)with electrolyte imbalance, 36 patients (48.0%) with transient diabetes insipidus, 22 patients (29.3%) with hypopituitarism, 2 patients (2.7%) with permanent hypopituitarism, and 2 patients (2.7%)with epistaxis. The follow-up lasted 2-41 months (average, 19.3 months). No patient experienced recurrence after GTR, 1 patient undergoing subtotal experienced recurrence and underwent reoperation, 3 patients underwent postoperative Gamma Knife treatment, and 2 patients with refractory IPA were given temozolomide and metformin chemotherapy. CONCLUSIONS: According to the invasiveness of IPA, choosing the appropriate endoscopic surgical approach is helpful in removing tumors and reducing complications.

Differentiating skull base chordomas and invasive pituitary adenomas with conventional MRI.

Background It is difficult to distinguish between invasive pituitary adenomas (IPAs) and skull base chordomas based on tumor location and clinical manifestations. Purpose To investigate the value of the apparent diffusion coefficient (ADC), T2-weighted (T2W) imaging, and dynamic contrast enhancement (DCE) in differentiating skull base chordomas and IPAs. Material and Methods Data for 21 patients with skull base chordomas and 27 patients with IPAs involving the paranasal sinus were retrospectively reviewed, and all diagnoses were pathologically confirmed. Each patient underwent conventional 3.0 T magnetic resonance imaging (MRI), including, ADC, T2W imaging, and DCE sequences. Regions of interest were drawn in the mass and in normal white matter on ADC maps and T2W imaging. The mean ADC, normal ADC, T2W imaging signal intensity (SI), and relative T2-weighted (rT2W) imaging values were measured. DCE parameters, including types of time signal-intensity curves (TIC), enhancement peak (EP), and maximum contrast enhancement ratio (MCER), were calculated. Differences between skull base chordomas and IPAs were evaluated using the independent samples t-test. Receiver operating characteristic (ROC) curve analyses were also performed. Results When comparing IPAs and chordomas, there were significant differences in mean ADC, normal ADC, rT2W imaging values, TIC, EP, and MCER ( P < 0.01). The areas under curves in the ROC analyses for normal ADC, mean ADC, T2W imaging, rT2W imaging, TIC, EP, and MCER were 1.0, 0.996, 1.0, 0.81, 0.987, and 0.987, respectively. Conclusion ADC, T2W imaging SI, and DCE-related parameters can contribute to the differential diagnosis of skull base chordomas and IPAs.

The relationship between RSUME and small ubiquitin related modifiers of HIF-1α with invasive pituitary adenomas / 中国神经精神疾病杂志

Objective AIM:To study whether the RWD containing sumoylation enhancer (RSUME) enhanced small ubiquitin related modifiers (SUMO) to competitively inhibit Ubiquitin B (UBB)-mediated degradation of hypoxia hypoxia-inducible factor 1α.(HIF-1α) and the invasive pituitary adenomas.Methods The expression of protein and mRNA levels of RSUME,SUMO-1,UBB and HIF-1α were detected by using immunohistochemistry,western blot and qPCR in 38 cases of non-invasive pituitary adenoma,38 cases of invasive pituitary adenomas and 10 cases of normal pituitary capsule.The expression of SUMO-1 was analyzed in different types of pituitary adenomas.Results The protein,and mRNA levels of RSUME,SUMO-HIF-1αwere significantly higher in the invasive pituitary adenomas than in the non-invasive pituitary adenomas and normal pituitary capsule (P＜0.01).The protein and mRNA levels of RSUME,SUMO-HIF-1αwas higher in non-invasive pituitary adenomas than in normal pituitary capsule(P＜0.01).However,the protein levels of UBB-HIF-1α were significantly lower in the invasive pituitary adenomas than in the non-invasive pituitary adenomas and normal pituitary capsule (P＜0.01).The protein of UBB-HIF-1α were lower in non-invasive pituitary adenomas than in normal pituitary capsule (P＜0.01).The expression levels of SUMO were not significantly different among different types of pituitary adenomas (P＞0.05).Conclusion RSUM may increase pituitary adenomas angiogenesis and promote tumor invasion through enhancement of SUMO of HIF-1α which competitively inhibits ubiquitination of HIF-1 α.

ADC and T2WI in differentiating skull base chordoma and invasive pituitary adenomas / 实用放射学杂志

Objective To investigate the value of ADC and T2WI in differentiating of skull base chordoma and invasive pituitary adenomas(IPA).Methods 15 patients with skull base chordoma and 19 patients with IPA which involve paranasal sinus were reviewed retrospectively.All diagnosis were demonstrated by pathology.Quantitative analysis of minimum ADC, normal ADC and rT2WI values were performed.Differences in minimum ADC, normal ADC and rT2WI values between skull base chordoma and IPA were evaluated using the independent samples t test and receiver operating curves(ROC).Results Statistical analysis revealed a significant difference among normal ADC, minimum ADC and rT2WI values (P<0.01),and the area under the ROC curves decreased in turn.Conclusion Both ADC values and rT2WI SI are effective parameter for differentiating diagnosis of skull base chordoma and IPA.

Expression of MMP14 in invasive pituitary adenomas: relationship to invasion and angiogenesis.

Pituitary adenomas (PAs) are noncancerous tumors, and about 35% of those reported to be invasive have been classified as "invasive pituitary adenomas (IPAs)". In clinical, operative complications, total resection failures, and high relapse rates result from invasive features during the therapeutic process. Invasive mechanism is a complex process, including metalloproteases, inhibitors and tumor microenvironment factors etc. Thus, studying invasive mechanism of PAs might contribute to understanding its biological behavior. In our research, three type tissue samples of human, pituitaries, PAs, IPAs, their mRNA expression of MMP1, MMP2, MMP9, MMP14 and MMP15 were measured using real-time PCR. MMP2 and MMP14 protein levels also were measured with immunohistochemistry in same samples. We confirmed that elevated matrix metalloproteinase-14 expression correlates with invasive characteristics of IPAs. To investigate molecular mechanism of how MMP14 contributes to invasiveness, an ATT20 cell was used in this study. After transient-transfection of the MMP14-shRNA expression vector into ATT20 cells, we observed that mRNA expression of PTTG, VEGF, and TGFß was significantly suppressed in interference groups. Meanwhile, ATT20 cells in high concentration TIMP-1 environment exhibit reduced PTTG, VEGF, and TGFß expression accompanied with the down-regulation of MMP14. Thus, we propose that MMP14 plays an important role in tumor invasion and angiogenesis and that a novel regulatory pathway for MMP14 may exist through VEGF and PTTG. In brief, MMP14 may be a target for therapeutic treatment.

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.

Expression and relationship of Beclin1 and Bci2 in invasive pituitary adenomas / 中华内分泌外科杂志

Objective To detect the expression of Beclin1 and Bcl2 in invasive pituitary adenomas and to explore the relationship of Beclin1 and Bci2 in invasive pituitary adenomas and the relativity between the 2 genes.Methods 61 specimens were classified into invasive group (32 cases) and non-invasive group (29 cases) according to the comprehensive evaluation of invasive pituitary adenomas.lmmunofluorescence analysis and RT-PCR were adopted respectively to detect the protein and mRNA expressions of Beclinl and Bcl2.The difference and relativity of Beclin1 and Bcl2 expression in invasive group and non-invasive group were analyzed.Results 32 specimens of pituitary adenoma were invasive and 29 were non-invasive.Beclin1 protein and mRNA expressions were lower in the invasive group than in the non-invasive group (P ＜0.01 ).Bcl2 protein and mRNA expressions were higher in the invasive group than in the non-invasive group (P ＜0.01 ).Pearson related analysis showed that Beclin1 mRNA expression was negtively correlated with Bcl2 mRNA expression in the invasive group ( r =-0.42,P =0.028 ).Conclusions Beclinl expression is decreased in invasive pituitary adenomas.The invasiveness of pituitary adenoma is closely related to the high expression of Bcl2 protein and mRNA,and the low expression of Beclin1 protein and mRNA.The inhibition of the autophagy may lead to the enhancement of the invasiveness of pituitary adenomas and that inhibition may come from the interaction of Beclin1 and Bcl2.