Is estrogen exposure a protective factor for pancreatic neuroendocrine tumours in female patients with multiple endocrine neoplasia syndrome type 1?

OBJECTIVE: Pancreatic neuroendocrine tumours (PNETs) are the most common cause of death in patients with multiple endocrine neoplasia type 1 (MEN1). Women have been shown to have improved survival, which may suggest a possible protective effect of female sex hormones. The aim of this study was to evaluate the relationship between estrogen exposure and PNET tumourigenesis, tumour growth and survival in female MEN1 patients with these tumours. DESIGN: We performed a retrospective chart review of the existing MEN1 database in our institution. Detailed information about female patients' menstrual and reproductive history, and PNET clinicopathologic characteristics was collected. Questionnaires regarding estrogen exposure were used to collect information that was missing in the database. PATIENTS: Of 293 confirmed MEN1 cases, 141 women met the inclusion criteria. MEASUREMENTS: We used measures of cumulative estrogen exposure time (CEET), parity, live birth pregnancies and bilateral oophorectomy to estimate estrogen exposure. RESULTS: There was no significant association between CEET and time to PNET diagnosis (hazard ratio = 0·966, P = 0·380). For the correlation between estrogen exposure and PNET type, size, numbers, distant metastasis, lymph node metastasis, lymphovascular invasion, AJCC (American Joint Committee on Cancer) stage and overall survival, only CEET was significantly correlated with PNET size (P = 0·043). CONCLUSIONS: In female patients with MEN1, estrogen exposure may inhibit PNET growth. A demonstrable protective effect against PNET tumourigenesis, tumour growth and survival of patients with these tumours may require a larger cohort.

Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy.

Nine cancer patients were treated with adoptive cell therapy using autologous anti-MAGE-A3 T-cell receptors (TCR)-engineered T cells. Five patients experienced clinical regression of their cancers including 2 on-going responders. Beginning 1-2 days postinfusion, 3 patients (#'s 5, 7, and 8) experienced mental status changes, and 2 patients (5 and 8) lapsed into comas and subsequently died. Magnetic resonance imagining analysis of patients 5 and 8 demonstrated periventricular leukomalacia, and examination of their brains at autopsy revealed necrotizing leukoencephalopathy with extensive white matter defects associated with infiltration of CD3(+)/CD8(+) T cells. Patient 7, developed Parkinson-like symptoms, which resolved over 4 weeks and fully recovered. Immunohistochemical staining of patient and normal brain samples demonstrated rare positively staining neurons with an antibody that recognizes multiple MAGE-A family members. The TCR used in this study recognized epitopes in MAGE-A3/A9/A12. Molecular assays of human brain samples using real-time quantitative-polymerase chain reaction, Nanostring quantitation, and deep-sequencing indicated that MAGE-A12 was expressed in human brain (and possibly MAGE-A1, MAGE-A8, and MAGE-A9). This previously unrecognized expression of MAGE-A12 in human brain was possibly the initiating event of a TCR-mediated inflammatory response that resulted in neuronal cell destruction and raises caution for clinical applications targeting MAGE-A family members with highly active immunotherapies.