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The PD-1 (programmed death-1)/PD-L1 (PD-ligand 1) checkpoint is a critical regulator of activated T cell-cancer cell interactions, defending tumor cells against immune destruction. Nano-diamino-tetrac (NDAT; Nanotetrac) is an anticancer/anti-angiogenic agent targeted to the thyroid hormone-tetrac receptor on the extracellular domain of integrin αvβ3. NDAT inhibits the cancer cell PI3-K and MAPK signal transduction pathways that are critical to PD-L1 gene expression. We examined actions in vitro of thyroid hormone (l-thyroxine, T) and NDAT on PD-L1 mRNA abundance (qPCR) and PD-L1 protein content in human breast cancer (MDA-MB-231) cells and colon carcinoma (HCT116 and HT-29) cells. In MDA-MB-231 cells, a physiological concentration of T (10M total; 10M free hormone) stimulated PD-L1 gene expression by 38% and increased PD-L1 protein by 2.7-fold (p<0.05, all changes). NDAT (10M) reduced PD-L1 in T-exposed cells by 21% (mRNA) and 39% (protein) (p<0.05, all changes). In HCT116 cells, T enhanced PD-L1 gene expression by 17% and protein content by 24% (p<0.05). NDAT reduced basal PD-L1 mRNA by 35% and protein by 31% and in T-treated cells lowered mRNA by 33% and protein by 66%. In HT-29 cells, T increased PD-L1 mRNA by 62% and protein by 27%. NDAT lowered basal and T-stimulated responses in PD-L1 mRNA and protein by 35-40% (p<0.05). Activation of ERK1/2 was involved in T-induced PD-L1 accumulation. We propose that, by a nongenomic mechanism, endogenous T may clinically support activity of the defensive PD-1/PD-L1 checkpoint in tumor cells. NDAT non-immunologically suppresses basal and T-induced PD-L1 gene expression and protein accumulation in cancer cells.

A clinicopathological study of 56 pediatric patients with non-ACTH-secreting pituitary adenomas removed by a transsphenoidal neurosurgical approach was undertaken to better define the clinical presentation, to assess demographic factors, to determine the immunohistochemical staining characteristics of the tumors, and to evaluate the outcome of transsphenoidal surgical treatment and other adjuvant therapies. A separate analysis of prolactinoma patients was performed. All tumors were confirmed histologically and immunophenotyped for pituitary hormones. Forty-one patients had tumors that stained for PRL alone, eight patients had tumors that stained for PRL and GH, six patients had plurihormonal adenomas, and one patient had a tumor that stained for glycoprotein hormones. No tumors contained GH alone. Macroadenomas exceeded microadenomas (1.4:1). There were no male patients with microadenomas of any type. Females outnumbered males (3.3:1). Patients presented most frequently with headache, menstrual dysfunction (in females), galactorrhea, and hypopituitarism. All but one of the patients with hypopituitarism at presentation had macroadenomas. Tumor staining characteristics did not always correlate well with clinical status, especially with regard to GH-containing tumors. Pediatric pituitary tumors did not appear to be more invasive or more aggressive than adult pituitary tumors, contrary to some previous reports. The patients with microadenomas had a 70% operative cure rate and a 65% long term cure rate; the recurrence rate for microadenoma patients was 25%. Macroadenoma patients had a 33% operative cure rate, a 55% long term cure rate, and a recurrence rate of 33%. Thus, microadenoma and macroadenoma patients had similar long term cure rates, but macroadenoma patients required more aggressive adjuvant therapy (second surgery, radiation, or bromocriptine) and had higher rates of hypopituitarism (52% of macroadenoma patients vs. 0% of microadenoma patients required long term hormone replacement).

Sporadic single case reports linking glucocorticoidlike activity to megestrol acetate have been reported in the literature. These findings have important implications for patient care. Adverse drug experience reports to the US Food and Drug Administration from 1984 through 1996 and a MEDLINE search of the literature from 1984 through 1996 provided the case reports. Five cases of Cushing syndrome, 12 cases of new-onset diabetes, and 16 cases of adrenal insufficiency were identified in association with megestrol therapy. Twelve cases in which preexisting diabetes was exacerbated and 17 cases of possible adrenal insufficiency were identified. Therapy with megestrol can result in clinical manifestations of glucocorticoidlike activity, including Cushing syndrome, diabetes, and adrenal insufficiency. Clinicians need to be aware of this association as these complications can be life-threatening if not recognized.