Postsurgical outcomes of nonfunctioning pituitary adenomas: a patient-level meta-analysis.

BACKGROUND: Surgical resection is the main treatment for symptomatic nonfunctioning pituitary adenomas (NFPA). We aimed to analyze the impact of surgical approach, completeness of resection, and postoperative radiotherapy on long-term progression-free survival (PFS) of NFPA, using individual patient data (IPD) meta-analysis. METHODS: An electronic literature searched was conducted on PubMed, EMBASE, and Web of Science from database inception to 6 November 2022. Studies describing the natural history of surgically resected NFPA, with provision of Kaplan-Meier curves, were included. These were digitized to obtain IPD, which was pooled in one-stage and two-stage meta-analysis to determine hazard ratios (HRs) and 95%CIs of gross total resection (GTR) versus subtotal resection (STR), and postoperative radiotherapy versus none. An indirect analysis of single-arm data between endoscopic endonasal (EES) and microscopic transsphenoidal (MTS) surgical technique was also performed. RESULTS: Altogether, eleven studies (3941 patients) were retrieved. PFS was significantly lower in STR than GTR (shared-frailty HR 0.32, 95%CI 0.27-0.39, p < 0.001). Postoperative radiotherapy significantly improved PFS compared to no radiotherapy (shared-frailty HR 0.20, 95%CI 0.15-0.26, p < 0.001), including in the subgroup of patients with STR (shared-frailty HR 0.12, 95%CI 0.08-0.18, p < 0.001). Similar PFS was observed between EES and MTS (indirect HR 1.09, 95%CI 0.92-1.30, p = 0.301). CONCLUSIONS: This systematic review and patient-level meta-analysis provides a robust prognostication of surgically treated NFPA. We reinforce current guidelines stating that GTR should be the standard of surgical resection. Postoperative radiotherapy is of considerable benefit, especially for patients with STR. Surgical approach does not significantly affect long-term prognosis. REGISTRATION: PROSPERO CRD42022374034.

Characteristics and genetic testing outcomes of patients with clinically suspected paraganglioma/pheochromocytoma (PGL/PCC) syndrome in Singapore.

BACKGROUND: Hereditary paraganglioma (PGL) and pheochromocytoma (PCC) syndromes are rare conditions, with limited data on spectrum of causative gene variants of these syndromes in Asian patients. METHODS: We describe the clinical characteristics and genetic testing outcomes of patients with suspected hereditary PGL/PCC who were referred to a tertiary cancer genetics clinic in Singapore. RESULTS: Among 2196 patients with suspected hereditary cancer syndrome evaluated at the cancer genetics clinic from 2000 to 2019, 13/2196 (0.6%) patients fulfilled clinical suspicion for hereditary PGL/PCC syndrome. After genetic counselling, 10 patients underwent multi-gene next generation sequencing and deletion/duplication analysis, including SDHAF2, SDHA, SDHB, SDHC, SDHD, VHL, NF1, RET, MAX, and TMEM127. Seven of 10 patients (70%) were identified to carry pathogenic variants, including 3 unrelated Chinese patients with head and neck PGL who carried the same SDHD: c.3G > C (p.Met1Ile) variant that was previously reported to be a possible founder variant in Chinese, and 3 patients with urogenital PGL and 1 patient with retroperitoneal PGL who carried different SDHB variants. Variant carriers were younger, more likely to present with multiple tumours, or have family history of paraganglioma or pheochromocytoma, than non- variant carriers. CONCLUSION: Hereditary PGL/PCC accounts for only 0.6% of patients seen in an adult cancer genetics clinic in Asia. SDHD and SDHB genes remain the most important causative genes of hereditary PGL/PCC in Asia even when patients are tested with multi-gene NGS panel.

Use of cabergoline for the management of persistent Cushing's disease in pregnancy.

Cushing's disease (CD) is rare during pregnancy and is associated with significant maternal and fetal complications. It is important to control hypercortisolism during pregnancy, either surgically or medically, for a successful maternal and fetal outcome. We report a patient with recurrent CD who was treated with low-dose cabergoline (CAB) for persistent hypercortisolism throughout pregnancy. A 36-year-old woman was diagnosed with CD at the age of 23. She underwent trans-sphenoidal surgery with initial complete remission. However, 4 years after surgery, CD recurred and she underwent Gamma Knife radiosurgery (GKRS). Following GKRS, her cortisol levels remained elevated despite no evidence of visible tumour on pituitary MRI. Medical treatment was commenced with ketoconazole and cyproheptadine. This was changed to CAB as she was keen for pregnancy. She conceived spontaneously and was on CAB throughout pregnancy. She delivered a healthy male neonate, weighing 3195 g at 40 weeks of gestation.

Spuriously elevated free thyroxine associated with autoantibodies, a result of laboratory methodology: case report and literature review.

OBJECTIVE: We describe a case of spurious hyperthyroxinemia secondary to thyroid hormone autoantibodies (THAAbs) in a clinically euthyroid patient with Turner mosaic syndrome. METHODS: Several commonly available laboratory-based approaches were used, which indicated a disproportionate elevation of free thyroxine (T4) and ultimately led to the diagnosis of THAAbs. A literature review was undertaken to examine the clinical and laboratory associations of THAAbs. RESULTS: The free T4 result of the patient was highly discrepant when measured using an Advia Centaur platform (5.89 ng/dL) as compared with the Vitros 5600 and DxI 800 platforms (1.03 and 0.74 ng/dL, respectively). Polyethylene glycol precipitation of the patient's sample showed reduced free T4 recovery (26%), suggesting the presence of a high-molecular-weight interfering substance. Rheumatoid factor and heterophile blocking tube studies were negative. These results suggested a presumptive diagnosis of THAAbs. Direct detection of THAAbs using a radiobinding method confirmed the diagnosis. A review of the literature showed that THAAbs are prevalent among patients with (autoimmune and nonautoimmune) thyroid disorders and nonthyroid autoimmune disorders but rarely cause spurious measurements. Possible pathogenesis includes molecular mimicry, exposure of the antigenic surfaces of iodinated thyroglobulin molecules to B lymphocytes in injurious or inflammatory conditions involving the thyroid gland. Free thyroid hormone methods using one-step analog and labeled antibody designs are prone to falsely high measurements, whereas two-step analog designs may produce spuriously low results. CONCLUSION: THAAbs are an underrecognized cause of laboratory interference that is best approached by joint clinical-laboratory efforts. The routine laboratory techniques described above can suggest preliminary diagnosis of this rare entity.

Elevated free thyroxine and non-suppressed thyrotropin.

A young man was diagnosed with hyperthyroidism 10 years prior to current presentation after a random health screening revealed an elevated free thyroxine (fT4) of 36.9 pmol/L. During that time, he saw multiple physicians and was treated with carbimazole intermittently. His repeat thyroid function tests showed persistently elevated fT4 ranging 25-35.7 pmol/L and non-suppressed thyroid-stimulating hormone (TSH) concentrations of 6.78-22.1 mIU/L. He had a smooth, firm and non-tender goitre. At our institution, laboratory interference was first excluded by serial dilution study (TSH) and retesting of TSH and fT4 on alternate assay, which gave reproducible results. His normal α-subunit and sex hormone binding globulin, partially suppressed TSH by high dose triiodothyronine (T3), and positive TSH response to thyrotropin-releasing hormone stimulation were consistent with resistance to thyroid hormone syndrome. The diagnosis was confirmed by direct sequencing of thyroid hormone receptor-ß gene, revealing a heterozygous R320 L mutation that causes reduced T3 affinity and reduced corepressor dissociation.