Dopamine agonist resistant lactotroph adenoma

Dopamine agonist resistant lactotroph adenoma

While dopamine agonists are a primary method of therapeutic treatment for Lactotroph adenoma, the rate of resistance to these drugs continues to increase each year.

Surgery is typically indicated for patients who are resistant to medical therapy or intolerant of its adverse side effects, or are experiencing progressive tumor growth. Surgical resection can also be considered as a primary treatment for those with smaller focal tumors where a biochemical cure can be expected as an alternative to lifelong dopamine agonist treatment. Stereotactic radiosurgery also serves as an option for those refractory to medical and surgical therapy 1).


Coopmans et al., reported a patient with an highly aggressive, dopamine-resistant prolactinoma, who only achieved biochemical and tumor control during pasireotide long-acting release (PAS-LAR) therapy , a second-generation somatostatin receptor ligand (SRL). Interestingly, cystic degeneration, tumor cell necrosis, or both was observed after PAS-LAR administration suggesting an antitumor effect. This case shows that PAS-LAR therapy holds clinical potential in selective aggressive, dopamine-resistant prolactinomas that express somatostatin receptor 5 and appears to be a potential new treatment option before starting temozolomide. In addition, PAS-LAR therapy may induce cystic degeneration, tumor cell necrosis, or both in prolactinomas 2).


During previous long-term clinical investigations, Hu et al., from Department of Neurosurgery and Pituitary Tumor Center, The First Affiliated Hospital, Sun Yat-sen University, GuangzhouChina, found that partial resistant prolactinomas exhibited significantly more fibrosis than did sensitive adenomas, suggesting a role of fibrosis in their drug resistance. Furthermore, resistant adenomas with extensive fibrosis mainly express type I and type III collagens. Since TGF-β1 is the key factor in the initiation and development of tissue fibrosis, including in the pituitary, in this study, they aimed to determine whether TGF-β1 mediated fibrosis in prolactinomas and whether fibrosis was related to prolactinoma drug resistance. Using immunochemistry and western blotting, they found that the TGF-β1/Smad3 signaling pathway-related proteins were elevated in resistant prolactinoma specimens with high degrees of fibrosis compared to levels in sensitive samples, suggesting that this pathway may play a role in prolactinoma fibrosis. In vitro, TGF-β1 stimulation promoted collagen expression in normal HS27 fibroblasts. Furthermore, the sensitivity of rat prolactinoma MMQ cells to bromocriptine decreased when they were co-cultured with HS27 cells treated with TGF-β1. The TGF-β1/Smad3 signaling-specific inhibitor SB431542 counteracted these effects, indicating that TGF-β1/Smad3-mediated fibrosis was involved in the drug-resistant mechanisms of prolactinomas. These results indicate that SB431542 may serve as a promising novel treatment for preventing fibrosis and further improving the drug resistance of prolactinoma3).

References

1)

Wong A, Eloy JA, Couldwell WT, Liu JK. Update on prolactinomas. Part 2: Treatment and management strategies. J Clin Neurosci. 2015 Oct;22(10):1568-74. doi: 10.1016/j.jocn.2015.03.059. Epub 2015 Aug 1. Review. PubMed PMID: 26243714.
2)

Coopmans EC, van Meyel SWF, Pieterman KJ, van Ipenburg JA, Hofland L, Donga E, Daly AF, Beckers A, Van der Lely AJ, Neggers SJCMM. Excellent response to pasireotide therapy in an aggressive and dopamine-resistant prolactinoma. Eur J Endocrinol. 2019 Jun 1. pii: EJE-19-0279.R1. doi: 10.1530/EJE-19-0279. [Epub ahead of print] PubMed PMID: 31167168.
3)

Hu B, Mao Z, Jiang X, He D, Wang Z, Wang X, Zhu Y, Wang H. Role of TGF-β1/Smad3-mediated fibrosis in drug resistance mechanism of prolactinoma. Brain Res. 2018 Jul 26. pii: S0006-8993(18)30408-6. doi: 10.1016/j.brainres.2018.07.024. [Epub ahead of print] PubMed PMID: 30055965.

X-linked acrogigantism

X-linked acrogigantism

X-linked acrogigantism (X-LAG), a condition of infant-onset acrogigantism marked by elevated GHIGF-1, and prolactin (PRL), is extremely rare. Thirty-three cases, including three kindreds, have been reported. These patients have pituitary adenomas that are thought to be mixed lactotrophs and somatotrophs.

Pituitary tumors are undergoing a transformation in histopathologic and molecular classification, coincident with the continued refinement of increasingly powerful methods of genomic annotation and discovery.

Sporadic pituitary adenomas are associated with relatively few recurrent somatic mutations. Recurrent mutations occur largely in subsets of hormone-producing tumors, including GNAS and GPR101 in somatotroph adenomas and USP8 in corticotroph adenomas. Additionally, they manifest with a dichotomous signature of copy number alterations, ranging from almost none to widespread genome instability, while microduplication of chromosome Xq26.3, containing the GNAS gene, defines X-linked acrogigantism. Papillary craniopharyngiomas are defined by BRAF V600E mutations while β-catenin alterations characterize adamantinomatous craniopharyngiomas. Genomic annotation of pituitary tumors is defining increasing subsets of neuroendocrine adenohypophyseal tumors and craniopharyngiomas, offering rationale-based pharmacologic targets and potential biomarkers for clinical outcome 1).


Non-syndromic pituitary gigantism can result from AIP mutations or the identified Xq26.3 microduplication causing X-linked acrogigantism (XLAG). Within Xq26.3, GPR101 is believed to be the causative gene, and the c.924G > C (p.E308D) variant in this orphan G protein-coupled receptor has been suggested to play a role in the pathogenesis of acromegaly.We studied 153 patients (58 females and 95 males) with pituitary gigantism. AIP mutation-negative cases were screened for GPR101 duplication through copy number variation droplet digital PCR and high-density aCGH. The genetic, clinical and histopathological features of XLAG patients were studied in detail. 395 peripheral blood and 193 pituitary tumor DNA samples from acromegaly patients were tested for GPR101 variants.We identified 12 patients (10 females and 2 males; 7.8 %) with XLAG. In one subject, the duplicated region only contained GPR101, but not the other three genes in found to be duplicated in the previously reported patients, defining a new smallest region of overlap of duplications. While females presented with germline mutations, the two male patients harbored the mutation in a mosaic state. Nine patients had pituitary adenomas, while three had hyperplasia. The comparison of the features of XLAG, AIP-positive and GPR101&AIP-negative patients revealed significant differences in sex distribution, age at onset, height, prolactin co-secretion and histological features. The pathological features of XLAG-related adenomas were remarkably similar. These tumors had a sinusoidal and lobular architecture. Sparsely and densely granulated somatotrophs were admixed with lactotrophs; follicle-like structures and calcifications were commonly observed. Patients with sporadic of familial acromegaly did not have an increased prevalence of the c.924G > C (p.E308D) GPR101 variant compared to public databases.In conclusion, XLAG can result from germline or somatic duplication of GPR101. Duplication of GPR101 alone is sufficient for the development of XLAG, implicating it as the causative gene within the Xq26.3 region. The pathological features of XLAG-associated pituitary adenomas are typical and, together with the clinical phenotype, should prompt genetic testing 2).

Case reports

The patient’s mother, diagnosed with acrogigantism at 21 months, underwent pituitary tumor excision at 24 months. For over 30 years, stable PRL, GH, and IGF-1 concentrations and serial imaging studies indicated no tumor recurrence. During pre-conception planning, X-LAG was diagnosed: single-nucleotide polymorphism (SNP) microarray showed chromosome Xq26.3 microduplication. After conception, SNP microarray on a chorionic villus sample showed the same microduplication in the fetus, confirming familial X-LAG. The infant grew rapidly with rising PRL, GH, and IGF-1 concentrations and an enlarging suprasellar pituitary mass, despite treatment with bromocriptine. At 15 months, he underwent tumor resection. The pituitary adenoma resembled the mother’s pituitary adenoma, with tumor cells arranged in trabeculae and glandular structures. In both cases, many tumor cells expressed PRL, GH, and PIT1. Furthermore, the tumor expressed other lineage-specific transcription factors, as well as SOX2 and OCT4, demonstrating the multipotentiality of X-LAG tumors. Both showed an elevated Ki-67 proliferation index-5.6% (mother) and 8.5% (infant)-the highest reported in X-LAG.

This is the first prenatally diagnosed case of X-LAG. Clinical follow-up and biochemical evaluation have provided insight into the natural history of this disease. Expression of stem cell markers and several cell lineage-specific transcription factors suggests that these tumors are multipotential. 3).

References

1)

Bi WL, Larsen AG, Dunn IF. Genomic Alterations in Sporadic Pituitary Tumors. Curr Neurol Neurosci Rep. 2018 Feb 2;18(1):4. doi: 10.1007/s11910-018-0811-0. Review. PubMed PMID: 29396598.
2)

Iacovazzo D, Caswell R, Bunce B, Jose S, Yuan B, Hernández-Ramírez LC, Kapur S, Caimari F, Evanson J, Ferraù F, Dang MN, Gabrovska P, Larkin SJ, Ansorge O, Rodd C, Vance ML, Ramírez-Renteria C, Mercado M, Goldstone AP, Buchfelder M, Burren CP, Gurlek A, Dutta P, Choong CS, Cheetham T, Trivellin G, Stratakis CA, Lopes MB, Grossman AB, Trouillas J, Lupski JR, Ellard S, Sampson JR, Roncaroli F, Korbonits M. Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study. Acta Neuropathol Commun. 2016 Jun 1;4(1):56. doi: 10.1186/s40478-016-0328-1. PubMed PMID: 27245663; PubMed Central PMCID: PMC4888203.
3)

Wise-Oringer BK, Zanazzi GJ, Gordon RJ, Wardlaw SL, William C, Anyane-Yeboa K, Chung WK, Kohn B, Wisoff JH, David R, Oberfield SE. Familial X-Linked Acrogigantism: Postnatal Outcomes and Tumor Pathology in a Prenatally Diagnosed Infant and His Mother. J Clin Endocrinol Metab. 2019 Jun 5. pii: jc.2019-00817. doi: 10.1210/jc.2019-00817. [Epub ahead of print] PubMed PMID: 31166600.

Epilepsy after cranioplasty

Epilepsy after cranioplasty

Among the several cranioplasty complicationsepilepsy is a common complication with an incidence of 14.8-33.0% 1) 2).

Antiepileptic drugs can effectively reduce the occurrence of seizure3).

Systematic review

Seizures are a recognised complication of cranioplasty but its incidence and risk factors in TBI patients are unclear. Accurate prognostication can help direct prophylactic and treatment strategies for seizures. In a systematic review, Spencer et al., aimed to evaluate current literature on these factors. A PROSPERO-registered systematic review was performed in accordance with PRISMA guidelines. Data was synthesised qualitatively and quantitatively in meta-analysis where appropriate. A total of 8 relevant studies were identified, reporting 919 cranioplasty patients. Random-effects meta-analysis reveals a pooled incidence of post-cranioplasty seizures (PCS) of 5.1% (95% CI 2.6-8.2%). Identified risk factors from a single study included increasing age (OR 6.1, p = 0.006), contusion at cranioplasty location (OR 4.8, p = 0.015), and use of monopolar diathermy at cranioplasty (OR 3.5, p = 0.04). There is an association between an extended DC-cranioplasty interval and PCS risk although it did not reach statistical significance (p = 0.062). Predictive factors for PCS are poorly investigated in the TBI population to date. Heterogeneity of included studies preclude meta-analysis of risk factors. Further studies are required to define the true incidence of PCS in TBI and its predictors, and trials are needed to inform management of these patients. 4).

Case series

Two hundred and thirty-eight patients who received cranioplasty following craniectomy between January 2012 and December 2014 were included in a study. The risk factors of the patients with early and late post-cranioplasty seizures were compared to those with no post-cranioplasty seizures.

Seizures (73/238, 30.3%) were the most common complication after cranioplasty. Of these 73 patients, 17 (7.1%) had early post-cranioplasty seizures and 56 (23.5%) had late post-cranioplasty seizures. Early post-cranioplasty seizures were related to a longer interval between craniectomy and cranioplasty (P = 0.006), artificial materials (P < 0.001), and patients with late post-craniectomy seizures (P = 0.001). Late post-cranioplasty seizures were related to the presence of neurological deficits (P = 0.042). After stepwise logistic regression analysis, a longer interval between craniectomy and cranioplasty (P = 0.012; OR: 1.004, 95% CI: 1.001-1.007) and late post-craniectomy seizures (P = 0.033; OR: 4.335, 95% CI: 1.127-16.675) were independently associated with early post-cranioplasty seizures.

Delayed cranioplasty procedures and seizures before cranioplasty were significantly associated with early post-cranioplasty seizures. Further studies are warranted to investigate whether early surgery after craniectomy can reduce the risk of early post-cranioplasty seizures 5).


A retrospective study, covering the period between January 2008 and July 2015, compared postcranioplasty seizures (PCS) in postcranioplasty patients. Postcranioplasty seizures risk factors included diabetes mellitus, hypertension, time between DC and cranioplasty, duraplasty material, cranioplasty contusion location, electrocautery method, PCS type, and infection. Multivariate logistic regression analysis was performed and confidence intervals (CIs) were calculated (95% CI).

Of 270 patients, 32 exhibited initial PCS onset postcranioplasty with 11.9% incidence (32/270). Patients fell into immediate (within 24 hours), early (from 1 to 7 days), and late (after 7 days) PCS groups with frequencies of 12, 5, and 15 patients, respectively. Generalized, partial, and mixed seizure types were observed in 13, 13, and 6 patients, respectively. Multivariate logistic regression analysis showed increased risk with increasing age (>50 years). Cranioplasty contusion location, precranioplasty deficits, duraplasty material, and monopolar electrocautery were predictive of PCS onset (P < 0.05). Increased DC to cranioplasty interval increased risk but was not statistically significant (P = 0.062).

Understanding risk factors for PCS will benefit the management of cranioplasty patients 6).

References

1)

L. Lee, J. Ker, B.L. Quah, N. Chou, D. Choy, T.T. Yeo, A retrospective analysis and review of an institution’s experience with the complications of cranioplasty, Br. J. Neurosurg. 27 (2013) 629e635.
2)

A. Pechmann, C. Anastasopoulos, R. Korinthenberg, V. van Velthoven-Wurster, J. Kirschner, Decompressive craniectomy after severe traumatic brain injury in children: complications and outcome, Neuropediatrics 46 (2015) 5e12.
3)

Chen F, Duan Y, Li Y, Han W, Shi W, Zhang W, Huang Y. Use of an antiepileptic drug to control epileptic seizures associated with cranioplasty: A Randomised Controlled Trial. Int J Surg. 2017 Feb 18. pii: S1743-9191(17)30140-1. doi: 10.1016/j.ijsu.2017.02.017. [Epub ahead of print] PubMed PMID: 28223259.
4)

Spencer R, Manivannan S, Sharouf F, Bhatti MI, Zaben M. Risk factors for the development of seizures after cranioplasty in patients that sustained traumatic brain injury: A systematic review. Seizure. 2019 Mar 21;69:11-16. doi: 10.1016/j.seizure.2019.03.014. [Epub ahead of print] Review. PubMed PMID: 30952091.
5)

Shih FY, Lin CC, Wang HC, Ho JT, Lin CH, Lu YT, Chen WF, Tsai MH. Risk factors for seizures after cranioplasty. Seizure. 2019 Mar;66:15-21. doi: 10.1016/j.seizure.2018.12.016. Epub 2018 Dec 19. PubMed PMID: 30772643.
6)

Wang H, Zhang K, Cao H, Zhang X, Li Y, Wei Q, Zhang D, Jia Q, Bie L. Seizure After Cranioplasty: Incidence and Risk Factors. J Craniofac Surg. 2017 Sep;28(6):e560-e564. doi: 10.1097/SCS.0000000000003863. PubMed PMID: 28796104.
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