Medical treatment of acromegaly - When the tumor size matters: A narrative review.

Medical treatment of acromegaly is generally positioned as a second line of treatment after pituitary adenoma surgery. With the rising availability and variety of medications for acromegaly increases our understanding of their effectiveness and safety. Volume of the published data on the impact of medical therapy on biochemical control of acromegaly, contrasts a relative lack of publications which comprehensively address pituitary tumor alterations under different drug modalities. Assessment of changes in GH-secreting adenoma volume is often overshadowed by clinicians' focus on GH and IGF-I levels during acromegaly treatment. Close analysis of studies published in the last two decades, reveals that both an increase and decrease in somatotropinoma volume are possible during treatment with any of available drugs for acromegaly. Changes in pituitary tumor size may arise from the biological nature of adenoma itself, independently of the administered medications. Therefore, an individual approach is necessary in the treatment of patients with acromegaly, based on repeated insight to their clinical, biochemical, pathological and imaging characteristics. In this review, we summarize and comment how pituitary tumor size is affected by the treatment with all currently available drugs in acromegaly: long-acting somatostatin receptor ligands of the first generation (octreotide LAR and lanreotide autogel) and the second generation (pasireotide-LAR), as well as pegvisomant (PEG) and cabergoline (CAB).

Secondary vs. primary pituitary xanthogranulomas: which yellow is more mellow?

Pituitary xanthogranulomatomas (XG) are a rare pathological entity caused by accumulation of lipid laden macrophages and reactive granuloma formation usually triggered by cystic fluid leakage or hemorrhage. Our aim was to compare clinical characteristics and presenting features of patients with secondary etiology of XG and those with no identifiable founding lesion (primary -"pure" XG) in order to gain new insights into this rare pituitary pathology. In a retrospective review of 714 patients operated for sellar masses, at tertiary center, we identified 16 (2.24%) with histologically confirmed diagnosis of pituitary XG over the period of 7 years (2015-2021). Patients were further analyzed according to XG etiology: "pure"- XG (n = 8) with no identifiable founding lesion were compared to those with histological elements of pituitary tumor or cyst - secondary XG (n = 8). We identified 16 patients (11 male), mean age 44.8 ± 22.3 years, diagnosed with pituitary XG. Secondary forms were associated with Ratke's cleft cyst (RCC, n = 2) and pituitary adenoma (PA, n = 6). The most common presenting features in both groups were hypopituitarism (75%), headache (68.5%) and visual disturbances (37.5%). Predominance of male sex was noted (males 68.75%, females 31.25%), especially in patients with primary forms. Patients with primary pituitary XG were all males (p = 0.0256) and more frequently affected by panhypopituitarism (87.5% vs. 25%, p = 0.0406) compared to patients with secondary causes. Hyperprolactinemia was noted in pituitary tumor group with secondary etiology only (p = 0.0769). Majority of lesions were solid on magnetic resonance imaging - MRI (81.25%). Distinct clinical phenotype was observed dependent on the etiology of XG.

Plurihormonal Pituitary Neuroendocrine Tumours - A Single Centre Experience.

Introduction. Plurihormonal pituitary neuroendocrine tumours (PitNET)/adenomas are pituitary neuroendocrine tumours composed of monomorphous cell populations expressing anterior pituitary transcription factors and/or hormones belonging to more than one cell lineage. Studies dedicated to plurihormonal tumours are rare and quite heterogenous with their results, bearing in mind changes in diagnostic criteria and inconsistent use of antibodies for anterior pituitary transcription factors in the diagnostic immunohistochemical panel. Material and Methods. We retrospectively analysed all patients surgically treated for PitNETs from 2016 to July 2022 in a tertiary healthcare institution. All tumours previously diagnosed PitNETs with the word "plurihormonal" were re-examined and potentially re-classified, according to 2022 WHO classification of endocrine tumours. Results. Among 721 patients surgically treated for PitNET in 5.5 years period, the diagnosis of plurihormonal PitNET was established in 11 tumours (1.3%). All tumours showed diffuse and intensive positivity for anterior pituitary transcription factors PIT1 and SF1. Clinically, all patients presented with acromegaly. Conclusions. Retrospective studies related to newly defined plurihormonal PitNETs with a reassessment of diagnoses are necessary due to their rarity and ambition to investigate their origin and biological behaviour. The fact that the majority of plurihormonal PitNETs are clinically presented with acromegaly and show simultaneous positivity to PIT1 and SF1 transcription factors deserve special attention and need for further research in larger cohorts of these exceptional tumours.

Influence of stathmin 1 (STMN1) expression on neoangiogenesis in colorectal adenocarcinoma.

Stathmin1 is a microtubular regulatory protein. The expression disorders of this protein result in significant changes in cell migration, invasion, adhesion and colony formation in many malignant tumors. The aim of our research was to investigate the effects of Stathmin1 expression on neoangiogenesis in colorectal adenocarcinoma. Biopsy material that was obtained by the resection of colorectal carcinoma was used. The experimental group consisted of operative biopsies of colorectal cancer (n = 72), and the control group (n = 72) consisted of biopsies of adjacent non-tumor colon tissue. The biopsy material was taken from an operative preparation submitted to the Department of Pathology. After histopathological treatment, classical Hematoxylin- Eosin and immunohistochemical ABC methods with anti-Stathmin1, anti-VEGF and anti CD105 antibodies were applied on 4 µm thick sections. High expression of Stathmin1 is associated with severe (91.9%) and moderate (8.1%) expression of VEGF in a significantly high number of cases. This relation is defined by a highly significant correlation coefficient (r = 0.768; p = 0.000). High expression of Stathmin1 is associated with a high microvascular density index (mvdIDX) in a significant number of cases (73.0%) while low expression of Stathmin1 is in relation with low mvdIDX in a significant 73.7% of cases. This relationship is also defined by a highly significant correlation coefficient (r = 0.566; p = 0.000). ROC analysis showed that the sensitivity for Stathmin1 was 97.4% and the specificity was 91.4%. Based on Stathmin1 expression, it is possible to differentiate patients with increased risk for metastatic disease. The highly significant association of Stathmin1 expression with VEGF expression and microvascular density (MVD) suggests that Stathmin1 may be a serious candidate for therapeutic target.

Isolated Spleen Metastases of Endometrial Cancer: A Case Report.

BACKGROUND: Isolated splenic metastases from endometrial cancer, which is a relatively common malignancy, are extremely rare findings; to date, only 14 cases have been reported in the literature. CASE SUMMARY: We report a patient with isolated splenic metastases of endometrial cancer 3 years after radical surgery of the primary tumor. The patient was successfully treated by splenectomy and six cycles of paclitaxel. Fifty months after splenectomy, she was alive and well, and with no evidence of disease. CONCLUSION: Isolated spleen metastasis of endometrial cancer is very rare. Radical surgery and adjuvant therapy may offer excellent long-term survival.

The sellar region as presenting theater for hematologic malignancies-A 17-year single-center experience.

Hematological neoplastic mass lesions of the sellar region are rare. We identified five cases of hematological malignancy with first presentation in the sellar region from our departmental database of 1,405 patients (0.36%) with sellar lesions diagnosed over the 17-year period (2005-2021). All patients were females (mean age 55.2 ± 3.4 years). One patient had multiple myeloma (MM), one patient had acute myeloid leukemia (AML), while three other patients had lymphoma (intravascular lymphoma (IVL, n = 1) or non-Hodgkin's lymphoma (NHL, n = 2). Most patients presented with ophthalmoplegia, and one patient with diabetes insipidus (DI), with short duration of symptoms (median 30 days). All patients had an elevated erythrocyte sedimentation rate and altered blood count, while patients with lymphoma had elevated lactate dehydrogenase (LDH). Sellar mass was demonstrated in three patients while the patient with IVL had an empty sella and in the AML patient posterior lobe T1W hyperintensity was lost. Two patients (IVL and NHL) presented with multiple anterior pituitary deficiencies and one patient (AML) had DI. All patients were treated with chemotherapy. Two patients responded well to treatment (one had reversed hypopituitarism), while three patients died. Differential diagnosis of sellar-parasellar pathology should include suspicion of hematological malignancy, particularly in patients with short duration of nonspecific symptoms, neurological signs (ophthalmoplegia), blood count alterations and LDH elevation, pituitary dysfunction and imaging features atypical for pituitary adenoma. Early diagnosis is crucial for timely initiation of hematological treatment aimed at inducing disease remission and partial or full recovery of pituitary function.

Pituitary tumors and the risk of other malignancies: is the relationship coincidental or causal?

Pituitary adenomas are benign neoplasms of the pituitary. The most prevalent are prolactinomas and non-functioning pituitary adenomas, followed by growth hormone- and ACTH-secreting adenomas. Most pituitary adenomas seem to be sporadic and their persistent growth is very atypical. No molecular markers predict their behavior. The occurrence of pituitary adenomas and malignancies in the same patient can be either pure coincidence or caused by shared underlying genetic susceptibility involved in tumorigenesis. Detailed family history on cancers/tumors in the first, second and third generation of family members on each side of the family has been reported in a few studies. They found an association of pituitary tumors with positive family history for breast, lung and colorectal cancer. We have reported that in about 50% of patients with pituitary adenomas, an association with positive family history for cancer has been found independent of secretory phenotype (acromegaly, prolactinoma, Cushing's disease or non-functioning pituitary adenomas). We also found earlier onset of pituitary tumors (younger age at diagnosis of pituitary tumors) in patients with a strong family history of cancer. In our recent unpublished series of 1300 patients with pituitary adenomas, 6.8% of patients were diagnosed with malignancy. The latency period between the diagnosis of pituitary adenoma and cancer was variable, and in 33% of patients, it was longer than 5 years. Besides the inherited trophic mechanisms (shared underlying genetic variants), the potential influence of shared complex epigenetic influences (environmental and behavioral factors - obesity, smoking, alcohol intake and insulin resistance) is discussed. Further studies are needed to better understand if patients with pituitary adenomas are at increased risk for cancer.

Mapping the journey of transition: a single-center study of 170 childhood-onset GH deficiency patients.

OBJECTIVE: To analyze metabolic parameters, body composition (BC), and bone mineral density (BMD) in childhood-onset GH deficiency (COGHD) patients during the transition period (TP). DESIGN: Single- center, retrospective study was performed on 170 consecutive COGHD patients (age 19.2 ± 2.0 years, range 16-25) transferred after growth completion from two pediatric clinics to the adult endocrine unit. Two separate analyses were performed: (i) cross-sectional analysis of hormonal status, metabolic parameters, BC, and BMD at first evaluation after transfer from pediatrics to the adult department; (ii) longitudinal analysis of BC and BMD dynamics after 3 years of GH replacement therapy (rhGH) in TP. RESULTS: COGHD was of a congenital cause (CONG) in 50.6% subjects, tumor-related (TUMC) in 23.5%, and idiopathic (IDOP) in 25.9%. TUMC patients had increased insulin and lipids levels (P < 0.01) and lower Z score at L-spine (P < 0.05) compared to CONG and IDOP groups. Patients treated with rhGH in childhood demonstrated lower fat mass and increased BMD compared to the rhGH-untreated group (P < 0.01). Three years of rhGH after growth completion resulted in a significant increase in lean body mass (12.1%) and BMD at L-spine (6.9%), parallel with a decrease in FM (5.2%). CONCLUSION: The effect of rhGH in childhood is invaluable for metabolic status, BC, and BMD in transition to adulthood. Tumor-related COGHD subjects are at higher risk for metabolic abnormalities, alteration of body composition, and decreased BMD, compared to those with COGHD of other causes. Continuation of rhGH in transition is important for improving BC and BMD in patients with persistent COGHD.

Expression of kisspeptin and KISS1 receptor in pituitary neuroendocrine tumours - an immunohistochemical study.

INTRODUCTION: Pituitary neuroendocrine tumours (PitNETs), traditionally designated as pituitary adenomas, show elatively frequent invasive growth with exceptional metastatic potential, the causes of which are not entirely elucidated. Kisspeptins, which perform their activity through KISS1 receptor (KISS1R), are recognised as metastatic suppressors in many malignant tumours. This study aimed to investigate the immunohistochemical expression of kisspeptin and KISS1R in different types of PitNETs and to compare it with the expression in the normal anterior pituitary, using tissue microarray. MATERIAL AND METHODS: The experimental group consisted of 101 patients with PitNETs, with 45 (37.3%) being of gonadotroph, 40 (33.9%) somatotroph, 4 (3.4%) corticotroph, 4 (3.4%) thyrotroph, 3 (2.5%) lactotroph, and 6 (5.1%) null-cell type. The control group consisted of anterior pituitary tissue accidentally removed during the surgery for PitNETs in 17 patients. RESULTS: Kisspeptin expression was observed in both experimental and control groups, without statistically significant differences in the staining intensity. Negative kisspeptin staining was detected in 10 (9.9%), weak in 79 (78.2%), and moderate in 12 tumours (11.9%); none of the tumours had strong staining intensity. The weak staining intensity was predominant in all PitNET types except thyrotroph tumours. Significant statistical difference in terms of kisspeptin expression between types of PitNET and the control group was not observed. Immunohistochemical expression of KISS1R was not observed in the control group or in the experimental group. CONCLUSIONS: We conclude that immunohistochemistry, as a method, cannot confirm the involvement of kisspeptin in tumourigenesis and aggressiveness of PitNETs, but potentially supports its antimetastatic role. The absence of KISS1R immunohistochemical expression in all anterior pituitaries and PitNETs in our cohort needs verification through the use of different procedures designed for the detection of the presence and localisation of proteins in the cell.

Xanthine Oxidase/Dehydrogenase Activity as a Source of Oxidative Stress in Prostate Cancer Tissue.

Prostate cancer (PC) is one of the most frequent malignancies. Better biomarkers are constantly wanted, such as those which can help with the prediction of cancer behavior. What is also needed is a marker which may serve as a possible therapeutic target. Oxidative stress (OS), which is a hallmark of cancer, is included in the pathogenesis and progression of PC. We have conducted the present study to determine whether xanthine oxidase/dehydrogenase activity is the source of OS in prostate tissue. We have also determined the concentration of TBA-reactive substances (TBARS) and advanced oxidation protein products (AOPP), as well as the activity of catalase. Xanthine oxidase (XO) activity is significantly higher (p < 0.001) in tumor tissue when compared to the control healthy tissue. The concentration of TBARS (p < 0.001) and AOPP (p < 0.05) are also higher in tumor tissue. Catalase has raised its activity (p < 0.05) versus the control. There is also a strong correlation between XO activity and prostate-specific antigen (PSA) levels in the serum. These results indicate a significant role of XO activity in OS in prostate carcinogenesis, and it could be a possible theranostic biomarker, which can be important for a better understanding of the disease, its evolution, and prognosis. A promising treatment may be using XO inhibitors such as allopurinol as adjuvant therapy.

Molecular mechanisms of liver damage during neoadjuvant treatment for hepatic metastases of colorectal cancer.

BACKGROUND: The main drawbacks of neoadjuvant chemotherapy of colorectal liver cancer metastases are related to the toxic liver damage. To determine the degree of biochemical and morphologic liver damage after therapeutic protocol treatment with "bevacizumab plus FOLFOX IV", as well as the correlation between the sex, age, the existence of metabolic syndrome, the length of neoadjuvant therapy treatment and the degree of liver damage. METHODS: The study includes the total of 60 colorectal cancer metastases operated patients, divided into two groups of 30 patients: the group of patients who were treated with "bevacizumab plus FOLFOX IV" protocol as a neoadjuvant therapy - prior to liver metastases surgery and the control group, patients with the liver resection done without previous neoadjuvant chemotherapy. The following parameters were examined: biochemical liver function parameters, the presence of metabolic syndrome, pathohistological assessment of the degree of steatosis and SOS syndrome. RESULTS: The increase in AF was observed in the experimental group (Z = 2.566, p = 0.010), Dbilirubin (Z = 1.970, p = 0.037), LDH (Z = 2.951, p = 0.003) and decrease in albumin values (t = 5.100, p <0.001). The pathohistological examination in only 3.3% showed moderate liver steatosis, while SOS syndrome was recorded in as many as two-thirds (66.66%) of patients in the study group. In 14 patients (46.7%) a mild degree was registered, and in 6 (20.0%) moderate levels of this type of liver damage. Pole (p = 0.13), age (p = 0.09) and length of administration of chemotherapy (p = 0.35), as well as the presence of metabolic syndrome (χ2 = 0.390, p = 0.830), did not have any statistically significant effect on the liver damage degree. CONCLUSION: In our study, after the administration of the "bevacizumab plus FOLFOX IV" protocol, a statistically significant increase in AF, Dbilirubin and LDH, as well as a decrease in albumin values, were found. Dominant liver damage was by type of SOS syndrome (66.7%), while steatosis of the liver was recorded in only 3.3% of patients. Gender, age, the presence of metabolic syndrome and the number of chemotherapy cycles did not have any statistic significance on the biochemical parameters and morphological degree of liver damage. KEY WORDS: Colorectal cancer metastases, Liver surgery, Oncology, Neoadjuvant chemotherapy, Liver damage.

Hypopituitarism in five PROP1 mutation siblings: long-lasting natural course and the effects of growth hormone replacement introduction in middle adulthood.

Twenty years after the first description of combined hypopituitarism (CPHD) caused by PROP1 mutations, the phenotype of affected subjects is still challenging for clinicians. These patients suffer from pituitary hormone deficits ranging from IGHD to panhypopituitarism. ACTH deficiency usually develops later in life. Pituitary size is variable. PROP1 mutation is the most frequent in familial congenital hypopituitarism (CH). Reports on initiation of hormonal replacement including growth hormone (GH) in adults with CH are scarce. We identified 5 adult siblings with CPHD due to PROP1 mutation (301-302delAG), aged 36-51 years (4 females), never treated for hormone deficiencies. They presented with short stature (SD from - 3.7 to - 4.7), infantile sexual characteristic, moderate abdominal obesity and low bone mineral density in 3 of them. Complete hypopituituitarism was confirmed in three siblings, while two remaining demonstrated GH, TSH, FSH and LH deficiencies. Required hormonal replacement including rhGH was initiated in all patients. After several months necessity for hydrocortisone replacement developed in all patients. After 2 years of continual replacement therapy, BMD and body composition (measured by DXA-dual X-ray absorptiometry) improved in all subjects, most prominently in two younger females and the male sibling. Besides rhGH therapy, these three patients have received sex hormones contributing to the favorable effect. The male sibling was diagnosed with brain glioblastoma two years following complete hormonal replacement. This report provides important experience regarding hormonal replacement, particularly rhGH treatment, in adults with long-term untreated CH. Beneficial effect of such therapy are widely acknowledged, yet these subjects could be susceptible to certain risks of hormonal treatment initiated in adulthood. Careful and continual clinical follow-up is thus strongly advised.

Lithium - Pharmacological and Toxicological Aspects: The Current State of the Art.

Lithium is the smallest monovalent cation with many different biological effects. Although lithium is present in the pharmacotherapy of psychiatric illnesses for decades, its precise mechanism of action is still not clarified. Today lithium represents first-line therapy for bipolar disorders (because it possesses both antimanic and antidepressant properties) and the adjunctive treatment for major depression (due to its antisuicidal effects). Beside, lithium showed some protective effects in neurological diseases including acute neural injury, chronic degenerative conditions, Alzheimer's disease as well as in treating leucopenia, hepatitis and some renal diseases. Recent evidence suggested that lithium also possesses some anticancer properties due to its inhibition of Glycogen Synthase Kinase 3 beta (GSK3ß) which is included in the regulation of a lot of important cellular processes such as: glycogen metabolism, inflammation, immunomodulation, apoptosis, tissue injury, regeneration etc. Although recent evidence suggested a potential utility of lithium in different conditions, its broader use in clinical practice still trails. The reason for this is a narrow therapeutic index of lithium, numerous toxic effects in various organ systems and some clinically relevant interactions with other drugs. Additionally, it is necessary to perform more preclinical as well as clinical studies in order to a precise therapeutic range of lithium, as well as its detailed mechanism of action. The aim of this review is to summarize the current knowledge concerning the pharmacological and toxicological effects of lithium.

Anthocyanins Protect Hepatocytes against CCl4-Induced Acute Liver Injury in Rats by Inhibiting Pro-inflammatory mediators, Polyamine Catabolism, Lipocalin-2, and Excessive Proliferation of Kupffer Cells.

: This study examined the hepatoprotective and anti-inflammatory effects of anthocyanins from Vaccinim myrtillus (bilberry) fruit extract on the acute liver failure caused by carbon tetrachloride-CCl4 (3 mL/kg, i.p.). The preventive treatment of the bilberry extract (200 mg anthocyanins/kg, orally, 7 days) prior to the exposure to the CCl4 resulted in an evident decrease in markers of liver damage (glutamate dehydrogenase, sorbitol dehydrogenase, malate dehydrogenase), and reduced pro-oxidative (conjugated dienes, lipid hydroperoxide, thiobarbituric acid reactive substances, advanced oxidation protein products, NADPH oxidase, hydrogen peroxide, oxidized glutathione), and pro-inflammatory markers (tumor necrosis factor-alpha, interleukin-6, nitrite, myeloperoxidase, inducible nitric oxide synthase, cyclooxygenase-2, CD68, lipocalin-2), and also caused a significant decrease in the dissipation of the liver antioxidative defence capacities (reduced glutathione, glutathione S-transferase, and quinone reductase) in comparison to the results detected in the animals treated with CCl4 exclusively. The administration of the anthocyanins prevented the arginine metabolism's diversion towards the citrulline, decreased the catabolism of polyamines (the activity of putrescine oxidase and spermine oxidase), and significantly reduced the excessive activation and hyperplasia of the Kupffer cells. There was also an absence of necrosis, in regard to the toxic effect of CCl4 alone. The hepatoprotective mechanisms of bilberry extract are based on the inhibition of pro-oxidative mediators, strong anti-inflammatory properties, inducing of hepatic phase II antioxidant enzymes (glutathione S-transferase, quinone reductase) and reduced glutathione, hypoplasia of Kupffer cells, and a decrease in the catabolism of polyamines.

Nanoliposome-encapsulated ellagic acid prevents cyclophosphamide-induced rat liver damage.

In this study, we aimed to evaluate whether the encapsulation of ellagic acid (EA) into nanoliposomes would improve its potential in preventing cyclophosphamide-induced liver damage. Stability and antioxidative potential of free and encapsulated EA were determined. Experimental study conducted in vivo included ten groups of rats treated with cyclophosphamide and ellagic acid in its free and encapsulated form during 5 days. The protective effect of EA in its free and encapsulated form was determined based on serum liver function, liver tissue antioxidative capacities, and oxidative tissue damage parameters. Also, tissue morphological changes following cyclophosphamide administration were studied using standard histopathological and immunohistochemical analyses. The encapsulation of EA significantly prevented its degradation and improved its antioxidant properties in in vitro conditions. In in vivo experiments in both forms of EA were found to prevent rat liver damage induced by cyclophosphamide estimated through the changes in serum liver-damage parameters and tissue antioxidant capacities, as well as based on oxidatively modified lipids and proteins. Also, changes in morphology of liver cells and the expressions of Bcl-2, HIF-1α, and CD15 molecules in livers of animals of different experimental groups are in accordance with the obtained biochemical parameters. Thus, the encapsulation process might be effective in preventing EA from different environmental influences and could significantly increase its hepatoprotective potential. The encapsulation could prevent ellagic acid degradation and might deliver this potent compound to its target tissue in significantly larger quantities than when it is administered in its free form.

Circulating aryl hydrocarbon receptor-interacting protein (AIP) is independent of GH secretion.

BACKGROUND: Aryl hydrocarbon receptor-interacting protein (AIP) is evolutionarily conserved and expressed widely throughout the organism. Loss-of-function AIP mutations predispose to young-onset pituitary adenomas. AIP co-localizes with growth hormone in normal and tumorous somatotroph secretory vesicles. AIP protein is detectable in circulation. We aimed to investigate possible AIP and GH co-secretion, by studying serum AIP and GH levels at baseline and after GH stimulation or suppression, in GH deficiency (GHD) and in acromegaly patients. SUBJECTS AND METHODS: Insulin tolerance test (ITT) was performed in GHD patients (n = 13) and age-BMI-matched normal GH axis control patients (n = 31). Oral glucose tolerance test (OGTT) was performed in active acromegaly patients (n = 26) and age-BMI-matched normal GH axis control patients (n = 18). In-house immunometric assay was developed for measuring circulating AIP. RESULTS: Serum AIP levels were in the 0.1 ng/mL range independently of gender, age or BMI. Baseline AIP did not differ between GHD and non-GHD or between acromegaly and patients with no acromegaly. There was no change in peak, trough or area under the curve during OGTT or ITT. Serum AIP did not correlate with GH during ITT or OGTT. CONCLUSIONS: Human circulating serum AIP in vivo was assessed by a novel immunometric assay. AIP levels were independent of age, sex or BMI and unaffected by hypoglycaemia or hyperglycaemia. Despite co-localization in secretory vesicles, AIP and GH did not correlate at baseline or during GH stimulation or suppression tests. A platform of reliable serum AIP measurement is established for further research of its circulatory source, role and impact.

Familial Cancer Clustering in Patients with Prolactinoma.

People are at higher risk for malignancy as they get older or have a strong family history of cancer. This study aims to collect family history of cancer in a large cohort of patients with pituitary adenomas (PA) in outpatient clinic from years 2005-2017. Overall, 46.6% of 1062 patients with PA had a family member affected with cancer. Breast cancer in family members was reported in 15.3% of patients with prolactinomas which was significantly higher than in families of patients with non-functioning pituitary adenomas (NFPA) (10.0%) or acromegaly (6.8%) (p = 0.004). Lung cancer in family members was reported in 12.1% of patients with prolactinomas, significantly higher than in families of NFPA patients (7.0%, p = 0.049). Colorectal cancer in relatives of patients with PA was reported with any type of PA. Furthermore, patients with a positive family history of malignancy were diagnosed with PA at an earlier age than patients with a negative family history (43.6 ± 15.9 vs 46.0 ± 16.4 years, p = 0.015). Female patients with prolactinoma are more commonly diagnosed before the age of 25 years. Forty-two percent of patients with PA diagnosed before the age of 25 years had a second- and third-degree relative with cancer, significantly higher than patients with PA diagnosed later in life (25.8%, p < 0.001). Breast, lung, and colon cancers in second- and third-degree relatives were reported in significantly higher proportion of patients with PA diagnosed before the age of 25 years, compared with patients with PA diagnosed later in life (breast cancer: 10.9 vs 6.1%, p = 0.033; lung cancer: 10.9 vs 5.8%, p = 0.02; colon cancer: 9.5 vs 4.0%, p = 0.004). These results suggest familial cancer clustering in patients with prolactinoma and young patients with PA (younger than 25 years at diagnosis of PA). In particular, there is a strong association between prolactinoma and family history of breast and lung cancers. Further research of possible shared genetic susceptibility of prolactinoma and breast and lung cancers is needed.

Intracerebral hemorrhage as a first sign of pheochromocytoma: case report and review of the literature.

Pheochromocytomas and sympathetic paragangliomas are rare catecholamine-secreting tumours that represent very rare causes of intracerebral haemorrhage in the young, with only a few cases reported. A 32-year-old man presented to our emergency department because of sudden onset of severe headache. He had a six-month history of paroxysmal headache, palpitations, and sweating. During examination he became somnolent and developed left-sided hemiplegia. A computed tomographic (CT) scan of the brain showed a right temporoparietal haematoma. He was admitted to the Clinic for Neurosurgery and the haematoma was evacuated. The patient was comatose, on assisted respiration, with frequent hypertensive crises. An examination for possible secondary causes of hypertension was undertaken. Plasma metanephrine value was elevated (414 pg/mL, reference values < 90 pg/mL). Abdominal CT scans revealed a large mass (6 cm) in the right adrenal gland. After adequate control of the hypertension was achieved with nonselectivealpha- and beta-adrenergic blockers the tumour was excised. The histopathologic findings confirmed the diagnosis of pheochromocytoma. The genetic analysis demonstrated a duplication in exon 1 of the VHL gene. We reported a rare, potentially fatal complication of pheochromocytoma - an intracerebral haemorrhage. This case and review of similar rare cases in the literature illustrate the importance of early recognition of the characteristic symptoms of catecholamine excess in young patients with hypertension.

Clinical case seminar: Familial intracranial germinoma.

BACKGROUND: Intracranial germinomas (ICG) are uncommon brain neoplasms with extremely rare familial occurance. Since ICG invades hypothalamus and/or pituitary, the endocrine dysfunction is one of the common determinants of these tumors. We presented two brothers with the history of ICG. Patient 1 is a 25-year-old male who had been suffering from the weakness of the right half of his body at the age of 18. Cranial MRI revealed mass lesion in the left thalamus. He underwent neurosurgery, tumor was removed completely. Histopathological (HP) and immunohistochemical analyses verified the diagnosis of pure germinoma. He experienced complete remission of the tumor after a radiation therapy. At the age of 22 the diagnosis of isolated growth hormone deficiency (IGHD) was established and GH replacement was initiated. Patient 2 is a 20-year old boy who was presented with diabetes insipidus at the age of 12. MRI detected tumor in the third ventricle and pineal region. After the endoscopic tumor biopsy the HP diagnosis was pure germinoma. He received chemotherapy followed by radiotherapy, and treated with GH during childhood. At the age of 18 GH replacement was reintroduced. A six month follow-up during the next two years in both brothers demonstrated the IGF1 normalization with no MRI signs of tumor recurrence. CONCLUSION: To the best of our knowledge so far, only six reports have been published related to familial ICG. The presented two brothers are the first report of familial ICG case outside of Japan. They are treated successfully with GH therapy in adult period. < /p > < p >.

Single center study of 53 consecutive patients with pituitary stalk lesions.

BACKGROUND: The etiological spectrum of pituitary stalk lesions (PSL) is wide and yet specific compared to the other diseases of the sellar and suprasellar region. Because of the pituitary stalk's (PS) critical location and role, biopsies of these lesions are rarely performed, and their underlying pathology is often a conundrum for clinicians. A pituitary MRI in association with a clinical context can facilitate their diagnosis. AIM: To present the various causes of PSL-their clinical, hormonal, histopathological, and MRI characteristics in order to gain better insight into this pathology. METHOD: A retrospective observational study consisting of 53 consecutive patients with PSL of the mean age 32 ± 4.2 years (range 6-67), conducted at the Department for Neuroendocrinology, Clinical Center of Serbia 2010-2018. RESULTS: Congenital malformations were the most common cause of PSL in 25 of 53 patients (47.1%), followed by inflammatory (9/53; 16.9%) and neoplastic lesions (9/53; 16.9%). The exact cause of PSL was established in 31 (58.4%) patients, of whom 23 were with congenital PS abnormalities and 8 with histopathology of PSL (7 neoplastic and 1 Langerhans Cell Hystiocytosis). A probable diagnosis of PSL was stated in 12 patients (22.6%): 6 with lymphocytic panhypophysitis, while Rathke cleft cyst, tuberculosis, dissemination of malignancy in PS were each diagnosed in 2 patients. In 10 patients (18.8%), the etiology of PSL remained unknown. CONCLUSION: Due to the inability of establishing an exact diagnosis, the management and prognosis of PSL are difficult in many patients. By presenting a wide array of causes implicated in this condition, we believe that our study can aid clinicians in the challenging cases of this pathology.