Peptide receptor radionuclide therapy for aggressive pituitary tumors: a monocentric experience

In aggressive pituitary tumors (PT) showing local invasion or growth/recurrence despite multimodal conventional treatment, temozolomide (TMZ) is considered a further therapeutic option, while little data are available on peptide receptor radionuclide therapy (PRRT). We analyzed PRRT effectiveness, safety and long-term outcome in three patients with aggressive PT, also reviewing the current literature. Patient #1 (F, giant prolactinoma) received five cycles (total dose 37 GBq) of 111In-DTPA-octreotide over 23 months, after unsuccessful surgery and long-term dopamine-agonist treatment. Patient #2 (M, giant prolactinoma) underwent two cycles (12.6 GBq) of 177Lu-DOTATOC after multiple surgeries, radiosurgery and TMZ. In patient #3 (F, non-functioning PT), five cycles (29.8 GBq) of 177Lu-DOTATOC followed five surgeries, radiotherapy and TMZ. Eleven more cases of PRRT-treated aggressive PT emerged from literature. Patient #1 showed tumor shrinkage and visual/neurological amelioration over 8-year follow-up, while the other PTs continued to grow causing blindness and neuro-cognitive disorders (patient #2) or monolateral amaurosis (patient #3). No adverse effects were reported. Including the patients from literature, 4/13 presented tumor shrinkage and clinical/biochemical improvement after PRRT. Response did not correlate with patients’ gender or age, neither with used radionuclide/peptide, but PRRT failure was significantly associated with previous TMZ treatment. Overall, adverse effects occurred only in two patients. PRRT was successful in 1/3 of patients with aggressive PT, and in 4/5 of those not previously treated with TMZ, representing a safe option after unsuccessful multimodal treatment. However, at present, considering the few data, PRRT should be considered only in an experimental setting

Tamoxifen in treatment of hepatocellular carcinoma: a randomised controlled trial

Background Results from small randomised trials on tamoxifen in the treatment of hepatocellular carcinoma (HCC) are conflicting, We studied whether the addition of tamoxifen to best supportive care prolongs survival of patients with HCC. Methods Patients with any stage of HCC were eligible, irrespective of locoregional treatment. Randomisation was centralised, with a minimisation procedure accounting for centre, evidence of disease, and time from diagnosis. Patients were randomly allocated best supportive care alone or in addition to tamoxifen, Tamoxifen was given orally, 40 mg per day, from randomisation until death. Results 496 patients from 30 institutions were randomly allocated treatment from January, 1995, to January, 1997. Information was available for 477 patients. By Sept 15, 1997, 119 (50%) of 240 and 130 (55%) of 237 patients had died in the control and tamoxifen arms, respectively. Median survival was 16 months and 15 months (p=0.54), respectively, No differences were found within subgroups defined by prognostic variables. Relative hazard of death for patients receiving tamoxifen was 1.07 (95% CI 0.83-1.39). Interpretation Our findings show that tamoxifen is not effective in prolonging survival of patients with HCC

Sequence analysis of the catalytic subunit of PKA in somatotroph adenomas.

OBJECTIVE: The pathogenetic mechanisms of sporadic somatotroph adenomas are not well understood, but derangements of the cAMP pathway have been implicated. Recent studies have identified L206R mutations in the alpha catalytic subunit of protein kinase A (PRKACA) in cortisol-producing adrenocortical adenomas and amplification of the beta catalytic subunit of protein kinase A PRKACB in acromegaly associated with Carney complex. Given that both adrenocortical adenomas and somatotroph adenomas are known to be reliant on the cAMP signalling pathway, we sought to determine the relevance of the L206R mutation in both PRKACA and PRKACB for the pathogenesis of sporadic somatotroph adenomas. DESIGN: Somatotroph adenoma specimens, both frozen and formalin-fixed, from patients who underwent surgery for their acromegaly between 1995 and 2012, were used in the study. METHODS: The DNA sequence at codon 206 of PRKACA and PRKACB was determined by PCR amplification and sequencing. The results were compared with patient characteristics, the mutational status of the GNAS complex locus and the tumour granulation pattern. RESULTS: No mutations at codon 206 of PRKACA or PRKACB were found in a total of 92 specimens, comprising both WT and mutant GNAS cases, and densely, sparsely and mixed granulation patterns. CONCLUSIONS: It is unlikely that mutation at this locus is involved in the pathogenesis of sporadic somatotroph adenoma; however, gene amplification or mutations at other loci or in other components of the cAMP signalling pathway, while unlikely, cannot be ruled out

MicroRNAs expression in pituitary tumors: differences related to functional status, pathological features, and clinical behavior

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at post-transcriptional level, having a role in many biological processes, such as control of cell proliferation, cell cycle, and cell death. Altered miRNA expression has been reported in many neoplasms, including pituitary adenomas (PAs). PURPOSE: In this study, we aimed to evaluate the expression of 20 miRNAs involved in pathways relevant to pituitary pathophysiology, in PAs and normal pituitary tissue and to correlate their expression profile with clinical and pathological features. METHODS: Pituitary tumor samples were obtained during transphenoidal surgery from patients with non-functioning (NFPA, n = 12) and functioning (n = 11, 5 GH-, 3 ACTH-, 3 PRL-omas) PAs. The expression of selected miRNAs in PAs and in normal pituitary was analyzed by RT-qPCR. miRNAs expression was correlated with demographic, clinical, and neuroradiological data and with histopathological features including pituitary hormones immunostaining, Ki-67 proliferation index, and p53 immunohistochemistry evaluation. RESULTS: All evaluated miRNAs except miR-711 were expressed in both normal and tumor pituitary tissue. Seventeen miRNAs were significantly down-regulated in pituitary tumors compared to normal pituitary. miRNAs were differentially expressed in functioning PAs or in NFPAs, as in the latter group miR-149-3p (p = 0.036), miR-130a-3p (p = 0.014), and miR-370-3p (p = 0.026) were significantly under expressed as compared to functioning tumors. Point-biserial correlation analysis demonstrated a negative correlation between miR-26b-5p and Ki-67 (p = 0.031) and between miR-30a-5p and 'atypical' morphological features (p = 0.038) or cavernous sinus invasion (p = 0.049), while 508-5p was inversely correlated with clinical aggressiveness (p = 0.043). CONCLUSIONS: In this study, we found a significant down-regulation of 17 miRNAs in PAs vs normal pituitary, with differential expression profile related to functional status and tumor aggressiveness

Germline or somatic GPR101 duplication leads to X-linked acrogigantism:a clinico-pathological and genetic study

Non-syndromic pituitary gigantism can result from AIP mutations or the recently identified Xq26.3 microduplication causing X-linked acrogigantism (XLAG). Within Xq26.3, GPR101 is believed to be the causative gene, and the c.924G > C (p.E308D) variant in this orphan G protein-coupled receptor has been suggested to play a role in the pathogenesis of acromegaly. We studied 153 patients (58 females and 95 males) with pituitary gigantism. AIP mutation-negative cases were screened for GPR101 duplication through copy number variation droplet digital PCR and high-density aCGH. The genetic, clinical and histopathological features of XLAG patients were studied in detail. 395 peripheral blood and 193 pituitary tumor DNA samples from acromegaly patients were tested for GPR101 variants. We identified 12 patients (10 females and 2 males; 7.8 %) with XLAG. In one subject, the duplicated region only contained GPR101, but not the other three genes in found to be duplicated in the previously reported patients, defining a new smallest region of overlap of duplications. While females presented with germline mutations, the two male patients harbored the mutation in a mosaic state. Nine patients had pituitary adenomas, while three had hyperplasia. The comparison of the features of XLAG, AIP-positive and GPR101&AIP-negative patients revealed significant differences in sex distribution, age at onset, height, prolactin co-secretion and histological features. The pathological features of XLAG-related adenomas were remarkably similar. These tumors had a sinusoidal and lobular architecture. Sparsely and densely granulated somatotrophs were admixed with lactotrophs; follicle-like structures and calcifications were commonly observed. Patients with sporadic of familial acromegaly did not have an increased prevalence of the c.924G > C (p.E308D) GPR101 variant compared to public databases. In conclusion, XLAG can result from germline or somatic duplication of GPR101. Duplication of GPR101 alone is sufficient for the development of XLAG, implicating it as the causative gene within the Xq26.3 region. The pathological features of XLAG-associated pituitary adenomas are typical and, together with the clinical phenotype, should prompt genetic testing. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-016-0328-1) contains supplementary material, which is available to authorized users