IgG4-related hypophysitis: a retrospective cohort study.

PURPOSE: IgG4-related hypophysitis (IgG4-RH) is a rare chronic inflammatory condition of the pituitary gland. This study reports the presentation, management and outcomes for patients with histologically proven IgG4-related hypophysitis. METHODS: A prospectively maintained electronic database was searched over a 14-year period from 1 January 2007 to 31 December 2020 at a single academic centre to identify all patients with a histological diagnosis of IgG4-RH. A retrospective case note review from electronic health records was conducted for each case to extract data on their presentation, management and outcomes. RESULTS: A total of 8 patients (5 male) with a median age of 51 years were identified. The most common presenting symptoms were headache (4/8; 50%), fatigue (3/8; 37.5%) and visual impairment (2/8; 25%). Three patients were initially treated with high-dose steroids aiming for reduction of the pituitary mass. However, ultimately all patients underwent transsphenoidal surgery. Post-operative changes included radiological reduction in pituitary mass in all patients that had imaging (7/7; 100%), improvement in vision (1/2; 50%), residual thick pituitary stalk (5/7; 71.4%), persistent anterior hypopituitarism (4/8; 50%) and panhypopopituitarism including diabetes insipidus (3/8; 37.5%). CONCLUSIONS: IgG4-RH is an increasingly recognised entity presenting with a variety of symptoms and signs. Clinical presentation is similar to other forms of hypophysitis. It is therefore important to consider IgG4-RH as a differential and to have a low threshold for pituitary biopsy, the diagnostic gold standard. The diagnosis of IgG4-RH will guide decisions for additional workup for IgG4-related disease, multi-disciplinary team involvement and follow-up.

Papillary thyroid microcarcinoma presenting as a metastasis to the brain.

The brain is a particularly rare site of metastasis from papillary microcarcinoma, with only few cases described in the literature. We present a case of 59-year-old man who presented with seizures and dysphasia due to left frontal lobe cystic mass, which was excised and turned out on histopathology to be of thyroid origin. Total thyroidectomy was performed and histology showed multifocal papillary microcarcinoma with the largest focus of 3mm with no other adverse features. The patient had ablative radioactive iodine postoperatively, with subsequent exit scan showing no uptake in the brain. Follow-up brain magnetic resonance imaging showed continuous regression of the surgical cavity. Although rare, such cases should be aggressively treated and followed up over the long term, because of reported associated high mortality.

Cell-cycle-phase progression analysis identifies unique phenotypes of major prognostic and predictive significance in breast cancer.

Multiparameter analysis of core regulatory proteins involved in G1-S and G2-M cell-cycle transitions provides a powerful biomarker readout for assessment of the cell-cycle state. We have applied this algorithm to breast cancer to investigate how the cell cycle impacts on disease progression. Protein expression profiles of key constituents of the DNA replication licensing pathway (Mcm2, geminin) and mitotic machinery (Plk1, Aurora A and the Aurora substrate histone H3S10ph) were generated for a cohort of 182 patients and linked to clinicopathological parameters. Arrested differentiation and genomic instability were associated with an increased engagement of cells into the cell division cycle (P<0.0001). Three unique cell-cycle phenotypes were identified: (1) well-differentiated tumours composed predominantly of Mcm2-negative cells, indicative of an out-of-cycle state (18% of cases); (2) high Mcm2-expressing tumours but with low geminin, Aurora A, Plk1 and H3S10ph levels (S-G2-M progression markers), indicative of a G1-delayed/arrested state (24% cases); and (3) high Mcm2-expressing tumours and also expressing high levels of the S-G2-M progression markers, indicative of accelerated cell-cycle progression (58% of cases). The active cell-cycle progression phenotype had a higher risk of relapse when compared with out-of-cycle and G1-delayed/arrested phenotypes (HR=3.90 (1.81-8.40, P<0.001)), and was associated with Her-2 and triple negative subtypes (P<0.001). It is of note that high-grade tumours with the G1-delayed/arrested phenotype showed an identical low risk of relapse compared with well-differentiated out-of-cycle tumours (HR=1.00 (0.22-4.46), P=0.99). Our biomarker algorithm provides novel insights into the cell-cycle state of dynamic tumour cell populations in vivo. This information is of major prognostic significance and may impact on individualised therapeutic decisions. Patients with an accelerated phenotype are more likely to derive benefit from S- and M-phase-directed chemotherapeutic agents.

CD4+ T cell down-regulation in human intestinal mucosa: evidence for intestinal tolerance to luminal bacterial antigens.

T cells from the intestinal mucosal proliferate poorly in vitro, and the contribution of Ag-specific recognition to this hyporesponsiveness is unclear, since the Ag repertoire of intestinal mucosal T cells is unknown. In this study, T cell proliferation in response to Ag-prepulsed autologous peripheral blood-derived APC was examined. Whereas T cells from peripheral blood proliferated to inner membrane and cytoplasmic Escherichia coli proteins, T cells from intestinal mucosa responded only to purified component Ags of these proteins and not to their combination. This suggests that the lack of proliferation in response to these Ags presented as a mixture is not due to the absence of E. coli-specific T cells in the mucosa, but, rather, to down-regulation after T cell recognition. Down-regulation was assayed by measuring the inhibition of autologous peripheral blood T cell proliferation in response to Ag-prepulsed APC. Coculture with leukocytes from intestinal mucosa and not from mesenteric lymph nodes, inhibited autologous peripheral blood T cell proliferation in response to E. coli proteins, but not to tetanus toxoid, PHA, or IL-2. Inhibition was independent of cell contact, provided APC were available to the mucosal cell population, and was reversible by neutralization of IL-10 or TGF-beta with mAb or depletion of mucosal CD4+ T cells. Taken together, the data suggest that mucosal T cell unresponsiveness to luminal Ags is mediated by production of inhibitory cytokines after specific Ag recognition by CD4+ T cells.

Accelerator mass spectrometry in biomedical dosimetry: relationship between low-level exposure and covalent binding of heterocyclic amine carcinogens to DNA.

Accelerator mass spectrometry (AMS) is used to determine the amount of carcinogen covalently bound to mouse liver DNA (DNA adduct) following very low-level exposure to a 14C-labeled carcinogen. AMS is a highly sensitive method for counting long-lived but rare cosmogenic isotopes. While AMS is a tool of importance in the earth sciences, it has not been applied in biomedical research. The ability of AMS to assay rare isotope concentrations (10Be, 14C, 26Al, 41Ca, and 129I) in microgram amounts suggests that extension to the biomedical sciences is a natural and potentially powerful application of the technology. In this study, the relationship between exposure to low levels of 2-amino-3,8-dimethyl[2-14C]imidazo[4,5-f]quinoxaline and formation of DNA adducts is examined to establish the dynamic range of the technique and the potential sensitivity for biological measurements, as well as to evaluate the relationship between DNA adducts and low-dose carcinogen exposure. Instrument reproducibility in this study is 2%; sensitivity is 1 adduct per 10(11) nucleotides. Formation of adducts is linearly dependent on dose down to an exposure of 500 ng per kg of body weight. With the present measurements, we demonstrate at least 1 order of magnitude improvement over the best adduct detection sensitivity reported to date and 3-5 orders of magnitude improvement over other methods used for adduct measurement. An additional improvement of 2 orders of magnitude in sensitivity is suggested by preliminary experiments to develop bacterial hosts depleted in radiocarbon. Expanded applications involving human subjects, including clinical applications, are now expected because of the great detection sensitivity and small sample size requirements of AMS.