Neoplasms

All Conditions

Nervous System Diseases

Gland and Hormone Related Diseases

Adenoma

Pituitary Diseases

Pituitary Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Hypothalamic Diseases

Brain Diseases

Central Nervous System Diseases

Endocrine System Diseases

Endocrine Gland Neoplasms

Hypothalamic Neoplasms

Supratentorial Neoplasms

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Yao Zhao, M.D.

Pituitary adenomas can cause compression of optic nerves and chiasm, which will lead to damage of vision. This study aims to evaluate the predictive factors for recovery of vision in patients with pituitary adenomas following trans-sphenoidal surgery.

The Predictive Factors of Vision Recovery in Patients With Pituitary Tumor

Huashan Hospital

Yao Zhao

Literature review was conducted to calculate the excision rate, postoperative recurrence rate and postoperative endocrine improvement of previous endoscopic intracapsular excision of pituitary tumor.

Dedicated high-resolution magnetic resonance imaging (MRI) protocols have been proposed to detect pituitary adenoma and accurately guide surgical removal. To accomplish complete PA removal and minimize the impact on pituitary functions, intraoperative navigation was used to identify the tumor pseudocapsule. Depending on different tumor sizes and pseudocapsule development, investigators adopted different resection strategies. The suspicious tissue was sent to the pathology department for histopathology intraoperatively. Long-term postoperative follow-up imaging and endocrine data were used to evaluate tumor prognosis before and after operation. Standardized management and established biobank is critical for pituitary adenomas.

Excision of pituitary tumor outside pseudocapsule

shi wei, MD

gao jianlin, MD

xiao mingbing, MD

Pituitary adenomas are one of the most common primary central nervous system tumors and have an estimated prevalence of 17%. Management of pituitary adenomas involves a multidisciplinary approach that can incorporate surgical, medical, and/or radiation therapies. Over the last two decades, the endoscopic endonasal approach (EEA) has been extensively developed and refined for the resection of pituitary adenomas (PAs). In recent years, extracapsular resection (ER), which emphasized the importance of the pseudocapsule between the adenoma and surrounding normal gland tissue as a surgical plane, was adopted for more radical resection of the tumor. Therefore, dedicated high-resolution magnetic resonance imaging (MRI) protocols have been proposed to detect pituitary adenoma and accurately guide surgical removal. The evaluation of preoperative imaging for pseudocapsule is very important to the surgical method. Depending on different tumor sizes and pseudocapsule development, investigators adopted different resection strategies. To accomplish complete PA removal and minimize the impact on pituitary functions, intraoperative navigation was used to identify the tumor pseudocapsule, also the suspicious tissue was sent to the pathology department for histopathology intraoperatively. Long-term postoperative follow-up imaging and endocrine data were used to evaluate tumor prognosis. Standardized management and established biobank is critical for pituitary adenomas.

一、Project basis The pseudocapsule was first described by Costello in the early 1900s, which was formed by the compression between the tumor and normal gland. Adenoma growth leads to compression of the acinar structure of the adjacent normal gland, resulting in a reticulin-rich pseudocapsule that encases the entire adenoma in. Over the last two decades, the endoscopic endonasal approach (EEA) has been extensively developed and refined for the resection of pituitary adenomas (PAs). The endoscopic panoramic view is superior in terms of efficacy and safety for sellar surgery, and studies have reported that PAs can be effectively resected by EEA with minimal postoperative morbidity. Oldfield and colleagues used the phrase "surgical capsule of adenoma" to describe the histologically confirmed pseudocapsule in 2006 which was found in about 50% of patients and tends to be more frequent in larger tumors. The studies elaborated procedure along the outer face of the pseudocapsule between the adenoma and surrounding normal gland tissue achieved radical removal of the tumor while preserving normal pituitary function. Thus, in recent years, extracapsular resection (ER), which emphasized the importance of pseudocapsule as a surgical plane, was adopted for more radical resection of the tumor.

In smaller tumors, the pseudocapsule tended to exist more prominently and to cover the whole tumor, whereas in larger tumors the pseudocapsule tended to be discontinuous or disrupted. Similarly, in the present study, investigators found that ER was more performed in microadenomas, whereas intracapsular resection (IR) was more adopted in macroadenomas. Furthermore, in some macroadenomas, the pseudocapsule could not be seen until proper intracapsular debulking. By contrast, some PAs exhibited no or undefinable pseudocapsule; during the entire procedure, the adenoma was excised piecemeal progressively with a dissector, blunt ring curette, and aspirator.

Although PAs were frequently present within the pseudocapsule and complete tumor resection using the ER technique has been reported to maximize the effectiveness for PAs with pseudocapsules, many authors believe that resection without compromising pituitary function is imperative to improving the ultimate health outcome of patients. In some selective cases, an incomplete adenoma resection is advised because it is expected that this is best for the patients, through lower complication rates and preserving pituitary function. The actual effects of ER-based complete resection of PA are still under debate.

Intact pituitary gland function is deemed more important than adenoma total removal, Theoretically, it is hard for surgeons to extirpate only tumor cells completely during surgery without removing any normal pituitary gland tissue because in most cases the adenoma directly contacts with the normal pituitary gland. Some scholars found that the capsule itself contains tumor cells and may be a main cause of persistent hypersecretion of the hormone and possibly the source of recurrence. In addition, some studies found that the pseudocapsule is disrupted by tumor invasion so that the extracapsular removal and management of tumor invasion outside of the pseudocapsule are crucial to accomplishing complete PA removal. For these refractory pituitary adenomas, some research recommend aggressive resection, especially in IR resection cases. Partial gland resection or resection of the cavernous sinus medial wall is necessary in some cases since studies showed that it could help improve biochemical remission for the pituitary gland.

Pseudocapsule-Based Resection for Pituitary Adenomas has become a hot topic in recent years. However, it often focuses on the influence of pituitary function after surgical resection and the management and evaluation of surgical complications. How to strengthen the recognition of normal pituitary and pituitary pseudocapsule by imaging before operation? How to combine preoperative image enhanced recognition of pseudocapsule during operation? How to confirm the boundary between normal tissue and pituitary gland by Intraoperative pathology? What kind of treatment strategy should be adopted for pituitary adenomas of different sizes? There are few relevant reports on the above doubts. Standardized operation for pituitary adenoma is also lack, even if it can reduce trauma and complications; There are few studies on relationship among postoperative magnetic resonance imaging and related endocrine function examination and the evaluation of Extr-apseudocapsular resection for Pituitary Adenomas. It is urgent to establish a biological sample bank of pituitary tumor.

二、Research Contents:

1. To identify the pituitary tissue and the pseudocapsule by preoperative imaging data.
2. To evaluate the significance of preoperative imaging by relationship between tumor and pseudocapsule during operation.
3. To research the significance of intraoperative rapid pathology in excision of pituitary tumor
4. To establish Standardized surgical treatment strategies for pituitary tumors.
5. Postoperative imaging data and clinical endocrine function examination were used to evaluate the surgical efficacy.
6. To establish biological sample bank of pituitary tumor.

三、Research method, technical route and work plan

1. General Data and Clinical Manifestations In this retrospective study, investigators will review patients in our and cooperation institutions (Department of Neurosurgery, Affiliated Hospital of Nantong University, Jiangsu, China; Department of Neurosurgery, Subei People's Hospital of Jiangsu province, China; Department of Neurosurgery, The First People's Hospital of Changzhou, Jiangsu, China) who undergo EEA for PAs. The information will collect from patients' electronic medical records included presenting symptoms, operative notes, postoperative course,, laboratory data. Informed consent will obtain from all patients.
2. Endocrinological Evaluations All patients undergo a baseline preoperative pituitary hormone examination including serum cortisol, free thyroxine, thyroid stimulation hormone (TSH), adrenocorticotropic hormone (ACTH), growth hormone (GH) and insulin-like growth factor-1 (IGF-1), prolactin (PRL), luteinizing hormone (LH) and follicle stimulating hormone (FSH), testosterone (in males), and estradiol (in females). Postoperative biochemical remission will be defined as a nadir serum GH level of 3,000 ml/day. Hormonal status will be evaluated at 1 week and 3 months after surgery and twice per year thereafter to evaluate anterior pituitary functions.
3. Imaging Analysis All patients undergo high-resolution magnetic resonance imaging (MRI) examination before operation, within 3 days, 3 months, 6 months, and twice per year after surgery. The distribution and density of the pituitary gland could be seen on T1-weighted MR images. The position of the anterior communicating artery and internal carotid artery could be seen on T2-weighted images, also enabling us to reduce the surgical risks. Computed tomography is useful for demonstrating the degree of pneumatization and locations of septations in the sphenoid sinus. The degree of resection was calculated by measuring the residual tumor volume using MRI data. The magnetic resonance imaging (MRI) scanning was performed before surgery to provide excellent details about the tumor's size and texture, especially to distinguish the boundary between the location of normal adenohypophysis and pseudocapsule.
4. Pathological Examinations All resected tumor tissues were evaluated by routine pathological and immunohistochemical examination. The composition of complete and fragmentary pseudocapsules was pathologically examined. All tissues obtained in the study were paraformaldehyde fixed and paraffin embedded. The sections were stained using hematoxylin and eosin staining or Masson's trichrome staining.

   Intact pituitary gland function is deemed more important than adenoma total removal, Theoretically, it is hard for surgeons to extirpate only tumor cells completely during surgery without removing any normal pituitary gland tissue because in most cases the adenoma directly contacts with the normal pituitary gland.To minimize the impact on pituitary functions, the suspicious tissue was sent to the pathology department for histopathology intraoperatively.
5. Treatment strategies for different types of pituitary tumors Non-function pituitary adenoma, PRL, GH, ACTH
6. Depending on different tumor sizes and pseudocapsule development, investigators adopted different resection strategies.

In microadenoma, the exposed surface of the pituitary gland looks completely normal; a small cut was made in the gland at the location where the adenoma is expected according to preoperative imaging. The right dissector was used to separate the tumor and to preserve the integrity of the pseudocapsule, and achieved total extracapsular resection. Usually, the microadenoma texture is soft, limiting the option of extracapsular dissection. With small ring curettes, the tumor is removed and the tumor cavity was explored meticulously.

For macroadenomas, no attempt is made to remove the entire tumor or pull it forward during the initial phases of the dissection. After the intracapsular tumor is debulked and partially removed followed by a median-lateral or basal-superior order, the residual tumor was separated carefully along the pseudocapsular interface.

If the pseudocapsule was not visible in the first stage, investigators used conventional conservative intracapsular resection. Internal debulking was continued until visualization of the pseudocapsule or cavernous sinus wall was achieved. Extracapsular resection was continued along the plane, preserving as much integrity of the pseudocapsule as possible.

After internal debulking, if the pseudocapsule was still unidentifiable, the adenoma was excised piecemeal progressively. Noteworthily, investigators adopted intensive excision and meticulous sweeping to remove small remnants that are hidden behind the fibrin membranes for PA. The surface of the pituitary gland was peeled off as thin a slice as possible, and the tumor bed was circumferentially resected to remove any small tumor remnant in Cushing disease or acromegaly patients.

To minimize the impact on pituitary functions, the suspicious tissue was sent to the pathology department for histopathology intraoperatively.

Application Research on Endoscopic Pseudocapsule-Based Resection for Pituitary Adenomas

Department of Neurosurgery, Affiliated Hospital of Nantong University

All patients undergo high-resolution magnetic resonance imaging (MRI) examination before operation, within 3 days, 3 months, 6 months, and twice per year after surgery. The degree of resection was calculated by measuring the residual tumor volume using MRI data. Comparing preoperative and postoperative tumor imaging changes, investigators will assess the helpfulness of preoperative imaging judgments for intraoperative tumor resection, and compare the efficacy of different surgical modalities.

All patients undergo a baseline preoperative pituitary hormone examination. Hormonal status will be evaluated at 24 hours, 1 week, 1 month and 3 months after surgery and twice per year to evaluate anterior pituitary functions. Comparing preoperative and postoperative endocrine reduction, investigators will assess efficacy among different groups and different types of pituitary tumors.

In this retrospective study, investigators will evaluate patients in our and cooperation institutions (Department of Neurosurgery, Affiliated Hospital of Nantong University, Jiangsu, China; Department of Neurosurgery, Subei People's Hospital of Jiangsu province, China; Department of Neurosurgery, The First People's Hospital of Changzhou, Jiangsu, China) who undergo EEA for PAs. Including incidence of cerebrospinal fluid leakage will collect from patients electronic medical records. Informed consent will obtain from all patients. All these characteristics will be compared with preoperation. Investigators will assess differences among different groups.

In this retrospective study, investigators will evaluate patients in our and cooperation institutions (Department of Neurosurgery, Affiliated Hospital of Nantong University, Jiangsu, China; Department of Neurosurgery, Subei People's Hospital of Jiangsu province, China; Department of Neurosurgery, The First People's Hospital of Changzhou, Jiangsu, China) who undergo EEA for PAs. Incidence of intracranial infection will collect from patients electronic medical records. Informed consent will obtain from all patients. All these characteristics will be compared with preoperation. Investigators will assess differences among different groups.

In this retrospective study, investigators will evaluate patients in our and cooperation institutions (Department of Neurosurgery, Affiliated Hospital of Nantong University, Jiangsu, China; Department of Neurosurgery, Subei People's Hospital of Jiangsu province, China; Department of Neurosurgery, The First People's Hospital of Changzhou, Jiangsu, China) who undergo EEA for PAs. Incidence of visual and visual impairment will collect from patients electronic medical records（Visual acuity will be measured according to the visual acuity standard comparison table, and the visual field will be operated according to the automatic visual field instrument). Informed consent will obtain from all patients. All these characteristics will be compared with preoperation. Investigators will assess differences among different groups.

In this retrospective study, investigators will evaluate patients in our and cooperation institutions (Department of Neurosurgery, Affiliated Hospital of Nantong University, Jiangsu, China; Department of Neurosurgery, Subei People's Hospital of Jiangsu province, China; Department of Neurosurgery, The First People's Hospital of Changzhou, Jiangsu, China) who undergo EEA for PAs. Incidence of subthalamic injury will collect from patients electronic medical records. Informed consent will obtain from all patients. All these characteristics will be compared with preoperation. Investigators will assess differences among different groups.

Subei People's Hospital of Jiangsu Province

The First People's Hospital of Changzhou

Affiliated Hospital of Nantong University

Yao Zhang, Dr.

Pituitary adenomas is a very common disease, but the cause and genetics hasn't been identified. The investigators are going to use genome-wide association study to identify genes that may be related to pituitary adenomas.

Genome-wide Association Study of Pituitary Tumors

Doctor

Musculoskeletal Diseases

Rare Diseases

Craniopharyngioma

Adamantinoma

Ameloblastoma

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Bone Neoplasms

Bone Diseases

Neuroepithelioma

Central Nervous System Depressants

All Drugs and Chemicals

Anti-Inflammatory Agents

Antineoplastic Agents

Anesthetics

Hydrocortisone

Hydrocortisone 17-butyrate 21-propionate

Hydrocortisone acetate

Hydrocortisone hemisuccinate

Prednisone

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

No glucocorticoid replacement will be given perioperatively.

Hydrocortisone 100mg i.v. before anesthesia induction, and postoperative day 1. 80mg hydrocortisone at day 2; 60mg at day 3; 20mg at day 4; 5mg oral prednisone acetate tablet at day 4 and day 5; 2.5mg at day 6;

Hydrocortisone 100mg i.v. before anesthesia induction, and postoperative day 1 and day 2. 60mg hydrocortisone at day 3; 60mg at day 3; 20mg at day 4; 5mg oral prednisone acetate tablet per day, since postoperative day 3.

Senlin Yin, M.D.

Shu Jiang, M.D.

Peizhi Zhou, M.D.

The purpose of this four-arm randomized controlled study is to determine whether eliminating glucocorticoids (GC) replacement in perioperative period in surgical patients with sellar lesion could result in similar or better outcomes comparing to traditional replacement therapy, regarding postoperative recovery of pituitary function and other postoperative complications (infection, pain, quality of life, recurrence). Surgical patients of our center with MRI-confirmed diagnosis of sellar lesion will be enrolled, insulin tolerance test (ITT) will be performed for assessment of the pituitary function at enrollment. Patients with normal pituitary function will be randomized into non-GC replacement group (group A) and low-dose GC replacement group (group B), while patients with impaired pituitary function will be randomized into low-dose GC replacement group (group C) and high-dose GC replacement group (group D). The primary outcome is the hypothalamic-pituitary-adrenal (HPA) -axis function of the patients, evaluated by plasma cortisol and adrenocorticotropic hormone (ACTH) levels. The secondary outcomes include the hypothalamic-pituitary-thyroid (HPT) axis function (TSH, thyroid-stimulating hormone, free T3, free T4), postoperative water-electrolyte balance, infection, recurrence and health-related quality of life.

Effect of Perioperative Glucocorticoid Replacement on Prognosis of Surgical Patients With Sellar Lesions

Plasma cortisol at 8:00, 16:00, 24:00 respectively

Concentration of sodium, potassium in the blood and urine

Routine blood test, body temperature fluctuation, cerebrospinal fluid test if necessary.

The 15-Dimensions measure of health-related quality of life

West China Hospital

Professor Shu Jiang

Symptoms and General Pathology

Behaviors and Mental Disorders

Recurrence

Aggression

Prolactinoma

Amino Acids

Lapatinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

All participants will be asked to take Lapatinib daily for a total of six months during the research study.

All participants will be asked to take Lapatinib daily for six months during the research study.

Odelia Cooper, MD

This study focuses on new therapies for a challenging disease in pituitary medicine, that of aggressive pituitary tumors which have limited therapeutic options beyond standard surgical, radiotherapy, and select medical therapies, each incurring significant morbidity and mortality, and each not optimally effective. To improve this gap in knowledge, we seek to translate findings from the laboratory into clinical practice and hone in on therapies directed at pituitary molecular targets, namely ErbB receptors. We have shown that human prolactinomas express nuclear EGFR and membranous ErbB2, ErbB3 and ErbB4, and expression correlates with tumor invasion. Pituitary tumor cell lines transfected with EGFR and ErbB2 translated to downstream effects on prolactin (PRL) gene expression and secretion,as well as cell proliferation. Animal models implanted with these cell lines developed larger tumors and PRL elevations. Treatment with ErbB tyrosine kinase inhibitors (TKIs) led to regression of tumors xenografted into these animals and attenuated PRL secretion. Primary culture of human prolactinomas confirmed expression of ErbB receptors and inhibitory effects of TKIs on PRL secretion and cell proliferation. Based on these exciting preliminary data, the objective of this new proposal is to conduct a Phase IIa clinical trial as a trenchant test of our translational hypothesis that tyrosine kinase inhibition constitutes highly effective targeted biologic therapy for these hitherto refractory pituitary adenomas. Specifically, our aims are to test the: 1) efficacy of TKI therapy with a clinical trial; 2) threshold level of tumor receptor expression to achieve TKI clinical response. Nineteen subjects will be treated with lapatinib for 6 months in combination with their current dopamine agonist therapy, with monthly measurements of PRL levels and MRI imaging every 3 months to evaluate the primary endpoints of achieving 40% reduction in tumor size and 50% reduction in PRL and secondary endpoints of radiologic stabilization and/or reduction and PRL normalization. Mean ErbB receptor protein expression will be compared between responders to lapatinib and non-responders by immunohistochemistry in pituitary tumor samples of these subjects collected from prior surgeries.

PURPOSE

The drug Lapatinib has been shown to inhibit both epidermal growth factor receptor (EGFR) and erbB2 tyrosine kinases resulting in an effective slowing of disease progression in breast cancer. It has also been demonstrated that erbB is overexpressed in human pituitary adenomas. The investigators are therefore assessing tumor size stabilization and pituitary tumor secretory profiles during the course of a six month therapy of lapatinib. The purpose of this trial will be to estimate the activity of lapatinib in slowing the growth rate of pituitary tumors. Lapatinib is an FDA approved drug used to treat breast cancer. However, in this study, the drug will be used to treat pituitary cancer.

STUDY POPULATION

This study will recruit patients from the Pituitary Center at CSMC who are over the age of 18 that have a recurrent nonfunctioning adenoma after at least one surgical resection as well as patients with prolactinomas who are resistant to dopamine agonist therapy and patients with recurrent Cushing's disease.

PARTICIPANT'S JOURNEY THROUGH THE RESEARCH

The principal investigator (PI) or co-investigator will determine patients' potential eligibility for the study based on inclusion and exclusion criteria.

The PI or the co-investigator will then approach subjects with recurrent nonfunctioning adenomas or prolactinomas resistant to dopamine agonist therapy or recurrent Cushing's disease during a visit in the clinic office and ask if these subjects would be interested in participating in this study. If the subjects express interest, they will be given the consent form to review. They will be encouraged to review it with family, friends, and/or other physicians. The PI, co-investigators, or research nurse will be available for any questions the subjects might have. If the subjects are still interested, they will be asked to sign and return the consent form to the office and a study visit will be scheduled.

The PI, co-investigator, or member of study staff may also attempt to contact current patients by phone to assess interest in participating in the study. The purpose and overall structure of the study will be discussed with the possible participant. They will be reminded that the study is strictly voluntary and that their involvement or disinterest in the study will not affect their ongoing care. If the patient is interested they will be mailed a consent to review and will be asked to call the center to schedule an appointment to further discuss the study if they decide they are interested.

Each participant will undergo 8 visits of the course of the study. Each participant will have a baseline visit where a medical history will be taken, a physical, visual field test, electrocardiogram (ECG), echocardiogram (ECHO), and blood draw will be performed. At this point lapatinib therapy will begin and the patients will be asked to take the drug daily for the next six months. Patients will take Lapatinib 1250 mg daily (orally), which is the standardized dose used to treat breast cancer patients. Visit 2 will be 1 month after the participant has started lapatinib. At visit 2 all participants will receive a physical exam, a history will be taken, an ECG will be performed, and a blood draw will occur. Visit 3 will be 2 months after starting lapatinib. A physical exam and history will be performed along with an ECG and echocardiogram and blood draw. Visit 4 will be 3 months after starting lapatinib. A physical, history, blood draw, ECG, visual field test, and a magnetic resonance imaging (MRI) of the pituitary will be performed. Visit 5 will occur 4 months after starting lapatinib. A physical exam and history along with a blood draw and ECG and echocardiogram will occur. Visit 6 will be 5 months after starting lapatinib. A physical exam, history, ECG, and a blood draw will occur. Visit 7 will occur 6 months after the start of lapatinib. A physical exam, history, blood draw, visual field test, ECG, echocardiogram and MRI of the pituitary will occur. At this point lapatinib will be discontinued. Visit 8 will occur 1 month after visit 7 and a physical exam, history, blood draw, and ECG and and echocardiogram will occur.

Targeted Therapy With Lapatinib in Patients With Recurrent Pituitary Tumors Resistant to Standard Therapy

Tumor volume will be assessed on MRI at 6 months on therapy and compared to baseline MRI.

50% reduction in prolactin level measured monthly on 6 months therapy compared to baseline level.

Percent prolactin change from start of lapatinib to end of study participant participation

Mean percent positive expression of EGFR and ErbB2 will be tested on pathologic tumor specimens from subjects treated with lapatinib

Cedars-Sinai Medical Center

Principal investigator

Prior to initiating therapy, patients were assessed with monthly echocardiogram,ECG, physical examinations, chemistry and hematology panels. Adverse events were graded by the NCI-CTC. Subjects with toxicity equal to Grade 3 on the NCI-CTC will have their dose held and resumed at a fifty percent dose reduction when the toxicity has resolved. Those subjects with toxicity equal to Grade 4 were discontinued on the study drug.

All participants will be asked to take Lapatinib 1250 mg po daily for a total of six months during the research study.

Lapatinib: All participants will be asked to take Lapatinib daily for six months during the research study.

All participants will be asked to take Lapatinib daily for a total of six months during the research study.

Lapatinib: All participants will be asked to take Lapatinib daily for six months during the research study.

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Prolactin

For one of the secondary outcomes, the ErbB receptor expression, only 3 subjects had tumor specimens available to immunostain. Therefore, only results on 3 subjects were reported for this outcome.

Odelia Cooper

Note: 1 subject was withdrawn after 6 weeks of lapatinib therapy and therefore not included in analysis. A 2nd subject was not included in this analysis as the drug was given on compassionate basis to prevent recurrence of her tumor. She had a negative baseline MRI and maintained a negative MRI at study end.

Change in Tumor Volume

There were 6 prolactinomas and 3 nonfunctioning tumors in this trial. Prolactin results are only reported for the prolactinomas.

Number of Participants With 50% Reduction in Prolactin Levels

Prolactin results only reported on the 6 prolactinomas in the trial and not for the nonfunctioning tumors.

% Change in Prolactin From Baseline to Study End

Of the subjects who participated in the trial, only 3 had available tumor tissue to immunostain. Therefore, results could not be reported on the other subjects.

ErbB Receptor Expression

Overall Study

Temozolomide

Antineoplastic Agents, Alkylating

Alkylating Agents

Undergoing fractionated radiotherapy at a dose of 2 Gy per fraction given once daily five days per week for a total dose of 54 Gy, plus continuous daily temozolomide (75 mg per square meter of body-surface area per day), followed by six cycles of adjuvant temozolomide.

Radiotherapy treatment alone undergoing fractionated radiotherapy, total 54 Gy, 2GyX27, received placebo.

undergoing fractionated radiotherapy at a dose of 2 Gy per fraction given once daily five days per week (Monday through Friday) over a period of six weeks, for a total dose of 54 Gy, plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle).

Radiotherapy plus temozolomide

undergoing fractionated radiotherapy at a dose of 2 Gy per fraction given once daily five days per week (Monday through Friday) over a period of six weeks, for a total dose of 54 Gy, plus placebo

Radiotherapy plus placebo

Renzhi Wang, Dr.

renzhi Wang, Dr.

The purpose of this study was to determine whether radiotherapy combined with Temozolomide is more effective than radiotherapy alone in the treatment of patients with refractory pituitary adenomas. The Basic treatment was Radiotherapy over a period of six weeks, for a total dose of 54 Gy. The150 participants were randomized to use either radiotherapy plus Temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), or radiotherapy plus placebo for 6 weeks. After a 4-week break, followed by six cycles of placebo or adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was Objective Response rate, the second end point was PFS. Greater response was anticipated in patients treated with Temozolomide+ radiotherapy than radiotherapy alone.

The purpose of this study was to determine whether radiotherapy combined with Temozolomide is more effective than radiotherapy alone in the treatment of patients with refractory pituitary adenomas. The Basic treatment was Radiotherapy, which is consisted of fractionated focal irradiation at a dose of 2 Gy per fraction given once daily five days per week (Monday through Friday) over a period of six weeks, for a total dose of 54 Gy. The150 participants were randomized to use either radiotherapy plus Temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), or radiotherapy plus placebo for 6 weeks. After a 4-week break, patients were then to receive up to six cycles of adjuvant temozolomide or placebo according to the standard 5-day schedule every 28 days. The dose was 150 mg per square meter for the first cycle and was increased to 200 mg per square meter beginning with the second cycle, so long as there were no hematologic toxic effects followed by six cycles of placebo or adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was Objective Response rate, the second end point was PFS. Greater response was anticipated in patients treated with Temozolomide+ radiotherapy than radiotherapy alone.

The Effect of Chemoradiotherapy in Patients With Refractory Pituitary Adenomas

Radiotherapy Plus Concomitant Temozolomide for Refractory Pituitary Adenomas，A Randomized，Double-blind, Placebo-controlled Phase II Trial

A tumor response was defned as a decrease of more than 30% of the largest tumor diameter or stable in Tumor volume

Hormonal response as a 50% or more decrease in baseline hormone levels.

Peking Union Medical College Hospital

Disease Attributes

All patients who underwent surgery for a NFPA in Reims university hospital between 01/01/1991 and 31/12/2004

Patients

Non functioning pituitary adenomas (NFPAs) are the most common pituitary adenomas. Their growth is usually slow and diagnosis is often made in the context of masse effect .The therapeutic alternatives are surgery and radiotherapy such as fractionated stereotactic radiotherapy. Nowadays, there is no clinical or histological prognostic factor to allow an individualized follow-up and recurrence could happen 10 or 15 years after the first surgery. In this study, the investigators evaluate NFPAs recurrence rate after surgery and try to find predictive factors of recurrence to personalized the follow-up of each patient.

Predictive Factors of Recurrence of Non Functioning Pituitary Adenomas : a Retrospective Study of 220 Patients in the Reims University Hospital, France

CHU de Reims

Acromegaly

Edotreotide

Radiopharmaceuticals

To give Ga-68 DOTATOC in pituitary patients doing PET/CT

They are compared with Ga-68 DOTATOC PET performed in another study on patients with no pituitary disease.

The intervention is to administer Ga-68 DOTATOC in pituitary patients doing PET/CT

Gallium-68 DOTATOC PET

Helena Filipsson Nyström, Ass Prof

Title: Gallium (GA) -68-DOTATOC -PET (positron emission tomography) in the management of pituitary tumours Medical product: Ga-68-DOTATOC in PET/computer tomography (CT) Route of administration: Intravenously Diseases of interest: Pituitary tumours Aim: To study the detection of pituitary tumours with Ga-68-DOTATOC -PET (Ga-PET) and to correlate the tracer expression to somatostatin receptor (sst) occurrence Study design: Prospective non-randomised case-control study with open design with GA-PET before and after pituitary surgery in patients with pituitary tumours Study population: patients with acromegaly (n=10), Cushing's' disease of pituitary origin (n=10), TSH (thyreotropin) producing tumours (TSHomas) (n=5) and non-functioning pituitary adenomas (NFPA) (n=20) Number of patients: 45 Inclusion criteria: Adult man or woman (over 18 years) and naïve, unoperated pituitary tumour with growth hormone (GH) or adrenocorticotrophic hormone (ACTH)) or TSH production or NFPA without treatment with somatostatin analogues (SSA) or dopamine agonists.

Exclusion criteria: Patient who may not attend to the protocol according to the investigators opinion. Pregnancy or lactating. Isolated prolactin producing tumours. Overproduction of gonadotropins. Carcinoids ie ectopic corticotrophin realising factor (CRF) production. Known or suspected allergy to the trial product or related products.

Controls: Adult patients with Thyroid associated ophthalmopathy (TAO) before iv steroid infusion (part of another study see this protocol)- Study variables: Tumour detection, Tracer uptake as Standardised uptake value (SUV) max (SUVmax), SUV hotspot and SUV mean in regions of interests (ROIs) Time schedule: Recruitment of patients 2015-2017. Study termination 3 years later

Background The most common cause to pituitary insufficiency is the pituitary adenoma (PA). PA may be divided into hormone producing PAs and non-functioning PAs (NFPA). Normal pituitary tissue, as well as tissues from PAs, expresses somatostatin receptors (sst). Five subtypes of sst receptors has been characterized.

Magnetic resonance tomography (MRI) presents anatomy, while in vivo diagnostics with somatostatin receptor scintigraphy (SRS) or position emission tomography (PET) reflect the functional properties of the tissue. The SRS have earlier been evaluated for diagnostics of pituitary diseases and has low discriminative ability to differ tumor tissue from normal pituitary tissue even though some secretory tumors and NFPA are seen. The superiority of the PET in diagnostics compared to the SRS is based on higher spatial resolution and a higher tumor to background ratio. Therefore it is of large interest to study Gallium 68 DOTATOC (Ga-PET) i small tumours that exhibit sst, such as in the pituitary, where high resolution is essential to discriminate from normal tissue and to evaluated residual tumor tissue postoperatively.

Aim with the project

To evaluate Ga-PET in the management of pituitary tumors and to seek the answer to the following questions:

1. Is the method of value in primary diagnostics in PAs? Does Ga-PET contribute with more functional information than that given from an conventional MRI?
2. Is the method of value in the follow-up, the detection of residual tumor tissue, and increase the possibility to differ scar tissue from true tumor?
3. Can relapses of PA be detected earlier with Ga-PET than with conventional MRI?
4. Are some of the sub-groups easier to detect that others??
5. Can the pathological-anatomical findings and the immunochemical expression of sst be correlated to the PET findings?
6. Can the treatment with somatostatin analogues be designed from the PET investigation and the sst analysis?

Method The aim is to recruit 10 patients with acromegaly (GH-producing PA), 10 patients with Cushing's disease (ACTH-producing PA), 5 patients with TSH-producing PA (TSHoma) and 20 patients with NFPA and to do Ga-PET before and after the pituitary surgery. In the Cushing patients, the TSHomas and in NFPA Ga-PET will also be dome after 3 years postoperatively to detect recurrences. At surgery, pituitary tissue is taken to investigate hormonal expression, sst and for further molecular genetic studies. At all PET occasions blood specimens from the patients are collected for future analyses. They will be kept in a freezer.

If difficulties to separate the Ga-Pet up-take in tumors from normal pituitary tissue the tumor expression may be enhanced by a somatostatin injection before Ga-PET that suppresses normal tissue.

The pituitary PET of pituitary tumours patients will be compared with the pituitary of patients with thyroid associated tumours performing PET according to the similar protocol in Another study

Significance This study is a pilot study. Ga-PET has not been used in pituitary tumors but there is known from studies in patients with gastrointestinal neuroendocrine tumors that the pituitary is seen on GA-PET. This is a "proof of concept". It addresses some of the clinical problems in the management of pituitary tumors. If the questions addressed in this study will be answered in advantage for PET, PET may be a routine investigation and the patients may avoid invasive procedures and repeated MRI. In addition, the patients may have better information regarding cure or not. If not, the treatment may be tailored from the sst receptor expression. This is of great importance for the patients and for the health care system.

Ga-68-DOTATOC -PET in the Management of Pituitary Tumours

Sahlgrenska University Hospital, Sweden

Uppsala University

Göteborg University

Adrenal Insufficiency

Adrenal Gland Diseases

Vasoconstrictor Agents

Respiratory System Agents

Dermatologic Agents

Epinephrine

Racepinephrine

Epinephryl borate

Hydrocortisone-17-butyrate

No hydrocortisone or other steroids are given before, during, and after the surgery, except that patients develop postoperative adrenal insufficiency. If a patient develops postoperative adrenal insufficiency, he/she needs to receive hydrocortisone treatment (20mg at 0800 and 20mg at 1600) for one month and then check the level of morning serum cortisol to decide if it is time to start the hydrocortisone taper program.

Normal saline

Hydrocortisone sodium succinate is given on the operation day (100mg at 0800 \& 100mg at 2000), the postoperative day 1 (100mg at 0800 \& 50mg at 2000), and the postoperative day 2 (25mg at 0800). Hydrocortisone (po.) is then given starting from the afternoon of postoperative day 2 (20mg at 1600 and 0800) to the end of the first postoperative week, and 20mg at 0800 during the second postoperative week. This is called the "hydrocortisone taper program". If a patient develops postoperative adrenal insufficiency, he/she needs to receive hydrocortisone treatment (20mg at 0800 and 20mg at 1600) for one month and then check the level of morning serum cortisol to decide if it is time to start the hydrocortisone taper program.

Bing Xing, MD

Xiaopeng Guo, MD

Wei Lian, MD

The investigators hypothesize that withholding hydrocortisone during the peri-operation in patients with pituitary adenomas whose hypothalamus pituitary adrenal axis are intact are safe.

Pituitary is the headquarters of the endocrine system of the body, secreting several hormones maintaining the normal function of the endocrine organs. After surgery, pituitary dysfunction is seen in a small proportion of patients, even in some patients resulting in severe consequence, i.e. adrenal insufficiency or pituitary crisis. Therefore, patients undergoing pituitary surgery have been usually given "stress dose" steroids whether their hypothalamus pituitary adrenal (HPA) axis are deficient or preserved.

Results of several retrospective studies showed that there was no significantly increase in postoperative adrenal insufficiency in no supplementation (of hydrocortisone) group than in supplementation group. Given the considerable side effects of using steroids, whether hydrocortisone administration is necessary for all patients with pituitary adenomas during peri-operation needs to be discussed.

For Chinese patients with pituitary adenomas except for those of Cushing's disease, hydrocortisone administration during the peri-operation is a routine practice. Peking Union Medical College Hospital is the China Pituitary Disease Registry Center. Here, the investigators aim to launch a single-center prospective randomized controlled trial to verify the hypothesis that withholding hydrocortisone during the peri-operation in patients with pituitary adenomas whose HPA axis are intact are safe.

Participants are assigned to one of two groups, whether using hydrocortisone or not during peri-operation, in parallel for the duration of the study.

Participant, investigator, and outcome assessors are all prevented from having knowledge of the interventions assigned to individual participants. Care provider knows the individualized interventions.

Hydrocortisone Use During Peri-operation for Pituitary Adenomas

Withholding Hydrocortisone vs Routine Use of Hydrocortisone During Peri-operation in Pituitary Adenoma Patients With Intact Hypothalamus-Pituitary-Adrenal Axis: Randomized Controlled Trial to Assess Safety and Complications

The individual participant data will be available upon reasonable requests to the study chair, Dr. Bing Xing, or the study director, Dr. Wei Lian.

A random reading of blood sugar level more than 200 mg/dL (11.1 mmol/L), or a reading after two hours (after OGTT) over 200 mg/dL (11.1 mmol/L) indicates diabetes mellitus.

Urine volume \> 300ml for more than 3h or \> 6 liter per day, specific gravity of urine \<1.003, and serum sodium levels \> 145 mmol/L indicate diabetes insipidus.

The level of Na+, K+, and Ca++ in the blood

Numbers of erythrocytes, leukocytes, neutrophils, lymphocytes, thrombocytes in the blood

Percentage of neutrophils, monocytes, lymphocytes of the leukocytes

Prothrombin time, activated partial thromboplastin time, and thrombin time

Deep venous thrombosis as detected by ultrasound

Decreased bone density, osteoporosis, fracture, acne, and infections.

Adrenal insufficiency: lower-than-normal serum cortisol level at 8 a.m., plus the following related symptoms, including serious fatigue, muscle weakness, decreased appetite, nausea, vomiting, diarrhea, low blood pressure, palpitation, and fever.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
The Predictive Factors of Vision Recovery in Patients With Pituitary Tumor	NCT01377701	Pituitary Adeno...		18 Years - 70 Years	Huashan Hospital
Application Research on Endoscopic Pseudocapsule-Based Resection for Pituitary Adenomas	NCT05466357	Pituitary Adeno...	Excision of pit...	18 Years - 75 Years	Affiliated Hospital of Nantong University
Genome-wide Association Study of Pituitary Tumors	NCT01442220	Pituitary Adeno...		-	Huashan Hospital
Effect of Perioperative Glucocorticoid Replacement on Prognosis of Surgical Patients With Sellar Lesions	NCT02190994	Pituitary Neopl... Craniopharyngio...	Hydrocortisone Prednisone	18 Years -	West China Hospital
Targeted Therapy With Lapatinib in Patients With Recurrent Pituitary Tumors Resistant to Standard Therapy	NCT00939523	Pituitary Adeno... Prolactinomas	Lapatinib	18 Years -	Cedars-Sinai Medical Center
The Effect of Chemoradiotherapy in Patients With Refractory Pituitary Adenomas	NCT04244708	Pituitary Adeno...	Radiotherapy pl... Radiotherapy pl...	18 Years - 80 Years	Peking Union Medical College Hospital
Predictive Factors of Recurrence of Non Functioning Pituitary Adenomas : a Retrospective Study of 220 Patients in the Reims University Hospital, France	NCT02803697	Pituitary Adeno...	Patients	18 Years -	CHU de Reims
Effect of Perioperative Glucocorticoid Replacement on Prognosis of Surgical Patients With Sellar Lesions	NCT02190994	Pituitary Neopl... Craniopharyngio...	Hydrocortisone Prednisone	18 Years -	West China Hospital
Ga-68-DOTATOC -PET in the Management of Pituitary Tumours	NCT02419664	Pituitary Tumou...	Gallium-68 DOTA...	18 Years -	Göteborg University
Targeted Therapy With Lapatinib in Patients With Recurrent Pituitary Tumors Resistant to Standard Therapy	NCT00939523	Pituitary Adeno... Prolactinomas	Lapatinib	18 Years -	Cedars-Sinai Medical Center
The Predictive Factors of Vision Recovery in Patients With Pituitary Tumor	NCT01377701	Pituitary Adeno...		18 Years - 70 Years	Huashan Hospital
Hydrocortisone Use During Peri-operation for Pituitary Adenomas	NCT04621565	Pituitary Adeno... Adrenal Insuffi... Surgery	Normal saline Hydrocortisone	18 Years - 70 Years	Peking Union Medical College Hospital

Spots Global Cancer Trial Database for pituitary adenomas