Axl as a potential therapeutic target for adamantinomatous craniopharyngiomas: Based on single nucleus RNA-seq and spatial transcriptome profiling.

Craniopharyngiomas (CPs), particularly Adamantinomatous Craniopharyngiomas (ACPs), often exhibit a heightened risk of postoperative recurrence and severe complications of the endocrine and hypothalamic function. The primary objective of this study is to investigate potential novel targeted therapies within the microenvironment of ACP tumors. Cancer-Associated Fibroblasts (CAFs) were identified in the craniopharyngioma microenvironment, notably in regions characterized by cholesterol clefts, wet keratin, ghost cells, and fibrous stroma in ACPs. CAFs, alongside ghost cells, basaloid-like epithelium cells and calcifications, were found to secrete PROS1 and GAS6, which can activate AXL receptors on the surface of tumor epithelium cells, promoting immune suppression and tumor progression in ACPs. Additionally, the AXL inhibitor Bemcentinib effectively inhibited the proliferation organoids and enhanced the immunotherapeutic efficacy of Atezolizumab. Furthermore, neural crest-like cells were observed in the glial reactive tissue surrounding finger-like protrusions. Overall, our results revealed that the AXL might be a potentially effective therapeutic target for ACPs.

Impact of three surgical approaches on the therapeutic efficacy of intraventricular craniopharyngiomas: a single-center retrospective analysis.

This study aimed to investigate the therapeutic efficacy of three different surgical approaches for the treatment of intraventricular craniopharyngiomas (IVCs). The three surgical approaches investigated in this study were the endoscopic endonasal approach (EEA), pterional trans-lamina terminalis approach (PTA), and interhemispheric trans-lamina terminalis approach (ITA). Patient demographics, preoperative symptoms, endocrine and hypothalamic status, tumor characteristics, and surgical outcomes were analyzed and compared among the different surgical groups. A total of 31 patients with IVCs were included in the analysis, with 12 patients in the EEA group, 8 patients in the ITA group, and 11 patients in the PTA group. The mean follow-up time was 39 ± 23 months. Statistical analysis of the data revealed significant differences in the gross total resection (GTR) rate among the three surgical groups (P = 0.033). The GTR rate for the EEA group was 100%, that for the ITA group was 88%, and that for the PTA group was 64%, which was the lowest rate observed. After surgery, only 8.3% of the patients in the EEA group did not experience new postoperative hypopituitarism, while the percentages in the ITA and PTA groups were 75% and 73%, respectively (P = 0.012). Finally, we found that postoperative hypopituitarism may be related to the transection of the pituitary stalk during the operation (P = 0.020). Based on the results of this study, we recommend using the EEA and the ITA instead of the PTA for the surgical resection of IVCs. Furthermore, the appropriate surgical approach should be selected based on the tumor's growth pattern.

Incidence, risk factors, management and prevention of severe postoperative epistaxis after endoscopic endonasal transsphenoidal surgery: a single center experience.

Objective: Postoperative epistaxis is a very rare but severe complication after endoscopic endonasal transsphenoidal surgery (EETS) that can lead to catastrophic consequences. However, the incidence, risk factors, management and prevention of postoperative epistaxis remain unclear. Patients and methods: Consecutive patients with pituitary adenoma (PA), Rathke's cleft cyst, craniopharyngioma, or clival chordoma who received EETS in our department between September 2020 and November 2022 were retrospectively analyzed. The incidence, risk factors, management and prevention of postoperative epistaxis were investigated and analyzed. Results: A total of 557 consecutive patients who received EETS were included in this study. Eight patients (1.4%) (7 PAs and 1 Rathke's cleft cyst) experienced severe postoperative epistaxis. The size of the PAs was 9.6 mm-46.2 mm, with a median size of 22.1 mm. Epistaxis occurred 4 h to 30 days (median 14.5 days) postoperatively. Bleeding was stopped in 3 patients after nasal packing with iodoform gauze. The remaining 5 patients for whom nasal packing was insufficient were all sent to the operating room, and posterior nasal septal artery (PNSA) bleeding was identified and successfully treated with endoscopic bleeding artery electrocauterization under general anesthesia. In the EETS, all 8 patients had downward extension of the septal mucosal incision, in which 6 had intraoperative bleeding of PNSA that were cauterized by bipolar diathermy. Four patients had causative factors, including administration of antiplatelet agents, Valsalva-like manoeuvre, nose blowing and removal of nasal packing, respectively. No patients had recurrent epistaxis during the follow-up period. Conclusion: Post-EETS epistaxis is a rare but severe complication that could lead to catastrophic consequences, and one of the most common bleeding sources is the PNSA. Endoscopic bleeding artery electrocauterization under general anesthesia may be a safe, economic and effective measure for epistaxis refractory to nasal packing. Avoiding excessive downward extension of the septal mucosal incision could contribute to the prevention of postoperative epistaxis.

Comprehensive Analysis of 34 Edible Flowers by the Determination of Nutritional Composition and Antioxidant Capacity Planted in Yunnan Province China.

The main purpose of this study was to reveal the nutritional value and antioxidant activity of 34 edible flowers that grew in Yunnan Province, China, through a comprehensive assessment of their nutritional composition and antioxidant indices. The results showed that sample A3 of Asteraceae flowers had the highest total flavonoid content, with a value of 8.53%, and the maximum contents of vitamin C and reducing sugars were from Rosaceae sample R1 and Gentianaceae sample G3, with values of 143.80 mg/100 g and 7.82%, respectively. Samples R2 and R3 of Rosaceae were the top two flowers in terms of comprehensive nutritional quality. In addition, the antioxidant capacity of Rosaceae samples was evidently better than that of three others, in which Sample R1 had the maximum values in hydroxyl radical (·OH) scavenging and superoxide anion radical (·O2-) scavenging rates, and samples R2 and R3 showed a high total antioxidant capacity and 2,2-diphenyl-1-pyridylhydrazine (DPPH) scavenging rate, respectively. Taken together, there were significant differences in the nutrient contents and antioxidant properties of these 34 flowers, and the comprehensive quality of Rosaceae samples was generally better than the other three families. This study provides references for 34 edible flowers to be used as dietary supplements and important sources of natural antioxidants.

Coexistence of TSH-secreting adenoma and primary hypothyroidism: a case report and review of literature.

BACKGROUND: Thyrotropin-secreting adenoma (TSHoma) is the least common type of pituitary adenoma, these patients often present with symptoms of hyperthyroidism. When TSHoma patients combined with autoimmune hypothyroidism, it is critically difficult to diagnose for the specific confusion in the results of thyroid function test. CASE PRESENTATION: One middle-aged male patient was presented with a sellar tumor on cranial MRI for headache symptoms. After hospitalization, a significant increase in thyrotropin (TSH) was revealed by the endocrine tests, while free thyronine (FT3) and free thyroxine (FT4) decreased, and the diffuse destruction of thyroid gland was revealed by thyroid ultrasound. Based on the endocrine test results, the patient was diagnosed as autoimmune hypothyroidism. After the multidisciplinary discussion, the pituitary adenoma was removed by endoscopic transnasal surgery, until the tumor was completely excised, for which TSHoma was revealed by postoperative pathology. A significant decrease of TSH was revealed by the postoperative thyroid function tests, the treatment for autoimmune hypothyroidism was conducted. After 20 months of follow-up, the thyroid function of patient had been improved significantly. CONCLUSION: When the thyroid function test results of patients with TSHoma are difficult to interpret, the possibility of combined primary thyroid disease should be considered. TSHoma combined with autoimmune hypothyroidism is rare, which is difficult to diagnose. The multidisciplinary collaborative treatment could help to improve the outcomes of treatment.

Diagnosis and Treatment of Nonfunctioning Pituitary Adenomas with Thyroid Disorders.

Objective: Patients with nonfunctioning pituitary adenoma (NFPA) can present with different types of thyroid disorders, which are easily misdiagnosed or missed and can even result in serious clinical consequences. This study was to summarize the different types of thyroid disorders in patients with NFPA with the aim of providing references for the diagnosis and treatment of such patients. Materials and Methods: The data of pituitary adenoma (PA) patients who underwent surgical treatment at Xuanwu Hospital, Capital Medical University, from 2017 to 2021 were retrospectively analyzed, and NFPA patients with preoperative thyroid disorders were screened out to analyze their imaging, endocrine, treatment, and prognosis data. Also, thyroid disorders were classified to summarize diagnostic methods and treatment principles for different types of thyroid disorders. Results: A total of 399 NFPA patients were included in this study, of which 67 (16.8%) had thyroid disorders before surgery. Fifty-four patients had (13.5%) central hypothyroidism (CH) caused by NFPA and were treated with levothyroxine (L-T4) supplementation before and after operation. Eleven patients (2.8%) had primary hypothyroidism and were treated with L-T4 during the perioperative period, and long-term treatment of primary hypothyroidism was provided after surgery. Two NFPA patients (0.5%) were combined with primary hyperthyroidism and treated with medication for primary hyperthyroidism after tumor resection. Conclusion: Thyroid disorders are relatively common in patients with NFPA, but are difficult to be diagnosed due to their different types. CH is the most common type of thyroid disorder, which requires aggressive L-T4 supplementation during the preoperative period. The primary disease of the thyroid gland is easily missed when NFPA is combined with primary hypothyroidism or primary hyperthyroidism, and the thyroid function test results require to be analyzed carefully for continued treatment for thyroid disease after resection of the NFPA.

Predicting delayed remission in Cushing's disease using radiomics models: a multi-center study.

Purpose: No multi-center radiomics models have been built to predict delayed remission (DR) after transsphenoidal surgery (TSS) in Cushing's disease (CD). The present study aims to build clinical and radiomics models based on data from three centers to predict DR after TSS in CD. Methods: A total of 122 CD patients from Peking Union Medical College Hospital, Xuanwu Hospital, and Fuzhou General Hospital were enrolled between January 2000 and January 2019. The T1-weighted gadolinium-enhanced MRI images and clinical data were used as inputs to build clinical and radiomics models. The regions of interest (ROI) of MRI images were automatically defined by a deep learning algorithm developed by our team. The area under the curve (AUC) of receiver operating characteristic (ROC) curves was used to evaluate the performance of the models. In total, 10 machine learning algorithms were used to construct models. Results: The overall DR rate is 44.3% (54/122). According to multivariate Logistic regression analysis, patients with higher BMI and lower postoperative cortisol levels are more likely to achieve a higher rate of delayed remission. Among the 10 models, XGBoost achieved the best performance among all models in both clinical and radiomics models with AUC values of 0.767 and 0.819 respectively. The results from SHAP value and LIME algorithms revealed that postoperative cortisol level (PoC) and BMI were the most important features associated with DR. Conclusion: Radiomics models can be built as an effective noninvasive method to predict DR and might be useful in assisting neurosurgeons in making therapeutic plans after TSS for CD patients. These results are preliminary and further validation in a larger patient sample is needed.

Intradural spinal seeding metastasis of clival chordoma: a case report.

Background: Clival chordoma is a locally aggressive tumor originating from remnants of the embryologic notochord. Although clival chordomas account for only 0.2% of all central nervous system tumors, they are characterized by local invasion and destruction, dural invasion, bone erosion, and cranial nerve palsy, and even metastasis. Case Description: We report a case of a 49-year-old female with an intradural spinal seeding metastasis 16 months after the initial endoscopic endonasal surgery (EES) for a clival chordoma. Gross total resection of tumor in upper clival region was achieved after initial EES and pathology revealed a classic chordoma. After 10 months, follow-up magnetic resonance (MR) showed a recurrence in situ and gamma knife was applied. After 16 months, the patient complained of neck pain and MR showed a new lesion in the spinal canal at C1 to C2 level. After craniotomy, the lesion in the spinal canal was totally removed, and pathology confirmed a chordoma with increased proliferative potential. The spinal chordoma might have occurred as a result of intradural spinal seeding metastasis through cerebral spinal fluid the during the initial operation. Conclusions: Chordomas are not only locally aggressive but also unpredictable and may metastasize through cerebral spinal fluid. Intensive follow-up is of great importance in the long term postoperatively time for clival chordoma patients.

A MEMS modulator-based dual-channel mid-infrared laser heterodyne radiometer for simultaneous remote sensing of atmospheric CH4, H2O and N2O.

The performance of a micro-electro-mechanical system (MEMS) modulator-based dual-channel mid-infrared laser heterodyne radiometer (MIR-LHR) was demonstrated in ground-based solar occultation mode for the first time. A MEMS mirror was employed as an alternative modulator to the traditional mechanical chopper, which makes the system more stable and compact. Two inter-band cascade lasers (ICL) centered at 3.53 µm and 3.93 µm, were employed as local oscillators (LO) to probe absorption lines of methane (CH4), water vapor (H2O) and nitrous oxide (N2O). The system stability greater than 1000 s was evaluated by Allan variance. The experimental MIR-LHR spectra (acquired at Hefei, China, on February 24th 2022) of two channels were compared and were in good agreement with simulation spectra from atmospheric transmission modeling. The mixing ratio of CH4, H2O and N2O were determined to be ∼1.906 ppm, 3069 ppm and ∼338 ppb, respectively. The reported MEMS modulator-based dual-channel MIR-LHR in this manuscript has great potential to be a portable and high spectral resolution instrument for remote sensing of multi-component gases in the atmospheric column.

Surgical Outcomes of Clival Chordoma Through Endoscopic Endonasal Approach: A Single-Center Experience.

Objective: Clival chordoma is a locally aggressive tumor with low metastatic potential. In the past decade, endoscopic endonasal approach (EEA) for clival chordoma has had a higher resection rate and a lower morbidity rate than transcranial approaches. Here, we present our initial single-center experience after EEA of clival chordomas. Patients and methods: This study retrospectively analyzed 17 consecutive patients with clival chordoma who received EEA in our department between March 2015 and September 2021. The operation was performed by a single surgeon with EEA. The clinical and pathological characteristics were analyzed along with the surgical outcomes and complications. Results: A total of 17 consecutive patients with clival chordoma received EEA with a median follow-up of 29.2 months (range 1-79). Gross total resection (GTR) was performed in 7 cases (41%), subtotal resection (STR) in 7 case (41%) and partially resection (PR) in 3 cases (18%). Cerebrospinal fluid leakage occurred in 2 cases (12%) and meningitis developed in 3 patients (18%) which were all successfully treated with intravenous antibiotics without any complications. There were no perioperative deaths or new focal neurological deficits postoperatively. Four in 7 patients with STR have had radiotherapy while the other three chose to be monitored. Till the last follow-up, three patients in STR group who received radiotherapy (3 in 4) had no tumor regrowth, while one in STR group with radiotherapy (1 in 4) showed tumor progression. Two patients in STR group without radiotherapy (2 in 3) showed stable tumor while the left one (1 in 3) showed tumor progression. One patient in the PR group died of tumor progression 2 years postoperation and the other one showed tumor progression and died of lung cancer 1 year postoperation. In addition, 1 in 7 patients with GTR had tumor recurrence in situ after 10 months and developed surgical pathway seeding in the spinal canal in C1 after 16 months. No recurrence occurred in the other 6 cases with GTR during the follow-up. Conclusion: Although more cases are needed, our case series showed EEA is a safe and reliable method for clival chordoma with high resection rates and low morbidity rates. GTR without tumor residuum would improve the outcome.

The Clinical and Pathological Characteristics of Refractory Pituitary Adenomas: A Single Center Experience.

Background: Most of pituitary adenomas (PAs) are slow-growing benign tumors which can be cured or controlled by conventional therapies, including surgery, medical treatment or radiotherapy. A small set of PAs, usually known as aggressive PAs or refractory PAs, present with more aggressive behavior and lead to poorer prognosis than classical PAs. Methods: We retrospectively analyzed the clinical and pathological characteristics of 44 patients who were diagnosed with refractory PAs by a multidisciplinary team (MDT). All the patients' demographic characteristics, radiological findings, Knosp grade, treatment details and clinical outcomes were abstracted from the medical records. Additionally, 44 patients with nonrefractory PAs (NRPAs) matched for age and gender were selected to serve as the control group. Results: Despite using all combined treatments including surgery, radiotherapy and conventional medical treatments, all the refractory PAs showed tumor progression or hormone hypersecretion which caused increased morbidity and mortality and remained challenging to management. Compared with those of the non-refractory PAs, the tumor size, invasive rate and tumor growth rate (TGR) were significantly higher in the refractory PAs. TGR >2.2% per month may be considered as a preoperative indicator of refractoriness. The Ki-67 index in the refractory PAs were all ≥3%. EGFR, but not MMP2 or MMP9, was significantly overexpressed in refractory PAs compared with the corresponding levels in nonrefractory PAs. Conclusion: Refractory PAs are unresponsive to surgery, radiotherapy and conventional medical treatments with a poor prognosis. Moreover, a TGR ≥2.2% per month, Ki-67 index ≥3% and EGFR overexpression may be independent predictors of clinical refractoriness.

Tractography of the stria terminalis in the human brain.

The aim of this study was to investigate the trajectory of the stria terminalis and develop a protocol for mapping the stria terminalis using multi-shell diffusion images based tractography. The stria terminalis was reconstructed by combining one region of interest at the amygdala with another region of interest at the bed nucleus of stria terminalis. In addition, one region of avoidance was placed on the fornix at the interventricular foramen and another was set at the anterior perforated substance. The fiber-tracking protocol was tested in a Human Connectome Project-842 template, 35 healthy subjects from Massachusetts General Hospital, and 20 healthy subjects from the Human Connectome Project using generalized q-sampling imaging based tractography. The stria terminalis was reconstructed in the Human Connectome Project-842 template, 35 Massachusetts General Hospital healthy subjects, and 20 Human Connectome Project healthy subjects with our protocol. The stria terminalis originated from the amygdala and traveled parallel to the fornix. Then, the stria terminalis followed a C-shaped trajectory around the inferior, posterior, and dorsal surfaces of the thalamus before projecting to the bed nucleus of stria terminalis between the thalamus and caudate nucleus. There were no significant differences in the quantitative anisotropy and fractional anisotropy values between the left and right stria terminalis. The stria terminalis was accurately visualized across subjects using multi-shell diffusion images through generalized q-sampling imaging based tractography. This method could be an important tool for the reconstruction and evaluation of the stria terminalis in various neurological disorders. One Sentence Summary The visualization of the stria terminalis through the multi-shell diffusion images using generalized q-sampling imaging based tractography.

Tractography of the ansa lenticularis in the human brain.

The aim of this study was to make a thorough investigation of the trajectory of the ansa lenticularis (AL) and its subcomponents using high-resolution fiber-tracking tractography. The subcomponents of the AL were reconstructed from one region of interest (ROI) in the area of the globus pallidus combined with another ROI in the red nucleus, substantia nigra, subthalamic nucleus, or thalamus. This fiber-tracking protocol was tested in an HCP-1065 template, 35 healthy subjects from Massachusetts General Hospital (MGH), and 20 healthy subjects from the human connectome project (HCP) using generalized q-sampling imaging (GQI)-based tractography. Quantitative anisotropy and fractional anisotropy were also computed for the AL subcomponents. The subcomponents of the AL could be reconstructed in the HCP-1065 template, 35 MGH healthy subjects, and 20 HCP healthy subjects. The AL descends from the globus pallidus and joins the ansa peduncularis for a short distance, subdividing later into fibers that continue separately to the red nucleus, substantia nigra, subthalamic nucleus, and thalamus. The study demonstrated the trajectory of the ansa lenticularis and its subcomponents using GQI-based tractography, improving our understanding of the anatomical connectivity between the globus pallidus and the thalamo-subthalamic region in the human brain. One Sentence Summary The investigation of the ansa lenticularis and its subcomponents using high-resolution diffusion images based tractography.

The trajectory of the medial longitudinal fasciculus in the human brain: A diffusion imaging-based tractography study.

The aim of this study is to investigate the trajectory of medial longitudinal fasciculus (MLF) and explore its anatomical relationship with the oculomotor nerve using tractography technique. The MLF and oculomotor nerve were reconstructed at the same time with preset three region of interests (ROIs): one set at the area of rostral midbrain, one placed on the MLF area at the upper pons, and one placed at the cisternal part of the oculomotor nerve. This mapping protocol was tested in an HCP-1065 template, 35 health subjects from Massachusetts General Hospital (MGH), 20 healthy adults and 6 brainstem cavernous malformation (BCM) patients with generalized q-sampling imaging (GQI)-based tractography. Finally, the 200 µm brainstem template from Center for In Vivo Microscopy, Duke University (Duke CIVM), was used to validate the trajectory of reconstructed MLF. The MLF and oculomotor nerve were reconstructed in the HCP-1065 template, 35 MGH health subjects, 20 healthy adults and 6 BCM patients. The MLF was in conjunction with the ipsilateral mesencephalic part of the oculomotor nerve. The displacement of MLF was identified in all BCM patients. Decreased QA, RDI and FA were found in the MLF of lesion side, indicating axonal loss and/or edema of displaced MLF. The reconstructed MLF in Duke CIVM brainstem 200 µm template corresponded well with histological anatomy. The MLF and oculomotor nerve were visualized accurately with our protocol using GQI-based fiber tracking. This GQI-based tractography is an important tool in the reconstruction and evaluation of MLF.

Pituitary Metastasis of Lung Neuroendocrine Carcinoma Mimicking Pituitary Adenoma:Case Report and Literature Review.

Pituitary metastasis is an unusual situation in clinical practice, while the incidence is increasing with age. Breast cancer for women and lung cancer for men were the most frequent primary origins of pituitary metastasis. Diagnosing asymptomatic patients with unknown primary malignant origin is difficult, thus pituitary metastasis may be diagnosed as primary pituitary adenoma. Here, we report a case of a 65-year-old patient with visual changes and diabetes insipidus, showing an extensive mass in the sellar region which was initially thought to be a primary pituitary adenoma. Patient corticotropic deficits were corrected, and transnasal transsphenoidal surgery was adopted, leading to total tumor resection. Tumor texture during surgical procedure was similar to that of pituitary adenoma. However, the histopathological and immunohistochemistry results suggested it as a pituitary metastasis from lung neuroendocrine tumor. Postoperative chest CT scan confirmed a pulmonary mass consistent with primary neoplasm. Abdominal CT further detected multiple metastases in liver, pancreas, and colon. Despite intensive treatment, the patient continued to show decreased level of consciousness due to cachexia, resulting in death 1 week after surgery. This case highlights the importance of differential diagnosis of invasive lesions of the sellar region, especially in individuals over 60 years of age with diabetes insipidus.

IgG4-Related Inflammatory Pseudotumor Involving the Clivus: A Case Report and Literature Review.

IgG4-related inflammatory pseudotumors are very uncommon and are characterized histologically by the presence of inflammatory swellings with increasing IgG4-positive plasma cells and lymphocytes infiltrating the tissues. As reports of intracranial IgG4-related pseudotumors are very rare, we report a case of an IgG4-related inflammatory pseudotumor involving the clivus mimicking meningioma. A 46-year-old male presented with intermittent headache for 2 years and a sudden onset of dysphagia and dysphonia of 7 days' duration along with lower limb weakness. Enhanced magnetic resonance imaging (MRI) of the skull base revealed an isointense signal on T1- and T2-weighted images from an enhanced mass located at the middle of the upper clivus region, for which a meningioma was highly suspected. Then, an endoscopic transsphenoidal approach was adopted and the lesion was partially resected, as the subdural extra-axial lesion was found to be very tough and firm, exhibiting fibrous scarring attaching to the brain stem and basal artery. After the surgery, brain stem and posterior cranial nerve decompression was achieved, and the patient's symptoms, such as dysphagia, dysphonia and lower limb weakness, improved. Pathological findings showed many IgG4-positive plasma cells and lymphocytes surrounded by collagen-rich fibers. The patient was sent to the rheumatology department for further glucocorticoids after the diagnosis of an IgG4-related inflammatory pseudotumor was made. This case highlights the importance of considering IgG4-related inflammatory pseudotumors as a differential diagnosis in patients with lesions involving the clivus presenting with a sudden onset of symptoms of dysphagia and dysphonia along with lower limb weakness when other more threatening causes have been excluded. IgG4-related inflammatory pseudotumors are etiologically enigmatic and unpredictable, and total resection might not be warranted. Glucocorticoids are usually the first line of treatment after diagnosis.

Diagnosis and treatment of refractory pituitary adenomas: a narrative review.

Although aggressive pituitary adenomas (PAs) have been proposed and widely discussed for more than a decade, there is no general agreement regarding their definition, diagnosis or management. As one of the largest pituitary centers in China, we have diagnosed and treated more than fifty cases of aggressive PA and 3 pituitary carcinomas in the past 5 years and proposed a new term, i.e., refractory PAs, to define these adenomas. The definitions of aggressive and refractory PAs overlap with each other, though there are some differences between them. We interpret the definition for refractory PA in this review, emphasizing that more attention and early identification of these adenomas are needed. Although temozolomide (TMZ) has been used to treat pituitary carcinomas and refractory PA since 2006, which has significantly improved the prognosis of these patients, treatment of refractory PA is a tremendous challenge for endocrinologists and neurosurgeons. Overall, refractory PA is defined as PA with a Ki-67 labeling index ≥3%, a faster growth rate than that of normal PA, infiltration of surrounding tissues, recurrence or regrowth in the early postoperative period, and continued growth and/or secretion of excessive hormones despite attempts to control it. These criteria for refractory PA are stricter than for aggressive PA. The diagnosis and treatment of refractory PA requires the collaboration of a multidisciplinary team to achieve the best results.

How to Classify and Define Pituitary Tumors: Recent Advances and Current Controversies.

Pituitary tumors are very complex and heterogeneous and have a very wide range of proliferative and aggressive behaviors, and how to define and classify these tumors remains controversial. This review summarizes the epidemiology and progress in the classification and definition of pituitary tumors, as well as controversial issues. Based on the results of radiologic and autopsy studies, the prevalence of pituitary tumors has recently increased significantly. However, the majority of pituitary tumors are incidentally discovered and asymptomatic, and such tumors are called pituitary incidentalomas. Most of these incidentalomas do not induce symptoms, remain stable in size, and do not need treatment. The recent revised classification strategies mainly depend on immunohistochemistry (IHC) to detect pituitary hormones and pituitary transcription factors; therefore, the accuracy of diagnosing pituitary tumors has improved. Although new classification strategies and definitions for pituitary tumors have been presented, there are still some controversies. The term pituitary neuroendocrine tumor (PitNET) was proposed by the International Pituitary Pathology Club, and this terminology can encompass the unpredictable malignant behavior seen in the subset of aggressive pituitary adenomas (PAs). However, some endocrinologists who oppose this change in terminology have argued that the use of tumor in the terminology is misleading, as it gives PAs a harmful connotation when the majority are not aggressive. Such terminology may add new ambiguity to the origin of PAs and unnecessary anxiety and frustration for the majority of patients with benign PAs. The classification of aggressive PAs mainly relies on subjective judgment of clinical behavior and lacks objective biomarkers and unified diagnostic criteria. However, the term "refractory" could more accurately represent the characteristics of these tumors, including their clinical behaviors, radiological features, and pathologic characteristics. Moreover, the diagnostic criteria for refractory PAs are stricter, more objective, and more accurate than those for aggressive PAs. Early identification of patients with these tumors through recognition and increased awareness of the definition of refractory PAs will encourage the early use of aggressive therapeutic strategies.