Salvage therapy with temozolomide in patients with aggressive or metastatic pituitary adenomas: experience in six cases

ObjectiveThe prognosis of either pituitary carcinoma or aggressive pituitary adenoma resistant to standard therapies is poor. We assessed the efficacy of treatment with temozolomide, an oral second-generation alkylating agent, in a consecutive series of six patients with aggressive pituitary adenomas.DesignThis was a 1-year prospective study of temozolomide therapy in six consecutive patients with pituitary carcinoma (one case) or atypical pituitary adenoma (five cases) resistant to standard therapies. There were three males and three females. Age at enrollment ranged between 52 and 64 years. Temozolomide was given orally at a dose of 150–200 mg/m2 per day for 5 days every 4 weeks for a maximum of 12 cycles.MethodsResponse assessment was based on measurable change in tumor size, as assessed on magnetic resonance imaging, and hormone levels. Response was defined as reduction of at least 50% of tumor size and hormone levels.ResultsFour patients completed the 12 cycles of temozolomide treatment, as planned. Two patients stopped the drug after 3 and 6 months respectively because of the progression of disease. Two patients responded to temozolomide, while the remaining two patients had stable disease. Immunohistochemistry for O6-methylguanine-DNA methyltransferase (MGMT) in tumor sample showed a partial association with treatment response.ConclusionsTemozolomide treatment has a wide range of efficacy in patients with pituitary carcinoma or locally aggressive pituitary adenoma. Positive staining for MGMT seems likely to predict a lower chance of response.

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Volumetry in the Assessment of Pituitary Adenoma Resection: Endoscopy versus Microscopy

Journal of Neurological Surgery Part B Skull Base ◽

10.1055/s-0038-1639618 ◽

2018 ◽

Vol 79 (06) ◽

pp. 538-544 ◽

Cited By ~ 1

Author(s):

Anthony Wang ◽

Ashish Shah ◽

Charif Sidani ◽

Brandon Gaynor ◽

Simon Dockrell ◽

...

Keyword(s):

Pituitary Adenoma ◽

Pituitary Adenomas ◽

Residual Tumor ◽

Extent Of Resection ◽

Volumetric Analysis ◽

Complete Resection ◽

Tumor Control ◽

Consecutive Series ◽

Complication Rates ◽

Recurrence Rates

Background Assessment of the extent of resection after surgical resection of pituitary adenomas is most commonly reported in terms of the presence or absence of residual tumor. A quantitative comparison of volumetric resection between endonasal endoscopy (EE) and microsurgery (MS) has rarely been done. Methods A retrospective analysis was performed on a consecutive series of 154 patients with pituitary adenomas treated by the same surgeon at a single institution. We employed volumetric analysis pre- and postoperatively on two cohorts of pituitary adenoma patients treated through MS (n = 37) versus EE approach (n = 117). Results Volumetric analysis revealed a higher incidence of complete resection (64.4 vs. 56.8%) and mean volume reduction in the EE cohort (92.7 vs. 88.4%), although not significant. Recurrence rates were significantly lower in the EE group (7.7% vs 24.3%, p = 0.015). Subgroup analysis identified that patients with preoperative tumor volumes >1 mL were less likely to recur through EE (7.8 vs. MS: 29.6%; p = 0.0063). A higher incidence of complete resection was also noted in patients with favorable Knosp grades (0–1) (EE: 87.8 vs. MS: 63.2%; p = 0.036). Postoperative complication rates were not significantly different between both techniques. Conclusion Both microscopy and endoscopy are well-tolerated, effective approaches in the treatment of pituitary adenomas. Our series demonstrated that EE may be superior to MS in preventing tumor recurrence and achieving a complete resection in certain subsets of patients. EE provides a slight advantage in tumor control outcomes that may justify the paradigm shift to pure endoscopy at our center.

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Immunocytochemical study of the hypophysis in 25 dogs with pituitary-dependent hyperadrenocorticism

Acta Endocrinologica ◽

10.1530/acta.0.1010015 ◽

1982 ◽

Vol 101 (1) ◽

pp. 15-24 ◽

Cited By ~ 60

Author(s):

Mark E. Peterson ◽

Dorothy T. Krieger ◽

William D. Drucker ◽

Nicholas S. Halmi

Keyword(s):

Pituitary Adenoma ◽

Pituitary Adenomas ◽

Immunocytochemical Staining ◽

Pars Intermedia ◽

Positive Staining ◽

Pars Distalis ◽

Immunocytochemical Study ◽

Double Immunostaining ◽

Cell Hyperplasia ◽

Intense Staining

Abstract. Pituitary adenomas were found in 21 (84%) of 25 dogs with spontaneous pituitary-dependent hyperadrenocorticism. Six dogs had pars intermedia adenomas, whereas 15 had tumours of the pars distalis. Diffuse corticotroph cell hyperplasia was found in 1 of the 4 pituitaries without adenoma; in 2 dogs with pituitary adenoma, coexisting hyperplasia of the surrounding corticotrophs was also present. Immunocytochemical staining of the pituitaries revealed positive staining for ACTH, β-lipotrophin, and β-endorphin in the majority of both pars distalis and pars intermedia adenomas. The most frequent and intense staining was found with anti-β-endorphin. In most part intermedia tumours, many cells stained strongly for α-MSH; double immunostaining of one pars intermedia adenoma for ACTH and α-MSH showed that some tumour cells stained only for ACTH or α-MSH whereas others contained both peptides. Only occasional cells stained for α-MSH in pars distalis adenomas.

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Anemia, testosterone, and pituitary adenoma in men

Journal of Neurosurgery ◽

10.3171/jns.2003.98.5.0974 ◽

2003 ◽

Vol 98 (5) ◽

pp. 974-977 ◽

Cited By ~ 35

Author(s):

Dilantha B. Ellegala ◽

Tord D. Alden ◽

Daniel E. Couture ◽

Mary L. Vance ◽

Nicholas F. Maartens ◽

...

Keyword(s):

Pituitary Adenoma ◽

Tumor Size ◽

Pituitary Adenomas ◽

Clinical Laboratory ◽

Serum Testosterone ◽

Testosterone Replacement Therapy ◽

Content Type ◽

Testosterone Levels ◽

Fine Print ◽

Low Serum

Object. Older men with clinically nonfunctioning pituitary tumors have been noted to be anemic, to have hypopituitarism, and to have low serum levels of testosterone. The authors hypothesized that men with pituitary adenomas and hypogonadism have a physiologically related decrease in hematocrit. Methods. A retrospective analysis was conducted of 216 patients older than 50 years of age who harbored pituitary adenomas. In 100 men serum testosterone levels and a complete blood (cell) count (CBC) were obtained before treatment; a CBC was also acquired in a series of women with pituitary adenomas. Using clinical laboratory standards, anemia was defined as a hematocrit less than 40% in men and less than 35% in women. Thirty-one (46.3%) of 67 men with low serum concentrations of testosterone were anemic. In men with low levels of testosterone, the average hematocrit was 39.9%, compared with 45.6% for men with normal testosterone levels (p < 0.001). Men with macroadenomas were most likely to have both anemia and a low serum concentration of testosterone. Anemia was associated with a low level of testosterone, adjusting for tumor size (odds ratio 19, 95% confidence interval 4.86–77.03). Of patients with anemia, 84% were men and 16% were women (p < 0.001). The prevalence of anemia in women was low and was not correlated with tumor size. Men receiving testosterone replacement therapy had a significantly higher hematocrit value than men with low or normal testosterone levels. Conclusions. These findings support a direct relationship between serum testosterone levels and hematopoiesis in men, and demonstrate that hematopoiesis is compromised in men who have low concentrations of testosterone due to a pituitary adenoma.

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Pituitary apoplexy: its incidence and clinical significance

Journal of Neurosurgery ◽

10.3171/jns.1981.55.2.0187 ◽

1981 ◽

Vol 55 (2) ◽

pp. 187-193 ◽

Cited By ~ 260

Author(s):

Susumu Wakai ◽

Takanori Fukushima ◽

Akira Teramoto ◽

Keiji Sano

Keyword(s):

Pituitary Adenoma ◽

Pituitary Adenomas ◽

Pituitary Apoplexy ◽

Clinical Symptoms ◽

Consecutive Series ◽

Content Type ◽

Histological Types ◽

Hormonal Function ◽

A Minor ◽

Fine Print

✓ The occurrence of hemorrhage from pituitary adenoma (so-called “pituitary apoplexy”) was investigated in a consecutive series of 560 cases operated on during the past 30 years. There were 93 cases (16.6%) in which hemorrhage from pituitary adenomas was confirmed either clinically or surgically. These patients were analyzed in terms of age, sex, symptoms and signs, size of tumor, hormonal function, and histological types of adenomas, and computerized tomography findings. In 90 cases (16.1%), hematoma or old bloody fluid was verified within the tumor tissue at surgery. Three other patients presented with subarachnoid hemorrhage, but there was no detectable intratumor hematoma in any of them. Among these 93 patients, 42 (7.5%) showed no evidence of clinical symptoms related to hemorrhage (asymptomatic hemorrhage). Fifty-one patients (9.1%) had definite histories of an acute episode that suggested sudden bleeding (symptomatic hemorrhage: pituitary apoplexy). Thirty-eight patients (6.8%) had a major attack manifested by disturbances of consciousness, hemiparesis, loss of vision, or ocular palsy. In two acromegalic patients, pituitary apoplexy developed during bromocriptine treatment. There was one case of sudden death due to massive hemorrhage from the tumor 14 months after the completion of postoperative radiation therapy. The other 13 symptomatic patients (2.3%) developed a minor attack which included headache, nausea, vomiting, and vertigo. Bleeding from pituitary adenomas was not statistically correlated with any of the following factors: sex, hormonal function of adenomas, and histological types, but it was correlated with age. The number of asymptomatic cases in the third decade was significantly greater than that of the whole group of pituitary adenoma patients in the same decade. The present investigation revealed that the incidence of pituitary apoplexy was unexpectedly high: a major attack in 6.8% of pituitary adenoma patients, a minor attack in 2.3%, and asymptomatic hemorrhage in 7.5% of the cases. This risk of pituitary apoplexy should be kept in mind in treating pituitary adenomas.

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Early Initiation of Temozolomide Therapy May Improve Response in Aggressive Pituitary Adenomas

Frontiers in Endocrinology ◽

10.3389/fendo.2021.774686 ◽

2021 ◽

Vol 12 ◽

Author(s):

Liza Das ◽

Nidhi Gupta ◽

Pinaki Dutta ◽

Rama Walia ◽

Kim Vaiphei ◽

...

Keyword(s):

Pituitary Adenomas ◽

Dna Methyltransferase ◽

Early Recognition ◽

Staining Intensity ◽

Median Number ◽

Early Initiation ◽

Lower Percentage ◽

Positive Staining ◽

Methylguanine Dna Methyltransferase ◽

Postmeiotic Segregation

IntroductionAggressive pituitary adenomas (APAs) are, by definition, resistant to optimal multimodality therapy. The challenge lies in their early recognition and timely management. Temozolomide is increasingly being used in patients with APAs, but evidence supporting a favorable response with early initiation is lacking.MethodsThis was a single-center study of all patients with APAs who received at least 3 cycles of temozolomide (150–200 mg/m2). Their baseline clinico-biochemical and radiological profiles were recorded. Immunohistochemical evaluation for cell-cycle markers O6-methylguanine-DNA methyltransferase (MGMT), MutS homolog 2 (MSH2), MutS homolog 6 (MSH6), MutL homolog 1 (MLH1), and postmeiotic segregation increased 2 (PMS2) was performed, and h-scores (product of the number of positive cells and staining intensity) were calculated. Response was assessed in terms of radiological response using the RECIST criteria. Patients with controlled disease (≥30% reduction in tumor volume) were classified as responders.ResultsThe study comprised 35 patients (48.6% acromegaly, 37.1% prolactinomas, and 14.3% non-functioning pituitary adenomas). The median number of temozolomide (TMZ) cycles was 9 (IQR 6–14). Responders constituted 68.6% of the cohort and were more likely to have functional tumors, a lower percentage of MGMT-positive staining cells, and lower MGMT h-scores. There was a significantly longer lag period in the initiation of TMZ therapy in non-responders as compared with responders (median 36 vs. 15 months, p = 0.01). ROC-derived cutoffs of 31 months for the duration between diagnosis and TMZ initiation, low-to-intermediate MGMT positivity (40% tumor cells), and MGMT h-score of 80 all had a sensitivity exceeding 80% and a specificity exceeding 70% to predict response.ConclusionEarly initiation of TMZ therapy, functional tumors, and low MGMT h-score predict a favorable response to TMZ in APAs.

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Incidence, demographics, and survival of patients with primary pituitary tumors: a SEER database study in 2004–2016

Scientific Reports ◽

10.1038/s41598-021-94658-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Cheng Chen ◽

Yu Hu ◽

Liang Lyu ◽

Senlin Yin ◽

Yang Yu ◽

...

Keyword(s):

Overall Survival ◽

Pituitary Adenoma ◽

Incidence Rate ◽

Tumor Size ◽

Pituitary Adenomas ◽

Pituitary Tumors ◽

The United States ◽

Reliable Estimate ◽

Seer Database ◽

Factors Associated

AbstractComprehensive investigations on the incidence and prognosis of pituitary tumors are still lacking. The present study aims to summarize the incidence, demographics, and survival outcome of pituitary adenoma on a population-based level. This study includes all pituitary adenomas reported in the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2016 in the United States. Extensive clinical and demographic characteristics were extracted and submitted to group comparisons. The standardized incidence rate was calculated and stratified by year at diagnosis, age/sex and age/treatment groups. The Kaplan–Meier analysis and multivariable regressions were performed to identify the factors associated with overall survival. A total of 47,180 pituitary tumors were identified, including 47,030 typical adenomas, 111 uncertain behavior pituitary adenomas, and 39 pituitary carcinomas. The overall standardized incidence rate was 4.8 cases per 100,000 person-years and the annual incidence rate continually trended upwards, with a peak seen in 2015. We noticed a bimodal age-related distribution in females and a unimodal distribution in males. In the multivariate regression analysis, the factors associated with prolonged survival included typical adenoma, younger age, and smaller tumor size. Whereas, black and male patients had worse overall survival. Our study provides a reliable estimate on the incidence of pituitary adenoma and confirms that the annual standardized incidence rate is increasing. Pituitary adenomas have a satisfactory long-term prognosis and age, tumor size, and tumor subtypes are related to overall survival. Though statistically significant, our inferential findings should be constrained within the limitations of SEER database.

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Correlation of Scintigraphic Results Using123I-Methoxybenzamide with Hormone Levels and Tumor Size Response to Quinagolide in Patients with Pituitary Adenomas

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.83.1.4493 ◽

1998 ◽

Vol 83 (1) ◽

pp. 248-252 ◽

Cited By ~ 19

Author(s):

Diego Ferone ◽

Secondo Lastoria ◽

Annamaria Colao ◽

Paola Varrella ◽

Gaetana Cerbone ◽

...

Keyword(s):

Tumor Size ◽

Pituitary Adenomas ◽

Hormone Levels

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Evaluation of 06-methylguanine-DNA methyltransferase expression in children and adolescent pituitary adenoma

10.21203/rs.3.rs-54592/v1 ◽

2020 ◽

Author(s):

Xueming Shen ◽

Yakun Yang ◽

Zuocheng Yang ◽

Ning Liu ◽

Xueling Qi ◽

...

Keyword(s):

Pituitary Adenoma ◽

Children And Adolescents ◽

Pituitary Adenomas ◽

Dna Methyltransferase ◽

Tumor Type ◽

Treatment Needs ◽

Ki 67 ◽

Children And Adolescent ◽

Methylguanine Dna Methyltransferase ◽

Mgmt Protein

Abstract BackgroundTemozolomide can be used in the treatment of pituitary adenoma. Its efficacy can be evaluated by the expression of 06-methylguanine-DNA methyltransferase (MGMT). However, the previous study population was mainly adult. This study was the first to evaluate the expression of MGMT in children and adolescents with pituitary adenomas.MethodsThe clinical features and biological characteristics of 38 cases of pituitary adenoma in children and adolescents were analyzed retrospectively. The expression of MGMT, Ki-67, p53 was marked by immunohistochemical staining.ResultsIn this cohort, the expression of MGMT protein is 16/38 (42.11%). The low expression rate of MGMT in children and adolescent somatotroph adenomas was only 11.11%, which was much lower than that of adults. Ki-67 expression range of 1% -10%（mean 4.24 ± 2.71%）. The positive rate of p53 was 22/38 (57.89%). The statistical analysis showed that the expression of MGMT was related to the diameter of the tumor (P=0.01), the diameter of the tumor was large, and the expression of MGMT was high. The expression of MGMT was not associated with age, sex, tumor type, invasiveness, texture, apoplexy, recurrence, and expression of p53 and Ki-67.ConclusionSomatotroph adenomas, large-diameter children and adolescent pituitary adenomas may be not suitable for temozolomide treatment. To determine whether temozolomide responds to salvage therapy in children and adolescents with pituitary adenomas, MGMT expression should be assessed in all pituitary adenomas, the time span between specimen collection and temozolomide treatment needs to be considered because of the instability of MGMT protein expression.

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Evaluation of the expression of necroptosis pathway mediators and its association with tumor characteristics in functional and non-functional pituitary adenomas

BMC Endocrine Disorders ◽

10.1186/s12902-021-00919-y ◽

2022 ◽

Vol 22 (1) ◽

Author(s):

Mohammad E. Khamseh ◽

Alireza Sheikhi ◽

Zahra Shahsavari ◽

Mohammad Ghorbani ◽

Hamideh Akbari ◽

...

Keyword(s):

Gene Expression ◽

Pituitary Adenoma ◽

Tumor Size ◽

Pituitary Adenomas ◽

Molecular Mechanisms ◽

Rna Extraction ◽

Pituitary Tumors ◽

Normal Tissues ◽

Cancer Pathogenesis ◽

Cell Death Pathway

Abstract Background Pituitary adenomas impose a burden of morbidity on patients and characterizing the molecular mechanisms underlying its pathogenesis received remarkable attention. Despite the appealing role of necroptosis as an alternative cell death pathway in cancer pathogenesis, its relevance to pituitary adenoma pathogenesis has yet to be determined that is perused in the current study. Methods The total number of 109 specimens including pituitary adenomas and cadaveric healthy pituitary tissues were enrolled in the current study. Tumor and healthy pituitary tissues were subjected to RNA extraction and gene analysis using Real-Time PCR. The expression levels of necroptosis markers (RIP1K, RIP3K and, MLKL) and their association with the patient’s demographic features were evaluated, also the protein level of MLKL was assessed using immunohistochemistry in tissues. Results Based on our data, the remarkable reduction in RIP3K and MLKL expression were detected in nonfunctional and GH-secreting pituitary tumors compared to pituitary normal tissues. Invasive tumors revealed lower expression of RIP3K and MLKL compared to non-invasive tumors, also the attenuated level of MLKL was associated with the tumor size in invasive NFPA. The simultaneous down-regulation of MLKL protein in pituitary adenoma tissues was observed which was in line with its gene expression. While, RIP1K over-expressed significantly in both types of pituitary tumors which showed no significant correlation with patient’s age, gender and tumor size in GHPPA and NFPA group. Notably, MLKL and RIP3K gene expression was significantly correlated in the GHPPA group. Conclusions According to our data, the reduced expression of necroptosis mediators (RIP3K, MLKL) in pituitary adenoma reinforces the hypothesis that the necroptosis pathway can be effective in regulating the proliferation and growth of pituitary tumor cells and tumor recurrence.

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PTTG has a Dual Role of Promotion-Inhibition in the Development of Pituitary Adenomas

Protein and Peptide Letters ◽

10.2174/0929866526666190722145449 ◽

2019 ◽

Vol 26 (11) ◽

pp. 800-818

Author(s):

Zujian Xiong ◽

Xuejun Li ◽

Qi Yang

Keyword(s):

Cell Cycle ◽

Pituitary Adenoma ◽

Pituitary Adenomas ◽

Cell Cycle Progression ◽

Key Factors ◽

Cycle Progression ◽

Sister Chromatids ◽

Regulation Of Cell Cycle ◽

Late Stages

Pituitary Tumor Transforming Gene (PTTG) of human is known as a checkpoint gene in the middle and late stages of mitosis, and is also a proto-oncogene that promotes cell cycle progression. In the nucleus, PTTG works as securin in controlling the mid-term segregation of sister chromatids. Overexpression of PTTG, entering the nucleus with the help of PBF in pituitary adenomas, participates in the regulation of cell cycle, interferes with DNA repair, induces genetic instability, transactivates FGF-2 and VEGF and promotes angiogenesis and tumor invasion. Simultaneously, overexpression of PTTG induces tumor cell senescence through the DNA damage pathway, making pituitary adenoma possessing the potential self-limiting ability. To elucidate the mechanism of PTTG in the regulation of pituitary adenomas, we focus on both the positive and negative function of PTTG and find out key factors interacted with PTTG in pituitary adenomas. Furthermore, we discuss other possible mechanisms correlate with PTTG in pituitary adenoma initiation and development and the potential value of PTTG in clinical treatment.

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