Myelomeningocele repair timing

Myelomeningocele repair timing

The optimal time to closure of a newborn with an open neural tube defect (NTD-myelomeningocele) has been the subject of a number of investigations. One aspect of timing that has received attention is its relationship to repair site and central nervous system (CNS) infection that can lead to irreversible deficits and prolonged hospital stays.

Clinical guidelines recommend repair of open spina bifida (SB) prenatally or within the first days of an infant’s life.


A prospective, randomized study (the MOMS trial) has shown that fetal surgery for MMC before 26 weeks’ gestation may preserve neurologic function, reverse the hindbrain herniation of the Chiari II malformation, and obviate the need for postnatal placement of a ventriculoperitoneal shunt. However, this study also demonstrates that fetal surgery is associated with significant risks related to the uterine scar and premature birth. In the future, research will expand our understanding of the pathophysiology of MMC, evaluate the long-term impact of in-utero intervention, and to refine timing and technique of fetal MMC surgery using tissue engineering technology 1).

Controversies

In a cohort from Texas, over one-quarter of patients undergoing postnatal myelomeningocele repair experienced a complication within 30 days. The complication rate was significantly higher in patients who had surgical repair within the first 24 hours of birth than in patients who had surgery after the 1st day of life 2).


Kancherla et al., examined 2006 to 2011 births from the California Perinatal Quality Care Collaborative, linking to hospital discharge and vital records. Selected maternal, infant, and delivery hospital characteristics were evaluated to understand disparities in timely repair. Poisson regression was used to estimate adjusted risk ratios (aRRs) and 95% confidence intervals (CIs).

Overall, 399 of the 450 (89%) infants had a timely repair and approximately 80% of them were delivered in level III/IV hospitals. Infants with hydrocephalus were significantly less likely to have a delayed myelomeningocele repair compared with those without (aRR = 0.22; 95% CI = 0.13, 0.39); infants whose medical care was paid by Medi-Cal or other nonprivate insurance were 2.2 times more likely to have a delayed repair compared with those covered by a private insurance (aRR = 2.23; 95% CI = 1.17, 4.27). Low birth weight was a significant predictor for delayed repair (aRR = 2.06; 95% CI = 1.10, 3.83).

There was a significant disparity in myelomenigocele repair based on medical care payer. Families and hospitals should work together for timely repair in hospitals having specialized multidisciplinary teams. Findings from the study can be used to follow best clinical practices for myelomeningocele repair 3).


Treatment outcomes following documented times to transfer and closure were evaluated at Children’s Hospital of Los Angeles (CHLA) for the years 2004 to 2014. Data of newborns with a myelomeningocele with varying time to repair were also obtained from non-overlapping abstracts of the 2000-2010 Kids’ Inpatient Database (KID) and Nationwide Inpatient Sample (NIS). Poisson multivariable regression analyses were used to assess the effect of time to repair on infection and time to discharge.

At CHLA, 95 neonates who underwent myelomeningocele repair were identified, with a median time from birth to treatment of 1 day. Six (6 %) patients were noted to have postrepair complications. CHLA data was not sufficiently powered to detect a difference in infection following delay in closure. In the NIS, we identified 3775 neonates with repaired myelomeningocele of whom infection was reported in 681 (18 %) patients. There was no significant difference in rates of infection between same-day and 1-day wait times (p = 0.22). Wait times of two (RR = 1.65 [1.23, 2.22], p < 0.01) or more days (RR = 1.88 [1.39, 2.54], p < 0.01), respectively, experienced a 65 % and 88 increase in rates of infection compared to same-day procedures. Prolonged wait time was 32 % less likely at facilities with increased myelomeningocele repair volume (RR = 0.68 [0.56 0.83], p < 0.01). The presence of infection was associated with a 54 % (RR = 1.54 [1.36, 1.74], p < 0.01) increase in the length of stay when compared to neonates without infection.

Myelomeningocele closure, when delayed more than 1 day after birth, is associated with an increased rate of infection and length of stay in the national cohort. High-volume centers are associated with fewer delays to repair. Though constrained by limitations of a national coded database, these results suggest that early myelomeningocele repair decreases the rate of infection 4).


In a retrospective, statewide, population-based study examined infants with open spina bifida (SB) born in Florida 1998-2007. Most infants with SB had surgical repair in the first 2 days of life. Lower level birth hospital nursery care was associated with later repairs 5).

References

1)

Adzick NS. Fetal surgery for spina bifida: past, present, future. Semin Pediatr Surg. 2013 Feb;22(1):10-7. doi: 10.1053/j.sempedsurg.2012.10.003. Review. PubMed PMID: 23395140; PubMed Central PMCID: PMC6225063.
2)

Cherian J, Staggers KA, Pan IW, Lopresti M, Jea A, Lam S. Thirty-day outcomes after postnatal myelomeningocele repair: a National Surgical Quality Improvement Program Pediatric database analysis. J Neurosurg Pediatr. 2016 Oct;18(4):416-422. Epub 2016 Jun 3. PubMed PMID: 27258591.
3)

Kancherla V, Ma C, Grant G, Lee HC, Shaw GM, Hintz SR, Carmichael SL. Factors Associated with Timeliness of Surgical Repair among Infants with Myelomeningocele: California Perinatal Quality Care Collaborative, 2006 to 2011. Am J Perinatol. 2019 Jul 15. doi: 10.1055/s-0039-1693127. [Epub ahead of print] PubMed PMID: 31307103.
4)

Attenello FJ, Tuchman A, Christian EA, Wen T, Chang KE, Nallapa S, Cen SY, Mack WJ, Krieger MD, McComb JG. Infection rate correlated with time to repair of open neural tube defects (myelomeningoceles): an institutional and national study. Childs Nerv Syst. 2016 Sep;32(9):1675-81. doi: 10.1007/s00381-016-3165-4. Epub 2016 Jul 21. PubMed PMID: 27444296.
5)

Radcliff E, Cassell CH, Laditka SB, Thibadeau JK, Correia J, Grosse SD, Kirby RS. Factors associated with the timeliness of postnatal surgical repair of spina bifida. Childs Nerv Syst. 2016 Aug;32(8):1479-87. doi: 10.1007/s00381-016-3105-3. Epub 2016 May 14. PubMed PMID: 27179533; PubMed Central PMCID: PMC5007061.

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.
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