Aggressive Pituitary Tumors Research Articles

Role of tyrosine kinase inhibitors in the treatment of pituitary tumours: from bench to bedside.

Treatment of aggressive pituitary tumours often yields suboptimal control of the tumour and confers significant morbidity. Lactotroph and corticotroph-derived tumours express ErbB receptors and ligands, and mutations in ubiquitin-specific protease 8 (USP8), which alters epidermal growth factor receptor (EGFR) degradation, have been implicated in Cushing disease pathogenesis. EGFR tyrosine kinase inhibitor (TKI) therapy has emerged as a potential new therapeutic approach for patients with aggressive prolactinomas and Cushing disease. Using EGFR or human epidermal growth factor receptor 2-driven prolactin (PRL) promoters, transgenic mice develop large tumours that respond to TKI inhibition. In human corticotroph primary cultures, treatment with the pan-ErbB TKI canertinib as well as the EGFR TKI gefitinib suppresses proopiomelanocortin mRNA. USP8 mutations, detected in up to two-thirds of Cushing disease, may underlie the increase in EGFR signalling in these tumours. Human prolactinomas have differential ErbB receptor expression associated with aggressive behaviour and data from an ongoing clinical trial suggest that resistant prolactinomas may respond to the EGFR TKI lapatinib. Preclinical and clinical models substantiate the role of the EGFR pathway in corticotroph and lactotroph adenomas. Although further study is needed, results to date suggest that targeting the ErbB pathway may be an effective therapeutic approach for patients with aggressive pituitary tumours.

Aggressive pituitary tumours: a multicenter study

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Aggressive pituitary tumours

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Aggressive pituitary tumours

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Aggressive pituitary tumours

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Aggressive pituitary tumours

Aggressive pituitary tumours

Aggressive pituitary tumors: a tertiary center experience

Aggressive pituitary tumors: a tertiary center experience

Use of temozolomide in a large cohort of patients with aggressive pituitary tumours and pituitary carcinomas: Results from a European Society of Endocrinology (ESE) survey

Use of temozolomide in a large cohort of patients with aggressive pituitary tumours and pituitary carcinomas: Results from a European Society of Endocrinology (ESE) survey

Aggressive pituitary tumours

Aggressive pituitary tumours

Aggressive pituitary tumours

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Temozolomide treatment can improve overall survival in aggressive pituitary tumors and pituitary carcinomas.

Only few retrospective studies have reported an efficacy rate of temozolomide (TMZ) in pituitary tumors (PT), all around 50%. However, the long-term survival of treated patients is rarely evaluated. We therefore aimed to describe the use of TMZ on PT in clinical practice and evaluate the long-term survival. Multicenter retrospective study by members of the French Society of Endocrinology. Forty-three patients (14 women) treated with TMZ between 2006 and 2016 were included. Most tumors were corticotroph (n = 23) or lactotroph (n = 13), and 14 were carcinomas. Clinical/pathological characteristics of PT, as well as data from treatment evaluation and from the last follow-up were recorded. A partial response was considered as a decrease in the maximal tumor diameter by more than 30% and/or in the hormonal rate by more than 50% at the end of treatment. The median treatment duration was 6.5 cycles (range 2-24), using a standard regimen for most and combined radiotherapy for six. Twenty-two patients (51.2%) were considered as responders. Silent tumor at diagnosis was associated with a poor response. The median follow-up after the end of treatment was 16 months (0-72). Overall survival was significantly higher among responders (P = 0.002); however, ten patients relapsed 5 months (0-57) after the end of TMZ treatment, five in whom TMZ was reinitiated without success. Patients in our series showed a 51.2% response rate to TMZ, with an improved survival among responders despite frequent relapses. Our study highlights the high variability and lack of standardization of treatment protocols.

Course of Aggressive Somatotroph, Corticotroph and Mammotroph Tumors under Temozolomide; Report of Three Cases and Review of the Literature.

Treatment of aggressive pituitary tumors may be challenging. Temozolomide (TMZ) is a promising agent when conventional treatment methods fail. We present three patients with aggressive pituitary tumors with atypical morphology, who were resistant to conventional treatments and treated with TMZ. First case had a somatotroph adenoma, second a corticotroph adenoma, and the third a macroprolactinoma. We also reviewed the literature reporting TMZ efficacy in somatotroph, corticotroph and mammotroph tumors of pituitary. TMZ, 150-200 mg/m2 for 5 days in 28 days schedule was given to all patients. Among our patients, even though only the case of macroprolactinoma had a favorable response to TMZ treatment, both radiological and hormonal recurrences occurred 30 months after cessation of TMZ treatment. Then TMZ treatment was applied again. Cases of somatotroph and corticotroph adenomas had progressed under TMZ treatment and patients were lost due to mass effect of the tumor. Review of the literature demonstrated 67.3%, 60% and 26.7% overall response rates to the TMZ treatment in prolactinoma, corticotropinoma and somatostatinoma cases, respectively. There is still need to define response criteria uniformly to TMZ treatment in aggressive pituitary tumors and duration of response should be reported for reliable evaluation of results.

A Rapid Biochemical and Radiological Response to the Concomitant Therapy with Temozolomide and Radiotherapy in an Aggressive ACTH Pituitary Adenoma

Background and Importance. In the last eight years temozolomide (TMZ) has been used as the last-line treatment modality for aggressive pituitary tumors to be applied after the failure of surgery, medical therapy, and radiotherapy. The objective was to achieve a rapid control of tumor growth and hormone normalization with concurrent chemoradiotherapy in a patient with very aggressive ACTH pituitary adenoma. Clinical Presentation. We describe a patient with an aggressive ACTH-producing adenoma treated with concurrent temozolomide and radiotherapy. The patient suffered from an aggressive ACTH adenoma resistant to surgical and medical treatment. After two months of concurrent temozolomide and radiotherapy, cortisol normalization and significant tumor shrinkage were observed. After 22 months of follow-up, there is still no evidence of tumor recurrence. Conclusion. Concurrent treatment with temozolomide and irradiation appears to be highly effective in the achievement of the tumor volume control as well as in the control of ACTH secretion in aggressive ACTH adenoma.

P21.07 Temozolomide for Progressive Pituitary Adenomas Refractory to Surgery and Radiation: A Case Series

AbstractIntroduction:Treatment of aggressive pituitary adenomas typically involves a multimodality approach based on histopathological features and may include pharmacotherapy, surgery and radiation therapy. In cases of treatment-refractory tumor progression, chemotherapy may be considered. However, no standard chemotherapeutic regimen has been established. Anecdotal reports suggest that temozolomide may have a beneficial role in a subset of cases.Materials and Methods:In this case series and institutional experience we report the outcome and unique clinical characteristics of seven patients with aggressive pituitary tumors treated with temozolomide given at various dose regimens.Results:Tumor pathology included somatotrope (n=1), corticotrope (n=3), and lactotrope (n=3) tumors. Four of the seven patients had at least two prior resections, and all had prior radiation and surgery before treatment with temozolomide was considered. Notably, all patients showed response to therapy, defined as either stable disease (43%) or partial response (57%), using standard tumor response assessment parameters. Excluding the two patients who remain on therapy to date, total duration of therapeutic benefit ranged between 5–15 months. Three patients showed radiographic and clinical benefit beyond one year.Conclusions:Our data suggest that temozolomide may have an important role in the management of aggressive functioning pituitary tumors that are resistant to standard therapies, and that optimization of therapy with temozolomide may involve individualized regimens. Future prospective clinical trials should be considered.

Diagnostic criteria in invasive pituitary adenomas

AbstractPituitary adenomas are benign pituitary primary tumors, the most frequent type of tumor in the pituitary fossa. An important part, around 1/3 of the pituitary adenomas manifests an aggressive behavior, growing faster and invading into parasellar areas (cavernous sinus, neural tissues and bones). Objectives: the first aim of this paper is to review the last findings about invasiveness diagnostic criteria, imagistic and biomarkers, which can be used in the classification of pituitary tumors and also to predict the probability of invasiveness, tumor recurrence and suspicion of malignancy. The second aim is to highlight the morphological and clinic types of invasive pituitary adenomas. Materials and methods: we performed a systematic review and analysis of the published articles, searching PubMed between January 1985 and December 2015. There were selected articles published in English, reviews and abstracts. During the advanced search type in PubMed, combinations of the following keywords were used: “pituitary adenoma”, “invasive”, “aggressive”, “biomarkers”, “classification”, “histological subtypes”, ‘”immunohistochemical markers”. Results: 215 articles were selected, regarding diagnostic, prognostic and therapeutic aspects. There were some histological subtypes of pituitary adenomas known as having an aggressive clinical behavior. Several biomarkers were identified as being associated with the invasive feature: proliferation markers (Ki-67 index, number of mitoses, p53 & p27 expression, microvascularization density, telomerase, topoisomerase 2 Alpha), matrix metalloproteinases, protein kinase C, cyclooxygenase-2, E-cadherin, transcription Factors, genetic alterations (PTTG gene, Galectin-3 protein/ LGALS3 gene), apoptosis markers. Based on their invasion and proliferation characteristics, pituitary tumors are proposed to be classified into five grades (1a, 1b, 2a, 2b, 3), the grade 2b tumor with high risk of recurrence being considered as tumor suspected of malignancy. Conclusions: Using a set of specific biological markers for invasive process, there is hope to establish an early diagnosis and prevention of invasive pituitary adenomas. Due to the fact that aggressive pituitary tumors are generally difficult to manage, unresponsive to therapy, quickly recurrent and associated with poor prognosis, the early diagnosis and the search for new therapeutic approaches is becoming mandatory. Instead of using “invasive” or “aggressive” adenoma, the term “tumor suspected of malignancy” would be used for more accuracy

Differential Effects of PI3K and Dual PI3K/mTOR Inhibition in Rat Prolactin-Secreting Pituitary Tumors.

Aggressive pituitary tumors are rare but difficult to manage, as there is no effective chemotherapy to restrict their growth and cause their shrinkage. Within these tumors, growth-promoting cascades, like the PI3K/mTOR pathway, appear to be activated. We tested the efficacy of two inhibitors of this pathway, NVP-BKM120 (Buparlisib; pan-PI3K) and NVP-BEZ235 (dual PI3K/mTOR), both in vitro on immortalized pituitary tumor cells (GH3) and on primary cell cultures of human pituitary tumors and in vivo on a rat model of prolactin (PRL) tumors (SMtTW3). In vitro, NVP-BEZ235 had a potent apoptotic and cytostatic effect that was characterized by decreased cyclin D/E and Cdk4/2 protein levels and subsequent accumulation of cells in G1 In vivo, the effect was transient, with a decrease in mitotic index and increase in apoptosis; long-term treatment had no significant inhibitory effect on tumor growth. In contrast, while NVP-BKM120 had little effect in vitro, it dramatically limited tumor growth in vivo Increased Akt phosphorylation observed only in the NVP-BEZ235-treated tumors may explain the differential response to the two inhibitors. Primary cell cultures of human PRL pituitary tumors responded to NVP-BEZ235 with reduced cell viability and decreased hormone secretion, whereas NVP-BKM120 had little effect. Altogether, these results show a potential for PI3K inhibitors in the management of aggressive pituitary tumors. Mol Cancer Ther; 15(6); 1261-70. ©2016 AACR.

Therapeutic innovations in endocrine diseases – part 3 : temozolomide and future therapeutics for aggressive pituitary tumors and carcinomas

Pituitary tumors are the most frequent intracranial tumor and classically considered as benign. However, clinical evidence and recent advances in pathological and molecular analyses suggest that these tumors should be considered as more than a simple endocrine disorder. Descriptions of aggressive pituitary tumors and pituitary carcinomas have increased notably over the last decade following the first report on the successful treatment of pituitary carcinomas using temozolomide. This alkylating agent, widely used to treat glioblastoma, is now the first-line treatment for pituitary tumors resistant to conventional therapies. However, only 40 to 50% of pituitary tumors are sensitive to this treatment. Here, we review results of temozolomide treatment in this indication and discuss the interest of different prognostic markers and perspectives for new therapeutics.

Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects.

Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG) syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic chromosome Xq26.3 duplications that include GPR101 We studied XLAG syndrome patients (n= 18) to determine if somatic mosaicism contributed to the genomic pathophysiology. Eighteen subjects with XLAG syndrome caused by Xq26.3 duplications were identified using high-definition array comparative genomic hybridization (HD-aCGH). We noted that males with XLAG had a decreased log2ratio (LR) compared with expected values, suggesting potential mosaicism, whereas females showed no such decrease. Compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1 and 53.8%. These characteristics were replicated using a novel, personalized breakpoint junction-specific quantification droplet digital polymerase chain reaction (ddPCR) technique. Using a separate ddPCR technique, we studied the feasibility of identifying XLAG syndrome cases in a distinct patient population of 64 unrelated subjects with acromegaly/gigantism, and identified one female gigantism patient who had had increased copy number variation (CNV) threshold for GPR101 that was subsequently diagnosed as having XLAG syndrome on HD-aCGH. Employing a combination of HD-aCGH and novel ddPCR approaches, we have demonstrated, for the first time, that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at chromosome Xq26.3. Somatic mosaicism was shown to occur in sporadic males but not in females with XLAG syndrome, although the clinical characteristics of the disease were similarly severe in both sexes.

Temozolomide therapy in patients with aggressive pituitary adenomas or carcinomas.

Temozolomide is effective in some patients with progressive pituitary adenoma or carcinoma. We report a survey study of Italian patients treated with Temozolomide because of aggressive pituitary adenoma or carcinoma resistant to standard therapies. Italian endocrinologists were surveyed and asked to participate into the study. A questionnaire was sent to all those who agreed and had used Temozolomide in at least one patient with pituitary tumor. Database was closed in December 2013. A literature review was also performed. Thirty-one patients were included into the analysis. Mean age at start of Temozolomide treatment was 58.3 ± 1.9 years (± standard error). Six of the 31 (19.4%) Italian patients had a pituitary carcinoma. Twenty-five patients (80.6%) had disease control during Temozolomide treatment, while 6 patients (19.4%) had disease progression. Median follow-up after beginning Temozolomide was 43 months. Thirteen patients had tumor growth after stopping Temozolomide. The 2-year progression-free survival was 47.7% (95% CI 29.5-65.9%), while the 2-year disease control duration was 59.1% (95% CI 39.1-79.1%). Eleven patients died of progressive disease and other two patients of unrelated causes. The 2-year and 4-year overall survival rates were 83.9% (95% CI 70.7-97.1%) and 59.6% (95% CI 40.0-79.2%), respectively. Temozolomide is an additional effective therapeutic option for the treatment of aggressive pituitary tumors. The drug is well tolerated and causes few severe adverse effects. Recurrence of the tumor can occur after an initial positive response and usually portends a grim outcome.

PO07TREATMENT OF AGGRESSIVE PITUITARY TUMOURS WITH TEMOZOLOMIDE

INTRODUCTION: The management of aggressive pituitary tumours is challenging and conventional treatments are unable to provide long-term tumour control. In the salvage setting, Temozolomide (TMZ) has shown promising results both in reducing tumour size and hormone hypersecretion. METHOD: We present two patients, case 1 with a rapidly growing atypical prolactinoma and case 2 with a clinically non-functioning pituitary carcinoma with a spinal metastasis, treated with TMZ (200mg/m2, d1-d5/28 days, 12 and 6 cycles respectively) at tumour progression after multiple treatment approaches. RESULTS: TMZ provided good control of disease in both cases in parallel with reduced serum prolactin in case 1. Treatment was well tolerated with minimal toxicity. Tumour recurrence was observed 36 months after treatment termination in case 1 and the patient received stereotactic radiosurgery. Eight months after the termination of TMZ, case 2 is asymptomatic with controlled disease. CONCLUSION: TMZ was effective in the management of two aggressive pituitary tumours that failed to respond to conventional treatments. Prospective controlled studies are needed to define optimal treatment dose and duration and uniform criteria to select patients who will benefit from TMZ.