ACTA ENDOCRINOLOGICA (BUC)

Context. Oxytocin has been investigated as a potential medication for psychiatric disorders. Objective and design. This study prospectively investigates correlations between oxytocin and other neuropeptides plasma levels in patients with autism spectrum disorders (ASD) according to severity and treatment, as compared to controls. Subjects and methods. Thirty-one children (6 neurotypical as control) participated in this study. The patients were classified into mildly and severely-affected, according to Autism Diagnostic Observation Schedule (ADOS) scores. Oxytocin, orexin A and B, α-MSH, β-endorphins, neurotensin and substance P were investigated using a quantitative multiplex assay or a competitive-ELISA method. Results. Plasma oxytocin levels differed between the groups (F (2, 24) =6.48, p=0.006, η2=0.35, observed power=86%): patients with the mild ASD had higher values of plasma oxytocin than those with the severe form (average difference=74.56±20.74pg/mL, p=0.004). Conclusions. These results show a negative correlation between plasma levels of oxytocin and the severity of ASD and support the involvement of oxytocinergic mechanisms in ASD.

INTRODUCTION: The aim of our study was to evaluate the cure rate of macroprolactinomas treated for a long term (> 4 years) or a short term (<4 years) with dopamine agonists (DA) alone or combined with radiotherapy (RT). Sometimes pituitary\r\nsurgery was performed.\r\nMATERIAL AND METHODS: We performed a retrospective study in 111 patients with macroprolactinomas, hospitalized in the Institute of Endocrinology, Bucharest, between 1978-2005. There were two groups, according to the length of DA therapy: group\r\nA =41 patients, treated more than 4 years and group B =70 patients, treated less than 4 years. Overall, 25 patients underwent additional radiotherapy, 13 in group A and 12 in group B. 28 patients were submitted to pituitary surgery, 9 in group A and 19 in group B.\r\nRESULTS: The cure rate (i.e. normalization of prolactin=PRL level and absence or minimal residual tumor mass, stable minimum 2 years after DA withdrawal) was 5/41 (12.1%) in group A and none in group B. 48 out of 111 patients achieved significant improvement (serum prolactin level less than 20 ng/ml and tumor shrinkage more than 50%) during DA therapy, but not after DA withdrawal: 17/41patients (41.5%) in group A and in 31/70 patients (44.3%) in group B, p=NS. Radiotherapy produced an additional improvement: in serum PRL levels only in group A, in 4/13 patients- 2/8 patients responsive to DA therapy and 2/5 patients resistant to DA therapy. In group B, the 3 patients resistant to DA submitted to radiotherapy were evaluated before the interval necessary for maximal effect of radiotherapy, but in 4/9 patients responsive to DA, we noticed further reduction in tumor volume, 2/4 progressing from mild to significant tumor shrinkage and ? progressing from no shrinkage to mild shrinkage. After radiotherapy, the medium prolactin level was 5.1 ng/ml in 10 patients from both groups on low bromocriptine (BRC) dose (7.5 mg/day), significantly less than in patients without radiotherapy, i.e. than in 19 patients from group A (serum PRL 49.5 ng/ml, p=0.02) and in 29 patients from group B (serum PRL 30.3 ng/ml, p=0.01). So, the daily BRC dose could safely decrease from 30 mg/day to 7.5 mg/day in those patients previously submitted to radiotherapy. Among 23 patients resistant to initial DA treatment, only 8 patients were submitted to radiotherapy, 2 became responsive to DA thereafter and 2 others obtained a significant decrease of prolactin levels.\r\nCONCLUSIONS: The overall cure rate is quite low in prolactinomas and it was noticed only after long-term treatment with dopamine agonists; it was improved up to 12.1% by the additional high voltage radiotherapy, useful even in DA resistant cases. The addition of radiotherapy is indicated for the cure of most prolactinomas.

Primary adrenal tumors include a broad variety of lesions, from nonfunctioning incidentalomas to secreting adrenocortical adenomas including Aldosteronism, Cushing or androgen secreting lesions. Primary tumors can occur either in the cortex or the medulla of the adrenal glands, having different histopathological features and also different clinical appearances and treatment approaches. In addition, the adrenal glands can become distant metastatic sites of numerous primary malignancies. The first line of treatment in a broad variety of cases is surgery. After pathology results, in selected cases, apart the oncologic approach, radiotherapy could be an important therapeutic tool. In this paper we will discuss the role of radiotherapy in the treatment of adrenal gland lesions.

Anthracyclines are used in breast cancer both in early and advanced stages and their recommendation together with taxanes, either concurrently or sequentially, is debatable and individualized by phenotype. Circulating biomarkers have already been introduced in clinical practice for metastatic disease monitoring. We questioned whether it might be a role for these markers in neoadjuvant and adjuvant settings too and a general review was conducted. CK18 and CTC were found predictive for anthracycline related response in preoperative setting. Soluble E-cadherin is promising, a retrospective analysis showing a direct correlation with clinical response. CEA, CA 15-3 and HER2 ECD are not of interest for their predictive role.

Background. Coronary artery disease (CAD), often asymptomatic, is the most common cause of morbidity, mortality and costs in diabetes. Early detection of CAD in patients with diabetes may be of paramount importance and substantially improve the outcome in diabetic patients. Objective. The aims of the current study were to determine if there are significant differences concerning the prevalence of occult CAD in asymptomatic type 2 diabetic patients compared to asymptomatic nondiabetic patients. Design, subjects and methods. The authors retrospectively reviewed a group of 120 non-diabetic (77 men, 43 women, mean age 61±10.2 years) and 120 diabetic (81 men, 39 women, mean age 58±11.4 years) asymptomatic patients that underwent coronary computed tomography angiography (CCTA) for various reasons between January 2013 and January 2014. Results. Coronary plaques were identified in 105 diabetic patients (87.5%) and in 75 non-diabetic patients (62.5%) the prevalence being significantly different (p=0.023). Regarding plaque composition and degree of stenosis, we found a higher prevalence of calcified (p=0.016) and significantly stenotic (≥50% luminal narrowing) plaques (p=0.008) in the diabetic group. Agatston calcium score, relevant for atherosclerotic plaque load, was higher (p=0.005) in type 2 diabetic patients (350.3) compared to non-diabetic patients (158.7). Conclusion. CCTA could represent a screening method able to detect silent atherosclerotic plaques thus contributing to the prevention of acute coronary syndrome (ACS) by an early and adequate treatment of CAD. Obstructive atherosclerotic plaques can be accurately identified using CCTA, limiting the use of invasive imaging methods and selecting patients that could benefit of coronary revascularization.

Aims. To assess the impact of prognostic factors on the outcome of ovarian carcinoma (OC) and to determine the difference between pre and postmenopausal patients. Design. Retrospective cohort, single centre study Subjects and Methods. One-hundred-sixty patients with stage IC-IV OC diagnosed between 2004-2016 were included. Treatment consisted in primary surgery followed by adjuvant chemotherapy (n=127, 79.4%), neoadjuvant chemotherapy followed by surgery (n=27, 16.9%) and chemotherapy alone (3.7%). Results. At diagnosis 62 patients (38.8%) were premenopausal. Most patients presented with advanced OC (stage III/IV, 63.1%). After a median follow-up of 60 months, median progression free survival (PFS) for all stages was 36 months and median overall survival (OS) was 96 months. Postmenopausal patients had a poorer oncologic outcome compared with pre-menopausal women (PFS 24 vs. 72 months, p=0.0001, HR=2.32). Other clinical prognostic factors identified were performance status 1 vs. 0 (p=0.0001), ascites (p=0.027). Pathology prognostic factors were tumour grade (G1 vs. G2 and G3, p=0.0001) and endometrioid subtype compared to serous (p=0.008). Patients with residual disease after surgery had an increased risk of recurrence and death (HR=6.1, p=0.0001 and HR=4.2, p=0.0001). Conclusion. Premenopausal patients had a better oncologic long-term outcome and stage, ascites, grading, residual disease, were independent prognostic factors.

Gastrointestinal effects of estrogens are emerging as an important topic in colorectal cancer management. Current research demonstrated the link between inflammation and this malignancy, so important estrogen dependent mediators of the inflammatory response have been identified. Radioresistance and chemoresistance still represent an important cause of therapeutic failure in colorectal cancer and lead to further studies of colorectal carcinogenesis and predictive markers.

controversial. Aim. This study retrospectively reviews the tumor evolution in patients with NFA macroadenomas treated with surgery and conventional RT, as compared to surgery alone. Methods. Of 107 unselected patients with operated NFA (aged 19 - 77 years), evaluated between 1977 - 2008, 71 patients were follow-up without RT (group A), while 36 patients were submitted to RT (group B). Patients submitted to radiosurgery were not included. Both groups underwent serial imaging studies with computed tomography or magnetic resonance. Tumor evolution was conventionally defined as a change of minimum 25% of diameter. Results. The surgical approach was transfrontal in 47% of patients, transsphenoidal in 43% or both in 10% of patients, similar in both study groups. In group B, 30 patients underwent highvoltage RT (mean total dose 50.5 Gy) and 6 patients low-voltage RT (mean emission dose 16,775 R). Mean follow-up after surgery in group A was 3.4 years (range 6 months - 10 years) and after RT in group B it was 6.8 years (range 2 &#8211; 24 years), p < 0.001. In group A, 16 out of 71 patients had no visible tumor remnants. In this subgroup, 2 patients (12.5%) showed tumor recurrence. Fifty-five out of 71 patients had residual tumors, 21 with extrasellar extension after surgery. In this subgroup, 21 patients (38%) showed tumor re-growth and 7 (13%) showed tumor decrease. In group B (n=36) all patients had tumor remnants after surgery with extrasellar extension in 30 patients. After RT, tumor re-growth occurred in 5 out of 36 patients (14%) as compared to subgroup A with residual tumors (p< 0.05) and tumor decrease in 14 out of 34 (41%), as compared to the same subgroup A (p < 0.01). The 5 year-tumor re-growth free survival rate of 88% in irradiated patients was significantly better than in non-irradiated patients with residual tumors (31%, log-rank test, p < 0.01, Kaplan-Meier analysis), but similar to that in patients without remnants (87.5%). Age, sex, tumor parasellar extension and size of residual tumor were not predictors of recurrency. Conclusion. Postoperative radiotherapy provides a significant improvement of local control in patients with residual NFA compared to surgery alone. It is necessary a long term follow-up due to recurrency noticed up to 8 years postsurgery. In patients without tumor remnants, a wait-and-see policy is indicated after surgery.

This study evaluates the differences of radiotherapy in patients with pituitary tumors, in relation to gonadotropin immunoreactivit.\r\nDesign. It is a longitudinal, retrospective study of 117 patients submitted to pituitary surgery and high voltage radiotherapy. The excised tumors were 70 non-functioning adenomas (NFA) and 47 GH-secreting adenomas producing active acromegaly (ACM). They were evaluated before and after pituitary surgery, before radiotherapy as baseline, then at 3 different intervals at 0 - 2, 2 - 5 and > 5 years after baseline.\r\nMethods and patients. Computer tomography was used for measuring the tumor size and specific immunoassays were used for FSH, LH and nadir GH during 75 g oral glucose load. Immunohistochemistry (IHC) was performed with avidin-biotine method. High voltage conformational radiotherapy used a linear accelerator of 10 meV, with a 50 Gy on target tumor. For statistics, student&#8217; t test was used. Data before surgery (tumor volume and hormonal sexretion) were available in 70 unselected patients (31 NFA and 39 ACM from the above group). Postsurgery we defined following groups: NFA-A1 exposed to radiotherapy (n=21) and NFA-C1 unexposed to radiotherapy (n=22); ACM-A2 exposed to radiotherapy (n=20) and ACM-C2 unexposed to radiotherapy (n=10).\r\nResults. Immunohistochemistry for NFA showed 27 immunopositive for FSH or/and LH (GD+) and 40 immunonegative for FSH and LH (GD-), 3 undetermined, while for ACM were 12 GD+, 33 GD-, 2 undetermined. Immunohistochemistry data on defined groups was as follows: NFA-A1 (n=21: 12 GD+, 9 GD-) and NFA-C1 (n=22: 6 GD+, 16 GD-); ACM-A2 (n=20: 4 GD+, 16 GD-) and ACM-C2 (n=10: 3 GD+, 7 GD-). In patients with NFA presented before therapy, there are not significant differences of tumor sizes or of the levels of FSH/LH between GD+ and GD- adenomas. In ACM, before any therapy, the GD+ patients showed a significantly higher FSH levels (20.7+11.4 U/L, n=6) than GD- patients (FSH 6.6+1.6 U/L, n=22, p< 0.05) and a nonsignificant lower serum GH levels (15.1+3.5 ng/mL, n=8 versus 33.5+8.9 ng/mL, n=30 p=0.06), although the tumor size was similar between the two groups. Radiotherapy upon NFA: GD+ adenomas did not decrease their volume after radiotherapy (cranio-caudal diameter 1.63+0.79 cm, before and 1.54+0.68 cm at 2 - 5 years post-radiotherapy n=6, p= NS), in contrast with GD- tumors in which a slightly, but significant decrement in volume could be demonstrated (from 2.79+0.53 cm to 2.43+0.31 cm at 2 - 5 years, n=5, p= 0.01). Radiotherapy in ACM resulted in a decrement of serum GH level and tumor size, as compared with the control group without radiotherapy. The effect was maximal at the interval of 2-5 years. The ACM, GD- tend to respond better to radiotherapy, (i.e. GH levels decreased from 15.1+5.4 to 6.6+2.4 ng/ml at 2-5 years, p=0.05), while in patients with ACM, GD+ the GH level did not show a significant decrease (serum GH was 7.3+3.3 ng/ml before and 5.1+4 ng/mL at 2-5 years post-radiotherapy, p = NS). The CC diameter of GD- decreased from 1.1+0.3 to 0.7+0.2 at 2-5 years, p=.059, while in GD+: from 1.64+0.4 to 1.2+0.3 ng/mL at 2-5 years, p = NS.\r\nConclusion. Pituitary adenomas, both NFA and ACM that contain gonadotropin immunoreactive cells tend to be more radioresistant than those without gonadotroph cells.

Aim: We aimed to assess the final outcome of combined therapeutic approaches in patients with macroprolactinomas that were resistant to dopamine agonists (DA).\r\nPatients: Records of patients with macroprolactinoma hospitalized in the Institute of Endocrinology, Bucharest, between 1978-2005, were reviewed. There were 29 eligible patients resistant to DA therapy (8 men and 21 women), out of 119 patients with macroprolactinomas (24.4%); age at diagnosis of the resistant patients ranged between 16-59 years (31.9 ? 2.4 years), with mean prolactin (PRL) levels 2,110.2 ? 656.6 ng/mL (range 42-16,000 ng/mL). The mean maximal tumor diameter was 2.7 ? 0.2 cm (range 1-6.8 cm).\r\nMethods: Rapid fluoroimmunoassay using Europium was used for hormonal levels; computed tomography imaging and/or MRI were used to assess tumor size. Study design: The resistance to DA drugs was evaluated using initial criteria: the lack of prolactinoma response to current daily dose of Bromocriptine (BRC) 7.5 mg/day or to Cabergoline (CAB) up to 2 mg/week for at least 6 months (step 1) or final criteria: the lack of response to high BRC doses (30 mg/day) or CAB doses between 2.5-4 mg/week for at least 6 months (step 2). The lack of response was considered if PRL levels remained above the upper normal limit (20 ng/mL) and the tumor mass size decreased by less than 50%. All resistant cases at step 1 received thereafter maximal medical therapy with DA drugs, according to step 2. Thereafter, resistant macroprolactinomas after step 2 were submitted to step 3 - high voltage radiotherapy ? surgery. Serum PRL levels and tumor size were finally evaluated 110 ? 26.5 months later (range: 6-381).\r\nResults: Outcome of medical therapy with DA (n=29): Overall, 7 out of 29 resistant macroprolactinomas (24.1%) were successfully treated by increasing BRC dose (n=5) or changing BRC to CAB (n=2). But 22/119 (18.5%) patients remained resistant to DA drugs independent of dose, duration or type of drug used. 14 patients failed to normalize PRL levels despite CAB treatment in doses up to 7 mg/week. Outcome of radiotherapy alone or combined with surgery (n=15): PRL normalization was achieved in 4 patients out of the only 7 assessed at least at 18 months after radiotherapy. Withdrawal of DA therapy revealed 2 cured cases, both after radiotherapy and surgery. Outcome of surgery: Only one patient normalized PRL levels after surgery, but she soon relapsed. Apparently, only one case of acquired resistance to DA drugs was revealed. We found that 15.1% (18/119) of the patients with macroprolactinoma did not finally normalize their serum PRL even after combined therapy approaches (DA + radiotherapy ? surgery), after 79 ? 17.4 months (range 6 to 206 months) treatment total duration and 45.4 ? 19 months (range 3 to 206 months) after radical therapies, respectively.\r\nConclusion: In summary, the resistance was successfully treated in 38% cases (11 out of 29).