Recurrence in acromegaly: two tertiary centers experience and review of the literature.

BACKGROUND: Recurrence of acromegaly after successful surgery is a rare event, but no clear data are reported in the literature about its recurrence rates. This study aimed to evaluate the recurrence rate in a series of acromegalic patients treated by transsphenoidal surgery (TSS) with a long follow-up. METHODS: We retrospectively analyzed data from 283 acromegalic patients who underwent TSS at two pituitary units in Milan (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and IRCCS Humanitas Research Hospital). The diagnosis and recurrence of acromegaly were defined by both elevated IGF-1 levels and a lack of GH suppression based on appropriate criteria for the assay used at the time of diagnosis. RESULTS: After surgery, 143 patients (50%) were defined as not cured, 132 (47%) as cured and 8 (3%) as partially cured because of normalization of only one parameter, either IGF1 or GH. In the cured group, at the last follow-up (median time 86.8 months after surgery), only 1 patient (0.7%) showed full recurrence (IGF-1 + 5.61 SDS, GH nadir 1.27 µg/l), while 4 patients (3%) showed only increased IGF1. In the partially cured group at the last follow-up, 2/8 (25%) patients showed active acromegaly (IGF-1 SDS + 2.75 and + 3.62; GH nadir 0.6 and 0.5 µg/l, respectively). CONCLUSIONS: In the literature, recurrence rates range widely, from 0 to 18%. In our series, recurrence occurred in 3.7% of patients, and in fewer than 1%, recurrence occurred with elevation of both IGF-1 and the GH nadir. More frequently (25%), recurrence came in the form of incomplete normalization of either IGF-1 or GH after surgery.

Growth patterns and outcomes of growth hormone therapy in patients with acrodysostosis.

INTRODUCTION: Severe short stature is a feature of acrodysostosis, but data on growth are sparse. Treatment with recombinant human growth hormone (rhGH) is used in some centers to increase final height, but no studies have been published so far. Our objective was to conduct a multicenter, retrospective, cohort study to investigate growth in individuals with both types of acrodysostosis, treated with rhGH or not; we used the new nomenclature to describe acrodysostosis, as this disease belongs to the large group of inactivating PTH/PTHrP signaling disorders (iPPSD); acrodysostosis refers to iPPSD4 (acrodysostosis type 1 due to PRKAR1A mutations) and iPPSD5 (acrodysostosis type 2, due to PDE4D mutations). METHODS: We present auxological data from individuals with genetically characterized iPPSD4, and participants with clinical features of iPPSD5. RESULTS: We included 20 and 17 individuals with iPPSD4 and iPPSD5, respectively. The rhGH-treated iPPSD4 patients (n = 9) were smaller at birth than those who did not receive rhGH (median - 2.2 SDS vs. - 1.7 SDS); they showed a trend to catch-up growth during rhGH therapy (median 0.5 SDS in the first year). The rhGH-treated patients (n = 5) reached a better final height compared to those who did not receive rhGH (n = 4) (median - 2.8 SDS vs. - 3.9 SDS), suggesting that rhGH is efficient to increase height in those patients. The difference in target height to final height ranged between 1.6 and 3.0 SDS for iPPSD4 not treated with rhGH (n = 4), 2.1-2.8 SDS for rhGH-treated iPPSD4 (n = 5), 0.6-5.5 SDS for iPPSD5 not treated with rhGH (n = 5) and 2.5-3.1 for rhGH-treated iPPSD5 (n = 2). CONCLUSION: Final height may be positively influenced by rhGH in patients with acrodysostosis/iPPSD. Our rhGH-treated cohort started therapy relatively late, which might explain, at least in part, the limited effect of rhGH on height.

Gamma knife radiosurgery in patients with Nelson's syndrome.

PURPOSE: Nelson's syndrome (NS) is a long-term complication of bilateral adrenalectomy in patients with Cushing's disease. The best therapeutic strategy in NS has not been well defined. Gamma knife radiosurgery (GKRS) is very effective to stop the growth of the pituitary adenoma, which is the main goal of the treatment of patients with NS. We report the largest series of patients with NS treated by GKRS at a single center. METHODS: The study was an observational, retrospective analysis of 28 consecutive patients with NS treated by GKRS in our department between 1995 and 2019. All patients had a growing ACTH-secreting pituitary adenoma. The main outcome of the study was to assess by the Kaplan-Meier method the risk of tumor progression after GKRS. RESULTS: The median follow-up after GKRS treatment was 98 months (IQR 61-155 months, range 7-250 months). Two patients (7.1%) had a recurrence of disease during follow-up. The 10-year progression-free survival was 91.7% (95% CI 80.5-100%). No patient had deterioration of visual function or oculomotor function after GKRS. New onset of hypogonadism and hypothyroidism occurred in 18.8% and 14.3% of the patients at risk. CONCLUSION: Our study confirms that GKRS may stop the tumor growth in the majority of patients with NS, even though very aggressive adenomas may ultimately escape this treatment. Safety of GKRS was good in our experience, but due attention must be paid to planning the distribution of radiation to critical structures, especially in patients previously treated by radiation.

Amifostine inhibits hematopoietic progenitor cell apoptosis by activating NF-kappaB/Rel transcription factors.

We investigated the involvement of NF-kappaB/Rel transcription factors that reportedly can inhibit apoptosis in various cell types in the antiapoptotic mechanism of the cytoprotectant amifostine. In the nontumorigenic murine myeloid progenitor 32D cells incubated with amifostine, we detected a reduction of the IkappaBalpha cytoplasmic levels by Western blotting and a raising of nuclear NF-kappaB/Rel complexes by electrophoretic mobility shift assay. Amifostine inhibited by more than 30% the growth factor deprivation-induced apoptosis, whereas its effect failed when we blocked the NF-kappaB/Rel activity with an NF-kappaB/Rel-binding phosphorothioate decoy oligodeoxynucleotide. In human cord blood CD34(+) cells, the NF-kappaB/Rel p65 subunit was detectable (using immunofluorescence analysis) mainly in the cytoplasm in the absence of amifostine, whereas its presence was appreciable in the nuclei of cells incubated with the cytoprotectant. In 4 CD34(+) samples incubated for 3 days in cytokine-deficient conditions, cell apoptosis was reduced by more than 30% in the presence of amifostine (or amifostine plus a control oligo); the effect of amifostine was abolished in cultures with the decoy oligo. These findings indicate that the inhibition of hematopoietic progenitor cell apoptosis by amifostine requires the induction of NF-kappaB/Rel factors and that the latter can therefore exert an antiapoptotic activity in the hematopoietic progenitor cell compartment. Furthermore, the identification of this specific mechanism underlying the survival-promoting activity of amifostine lends support to the possible use of this agent in apoptosis-related pathologies, such as myelodysplasias.

Differential regulation of the expression of interleukin-2 receptor gamma-chain during the in vitro differentiation of human myeloid cells.

The common gamma-chain (gamma c) is a shared component of cell-surface receptors for the interleukins- 2, -4 and -7, and possibly others. We studied its expression in cells and cell lines of myeloid origin and found ubiquitous presence of gamma c mRNA in all cells examined. Differential regulation of gamma c expression was observed in myeloid cell lines induced to differentiate in vitro. In K-562 erythromyeloid cells, a sharp rise in the levels of gamma c mRNA and protein accompanied megakaryocytic, but not erythroid, differentiation. Surface binding of interleukin-2, as well as the transcripts for cognate receptor chains, were scarcely detectable in K-562 cells, whereas a significant increase in the binding of granulocyte-macrophage colony-stimulating factor specifically occurred during their megakaryocytic maturation. Our data indicate that expression of gamma c is a common feature of human myeloid cells, and suggest that its expression may be a requirement for human myelopoiesis.

Desogestrel versus gestodene in oral contraceptives: influence on the clinical and histomorphological features of benign breast disease.

Forty-four female volunteers asking for oral contraception, affected by symptomatic benign breast disease (BBD) were evaluated to compare the effects on mastalgia and breast nodularity of two different low dose oral contraceptives (OCs), containing 20 micrograms [corrected] ethinylestradiol + 150 micrograms desogestrel (EE+D) and 30 micrograms ethinylestradiol + 75 micrograms gestodene (EE+G), respectively. Physical examination, bilateral thermography, X-ray and/or ultrasonography of breast, and needle and screw-needle biopsies of mammary tissue were performed in all patients before OCs administration and after six cycles of treatment. OCs administration caused an overall improvement of mastalgia in 53%. Breast nodularity improved only in 8% of patients in both groups. Epithelial tissue modifications in mammary biopsies were observed, with involutive and/or secretory histomorphological and ultrastructural changes, frequently coexisting in different areas of the same breast.

PIP: In Italy, researchers compared data on 22 women who used the low-dose oral contraceptive (OC) containing 20 mcg ethinyl estradiol and 150 mcg desogestrel (EE+D) with data on 22 other women who used the low-dose OC containing 30 mcg ethinyl estradiol and 75 mcg gestodene (EE+G) to determine the pharmacological effects of the 2 OCs on women affected by mastalgia and breast nodularity. Clinicians performed physical exams, bilateral thermography, X-ray and/or ultrasonography of breast and needle and screw-needle biopsies of mammary tissue before OC administration and after 6 cycles of OC treatment. An overall improvement of mastalgia and breast nodularity occurred in 53% and 8% of all patients, respectively. There were no significant differences between groups. Among EE+D treated women, a marked secretory attitude in breast epithelial cells occurred, probably due to a prominent progestin effect. Both OCs increased the number of cytoplasmatic organules and intraluminal secretory material without any apparent increase of cell proliferation. The observed involutive and/or secretory histomorphological and ultrastructural changes often occurred in different areas of the same breast. These results suggest that low dose OC use by women affected by benign breast disease improves mastalgia but not breast nodularity.

Polyamines and nucleic acids in gestational trophoblastic tumors.

To test the relationship between tumor malignancy and content and distribution of polyamines and nucleic acids, 2 forms of human gestational trophoblastic tumors were examined: the hydatidiform mole (self-limited form) and the human chorio-carcinoma (invasive form) xenografted into nude mice. The results indicate that there are 2 significant differences between the choriocarcinoma and the mole: 1) the choriocarcinoma is characterized by increased polyamine and nucleic acid levels, 2) tissues differ in their putrescine:spermidine and spermidine:spermine ratios. There is an increase in polyamines in the urine of mole-bearing patients over that of normal controls. The correlation between putrescine and spermidine with the chorionic gonadotropin indicates that these 2 polyamines reflect the biological activity of the mole.