Pretkazatelji kliničkoga ponašanja adenoma hipofize [Predictors of clinical behavior of pituitary adenomas]

The aim of this study was to investigate the expression of histological markers Ki-67, p53 and mitotic activity in pituitary adenomas and their correlation with the frequency of recurrence and progression of residual adenoma. Additional purpose of the study was the analysis of clinical course after operative treatment for a period of at least five years, and analysis of proliferative markers depending on the type and clinical behavior of pituitary adenoma. The study comprised 94 patients operated due to pituitary adenoma in the period from 2005 to 2011, who were treated at the Department of Endocrinology, University Hospital Center Zagreb. After the operation, 63.8% of patients had residual adenoma. In the minority of patients (12/60 patients, 20%) with residual adenoma we detected increase in size. In patients with complete adenoma resection, only few patienst had recurrence (3/34 patients, 8.8%). The analysis showed that the adenoma size had a significant prognostic value for residual tumor (p=0.027). In majority of adenoma samples (74.5%) expression of Ki-67 was less than 3%, 26.1% had positive p53 while only 9.6% had mitotic activity. Functional adenomas had significantly higher expression of Ki-67 compared to nonfunctional adenomas (p=0.012). The expression of the Ki-67 in the pituitary adenoma correlated positively with the recurrence of adenoma as well as the increase in residual adenoma (p<0.001). On the other hand, the expression of p53 and mitotic activity in adenoma tissue did not correlate with the recurrence or increase of residual adenoma (p=0.201 and p=0.26, respectively). Cut-off value of Ki-67 ≥3% was significant for the time of residual adenoma progression or adenoma recurrence after complete removal (p=0.007). All patients with residual adenoma, regardless of the clinical outcome, had a significantly higher expression of Ki-67 compared to patients without residue (p=0.009). Patients with residual adenomas had significantly larger and more invasive adenomas (p<0.001 and p=0.002, respectively). In patients with enlargement of residual adenoma or recurrence after complete removal, the expression of Ki-67 was higher compared to patients with stable residue or complete adenoma removal (p<0.001). Patients with increased residue size and recurrent adenomas had significantly larger initial size of the adenoma (p=0.045). Moreover, these patients had higher expression of Ki-67 compared only to the group of patients with stable residue (p=0.005). Based on this study we can conclude that patients with larger adenoma size and higher expression of proliferative marker Ki-67 should be monitored more closely because they have an increased chance of progression of residual adenoma or recurrence after complete removal

Metabolic Syndrome – Myth or Reality in the Endocrinology Clinic.

Metabolički je sindrom čest klinički problem koji podrazumijeva skup međusobno povezanih stanja: arterijsku hipertenziju, dislipidemiju, hiperglikemiju i centralni tip pretilosti. Važan je zato što su u ovakvih pacijenata znatno povećani kardiovaskularni rizik te rizik od razvoja šećerne bolesti tipa 2. Ovi se metabolički poremećaji češće pojavljuju udruženo te zajedno znatno povećavaju rizik u usporedbi sa svakim poremećajem zasebno. U osnovi patogeneze metaboličkog sindroma jesu pretilost i inzulinska rezistencija, no određenu ulogu imaju kronično proinflamatorno stanje, endotelijalna disfunkcija i prokoagulantno stanje. Liječenje je usmjereno na promjenu životnih navika i redovitu tjelesnu aktivnost, čime se postiže poboljšanje svih metaboličkih poremećaja u sklopu ovog sindroma. Farmakoterapija je usmjerena na smanjenje specifičnih čimbenika rizika za kardiovaskularne bolesti kada osnovne mjere zdravog načina života ne dovedu do željenog učinka, a krajnji je cilj izbjeći nastanak sustavnih učinaka metaboličkog sindroma.Metabolic syndrome is a common clinical problem that encompasses interconnected conditions: hypertension, dyslipidemia, hyperglycemia, and central obesity. It is important because these patients have significantly increased cardiovascular risk and risk of developing Type 2 diabetes. These metabolic disorders more commonly manifest as a syndrome, and together they significantly increase risk in comparison with a single isolated metabolic disorder. Obesity and insulin resistance seem to play a major role in the pathogenesis of metabolic syndrome. Chronic proinflammatory state, endothelial dysfunction, and procoagulant condition contribute as well. Lifestyle modification is the initial intervention of choice, thereby improving all metabolic disorders that are part of this syndrome. Pharmacological treatment should be considered in order to reduce specific risk factors for cardiovascular disease when lifestyle measures fail. The ultimate goal of treatment is the reduction of the systemic effects of metabolic syndrome

WHOQOL-BREF Questionnaire as a Measure of Quality of Life in Sarcoidosis

The aim of this study was to evaluate the usefulness of a short form of the WHOQOL questionnaire, the WHOQOL- -BREF, which consists of 24 questions, in evaluating quality of life (QOL) in sarcoidosis patients. A group of 97 sarcoidosis patients and a matched group of 97 healthy controls took part in the study. Their QOL was examined by means of the WHOQOL-BREF, and the respiratory functions were measured in sarcoidosis patients. The WHOQOL-BREF revealed significantly poorer QOL of sarcoidosis patients in the domains of Physical and Psychological Health in comparison to healthy controls. In contrast, sarcoidosis patients perceived their QOL significantly better than healthy controls in the domains of Social Relations and Environment. Differences between sarcoidosis patients and healthy controls were found in several items from the WHOQOL-BREF and some of them were modified by gender. However, the WHOQOL- -BREF did not prove to be a sensitivemeasure of fatigue, which is themost common symptom in sarcoidosis patients

Neurodevelopmental Outcome in Children with Periventricular Leukomalacia

The purpose of this study was to question the correlation of different grades of periventricular leukomalacia (PVL) and subsequent neurodevelopmental outcome. In a prospective study we followed 52 preterm infants. Infants were divided into three groups according to their cranial ultrasound findings of PVL (De Vries classification). Seventeen children had PVL 1, 20 children had PVL 2, and 15 children had PVL 3. All 15 (100%) children with PVL 3 developed cerebral palsy with additional visual perceptual dysfunctions and epilepsy. Children with PVL 1 had high frequency of mild neuromotoric delay and visual impairment. PVL 2 and 3 have great predictive value for subsequent severe neurodevelopmental disorder which refers to cerebral palsy, different cognitive deficits, vision impairment and epilepsy. We have determined that due to high frequency of visual impairment and epilepsy we need to include neurophysiologic examinations very early in children with PVL lesions

Management of patients with adrenal incidentaloma – 2019 update

Zadnjih desetak godina došlo je do značajnih promjena u zdravstvenom zbrinjavanju bolesnika s incidentalomima nadbubrežne žlijezde koje su rezultirale novim preporukama za dijagnostiku i liječenje ovih bolesnika napravljenim u suradnji Europskoga endokrinološkog društva i Europske mreže za istraživanje tumora nadbubrežne žlijezde. Na temelju navedenih preporuka i višegodišnjega vlastitog iskustva Referentni centar Ministarstva zdravstva Republike Hrvatske za bolesti nadbubrežne žlijezde predlaže izmjene i dopune preporuka za dijagnostiku i liječenje ovih bolesnika objavljenih u Liječničkom vjesniku 2010. godine.In the last decade, the clinical care of patients with adrenal incidentaloma has been significantly changed which prompted the European Society of Endocrinology and European Network for the Study of Adrenal Tumors to develop an updated clinical practice guideline for the management of these patients. In accordance with the aforementioned recommendations and based on its own experience, the Croatian Referral Center for adrenal gland disorders provides an update of the previous guideline for the clinical management of patients with adrenal incidentaloma published in Liječnički vjesnik in 2010

Predictors of clinical behavior of pituitary adenomas

Cilj ovog istraživanja bio je ispitivanje ekspresije histoloških markera Ki-67, p53 i mitotske aktivnosti u adenomima hipofize te njihova korelacija s učestalošću recidiva odnosno progresije veličine ostatnog adenoma. Dodatni cilj bio je analiza kliničkog tijeka nakon operativnog liječenja tih bolesnika u razdoblju od pet godina te analiza proliferacijskih markera ovisno o tipu i kliničkom ponašanju adenoma hipofize. U istraživanje je uključeno 94 bolesnika operiranih zbog adenoma hipofize u razdoblju od 2005. do 2011. godine koji su praćeni najmanje pet godina u Zavodu za endokrinologiju KBC Zagreb. Neurokirurškim zahvatom u 63,8% bolesnika nije bilo moguće odstraniti adenom u cijelosti i zaostaje rezidua. Kod manjine bolesnika s rezidualnim adenomom (12/60 bolesnika, 20%) došlo je do porasta veličine rezidue. Kod bolesnika kojima je adenom ostranjen u cjelosti vrlo rijetko su se tijekom petogodišnjeg praćenja javljali recidivi (3/34 bolesnika, 8,8%). Pokazano je da veličina adenoma ima prognostičku važnost za postojanje rezidue nakon operativnog zahvata (p=0,027). U većine adenoma hipofize (74,5%) ekspresija Ki-67 je bila manja od 3%. Manjina adenoma hipofize (26,1%) pokazivala je pozitivitet na p53, a mitotska je aktivnost bila vidljiva u 9,6% adenoma. Funkcionalni adenomi hipofize imali su značajno veću ekspresiju proliferacijskog markera Ki-67 u usporedbi s nefunkcionalnim adenomima (p=0,012). Ekspresija proliferacijskog markera Ki-67 u adenomu hipofize je pozitivno korelirala s pojavom recidiva adenoma kao i s porastom veličine rezidualnog adenoma (p<0,001). S druge strane, ekspresija histološkog markera p53 kao i mitotska aktivnost u tkivu adenoma nisu korelirale s pojavom recidiva niti s porastom rezidualnog adenoma (p=0,201 i p=0,26). U ovom istraživanju je pokazano da kod prijelomne vrijednosti Ki-67 ≥3% postoji razlika u vremenu do progresije rezidue odnosno pojave recidiva adenoma (p=0,007). Svi bolesnici s rezidualnim adenomom, neovisno o kliničkom tijeku rezidue, su tijekom praćenja imali značajno veću ekspresiju proliferacijskog markera Ki-67 u usporedbi s bolesnicima bez rezidue (p=0,009). Bolesnici s reziduom su imali značajno veći i invazivniji adenom (p<0,001 i p=0,002). U bolesnika kod kojih je došlo do porasta rezidualnog adenoma ili se pojavio recidiv tijekom praćenja, ekspresija Ki-67 je bila veća nego kod bolesnika sa stabilnom reziduom i bez rezidue (p<0,001). Bolesnici s rastućom reziduom i recidivom adenoma su pri postavljanju dijagnoze imali značajno veći adenom (p=0,045). Ovi bolesnici su, također, imali veću ekspresiju Ki-67 u usporedbi samo s bolesnicima sa stabilnim rezidualnim adenomom (p=0,005). Na temelju ovog istraživanja možemo zaključiti da bolesnike s većim adenomom hipofize i većom ekspresijom proliferacijskog markera Ki-67 treba pomnije pratiti jer imaju povećanu šansu za progresiju rezidualnog adenoma ili pojavu recidiva nakon kompletnog odstranjenja.The aim of this study was to investigate the expression of histological markers Ki-67, p53 and mitotic activity in pituitary adenomas and their correlation with the frequency of recurrence and progression of residual adenoma. Additional purpose of the study was the analysis of clinical course after operative treatment for a period of at least five years, and analysis of proliferative markers depending on the type and clinical behavior of pituitary adenoma. The study comprised 94 patients operated due to pituitary adenoma in the period from 2005 to 2011, who were treated at the Department of Endocrinology, University Hospital Center Zagreb. After the operation, 63.8% of patients had residual adenoma. In the minority of patients (12/60 patients, 20%) with residual adenoma we detected increase in size. In patients with complete adenoma resection, only few patienst had recurrence (3/34 patients, 8.8%). The analysis showed that the adenoma size had a significant prognostic value for residual tumor (p=0.027). In majority of adenoma samples (74.5%) expression of Ki-67 was less than 3%, 26.1% had positive p53 while only 9.6% had mitotic activity. Functional adenomas had significantly higher expression of Ki-67 compared to nonfunctional adenomas (p=0.012). The expression of the Ki-67 in the pituitary adenoma correlated positively with the recurrence of adenoma as well as the increase in residual adenoma (p<0.001). On the other hand, the expression of p53 and mitotic activity in adenoma tissue did not correlate with the recurrence or increase of residual adenoma (p=0.201 and p=0.26, respectively). Cut-off value of Ki-67 ≥3% was significant for the time of residual adenoma progression or adenoma recurrence after complete removal (p=0.007). All patients with residual adenoma, regardless of the clinical outcome, had a significantly higher expression of Ki-67 compared to patients without residue (p=0.009). Patients with residual adenomas had significantly larger and more invasive adenomas (p<0.001 and p=0.002, respectively). In patients with enlargement of residual adenoma or recurrence after complete removal, the expression of Ki-67 was higher compared to patients with stable residue or complete adenoma removal (p<0.001). Patients with increased residue size and recurrent adenomas had significantly larger initial size of the adenoma (p=0.045). Moreover, these patients had higher expression of Ki-67 compared only to the group of patients with stable residue (p=0.005). Based on this study we can conclude that patients with larger adenoma size and higher expression of proliferative marker Ki-67 should be monitored more closely because they have an increased chance of progression of residual adenoma or recurrence after complete removal

Pharmacological Treatment of Postmenopausal Osteoporosis: Guidelines vs. Daily Clinical Practice?

Farmakološko liječenje osteoporoze indicirano je kod pacijenata visokog rizika za prijelom kosti kod kojih su isključeni sekundarni uzroci osteoporoze i koji nemaju kontraindikacije za primjenu terapije. Danas su nam na raspolaganju: četiri bisfosfonata (alendronat, risedronat, ibandronat i zoledronatna kiselina), humano monoklonalno antitijelo na RANK ligand (denosumab; engl. receptor activator of nuclear factor kappa-B), analog paratiroidnog hormona (PTH, teriparatid) i selektivni modulatori estrogenskih receptora (SERM, raloksifen i bazedoksifen), te dva nova anabolika: analog PTH-sličnog proteina (abaloparatid) i humanizirano monoklonalno antitijelo na sklerostin (romosozumab). Abaloparatid i romosozumab još nisu dostupni u Hrvatskoj, a zoledronatna kiselina nije registrirana za liječenje osteoporoze, no koristi se u svakodnevnoj kliničkoj praksi za ovu indikaciju. Placebo-kontrolirana istraživanja pokazala su kako se farmakološkim liječenjem rizik za vertebralni prijelom može smanjiti za 30 – 70 %, za prijelom kuka do 50 %, a za ne-vertebralni za 15 – 35 %. U pacijenata visokog rizika za prijelom kao inicijalna farmakoterapija savjetuje se antiresorptivna terapija, dok se u onih s teškom osteoporozom i vrlo visokim rizikom za prijelom kao inicijalna terapija savjetuju anabolici. Hormonska terapija (estrogen i kombinacija estrogen/progestin) može se koristiti kod žena s postmenopauzalnom osteoporozom koje imaju perzistentne menopauzalne simptome i ne toleriraju drugu dostupnu terapiju za osteoporozu, uzevši u obzir potencijalne kontraindikacije i rizike. U odabiru optimalne terapije potrebno je u obzir uzeti individualni rizik za prijelom kod svakog pacijenta, te učinkovitost, cijenu, jednostavnost primjene i potencijalne nuspojave pojedinog lijeka.Pharmacological treatment of osteoporosis is indicated in patients with a high risk of fracture, in whom secondary causes have been excluded, and who have no contraindications for therapy. Currently we have at our disposal: four bisphosphonates (alendronate, risedronate, ibandronate and zoledronic acid), human monoclonal antibody to RANK ligand (denosumab), parathyroid hormone analogue (teriparatide), selective estrogen receptor modulators (raloxifene and bazedoxifene), and two new anabolics: a PTH-like protein analog (abaloparatide) and a humanized monoclonal antibody to sclerostin (romosozumab). Abaloparatide and romosozumab are not yet available in Croatia, and zoledronic acid is not registered for the treatment of osteoporosis, however it is used in daily clinical practice for this indication. Placebo-controlled studies have shown that with treatment the risk for vertebral fracture can be reduced by 30 - 70%, the risk for hip fracture by up to 50%, and for non-vertebral fractures by 15 - 35%. Antiresorptive treatment is recommended as initial therapy for patients with a high risk of fracture, while anabolics are recommended as initial therapy for severe osteoporosis and a very high risk of fracture. Hormonal therapy (estrogen and estrogen/progestin combination) can be used in women with postmenopausal osteoporosis who have persistent menopausal symptoms and can’t tolerate other available treatment for osteoporosis, taking into account potential contraindications and risks. When choosing the optimal tretament we have to consider the individual risk for fracture in each patient, as well as the effectiveness, price, route of administration and potential side effects of pharmacotherapy

Predictors of clinical behavior of pituitary adenomas

Cilj ovog istraživanja bio je ispitivanje ekspresije histoloških markera Ki-67, p53 i mitotske aktivnosti u adenomima hipofize te njihova korelacija s učestalošću recidiva odnosno progresije veličine ostatnog adenoma. Dodatni cilj bio je analiza kliničkog tijeka nakon operativnog liječenja tih bolesnika u razdoblju od pet godina te analiza proliferacijskih markera ovisno o tipu i kliničkom ponašanju adenoma hipofize. U istraživanje je uključeno 94 bolesnika operiranih zbog adenoma hipofize u razdoblju od 2005. do 2011. godine koji su praćeni najmanje pet godina u Zavodu za endokrinologiju KBC Zagreb. Neurokirurškim zahvatom u 63,8% bolesnika nije bilo moguće odstraniti adenom u cijelosti i zaostaje rezidua. Kod manjine bolesnika s rezidualnim adenomom (12/60 bolesnika, 20%) došlo je do porasta veličine rezidue. Kod bolesnika kojima je adenom ostranjen u cjelosti vrlo rijetko su se tijekom petogodišnjeg praćenja javljali recidivi (3/34 bolesnika, 8,8%). Pokazano je da veličina adenoma ima prognostičku važnost za postojanje rezidue nakon operativnog zahvata (p=0,027). U većine adenoma hipofize (74,5%) ekspresija Ki-67 je bila manja od 3%. Manjina adenoma hipofize (26,1%) pokazivala je pozitivitet na p53, a mitotska je aktivnost bila vidljiva u 9,6% adenoma. Funkcionalni adenomi hipofize imali su značajno veću ekspresiju proliferacijskog markera Ki-67 u usporedbi s nefunkcionalnim adenomima (p=0,012). Ekspresija proliferacijskog markera Ki-67 u adenomu hipofize je pozitivno korelirala s pojavom recidiva adenoma kao i s porastom veličine rezidualnog adenoma (p<0,001). S druge strane, ekspresija histološkog markera p53 kao i mitotska aktivnost u tkivu adenoma nisu korelirale s pojavom recidiva niti s porastom rezidualnog adenoma (p=0,201 i p=0,26). U ovom istraživanju je pokazano da kod prijelomne vrijednosti Ki-67 ≥3% postoji razlika u vremenu do progresije rezidue odnosno pojave recidiva adenoma (p=0,007). Svi bolesnici s rezidualnim adenomom, neovisno o kliničkom tijeku rezidue, su tijekom praćenja imali značajno veću ekspresiju proliferacijskog markera Ki-67 u usporedbi s bolesnicima bez rezidue (p=0,009). Bolesnici s reziduom su imali značajno veći i invazivniji adenom (p<0,001 i p=0,002). U bolesnika kod kojih je došlo do porasta rezidualnog adenoma ili se pojavio recidiv tijekom praćenja, ekspresija Ki-67 je bila veća nego kod bolesnika sa stabilnom reziduom i bez rezidue (p<0,001). Bolesnici s rastućom reziduom i recidivom adenoma su pri postavljanju dijagnoze imali značajno veći adenom (p=0,045). Ovi bolesnici su, također, imali veću ekspresiju Ki-67 u usporedbi samo s bolesnicima sa stabilnim rezidualnim adenomom (p=0,005). Na temelju ovog istraživanja možemo zaključiti da bolesnike s većim adenomom hipofize i većom ekspresijom proliferacijskog markera Ki-67 treba pomnije pratiti jer imaju povećanu šansu za progresiju rezidualnog adenoma ili pojavu recidiva nakon kompletnog odstranjenja.The aim of this study was to investigate the expression of histological markers Ki-67, p53 and mitotic activity in pituitary adenomas and their correlation with the frequency of recurrence and progression of residual adenoma. Additional purpose of the study was the analysis of clinical course after operative treatment for a period of at least five years, and analysis of proliferative markers depending on the type and clinical behavior of pituitary adenoma. The study comprised 94 patients operated due to pituitary adenoma in the period from 2005 to 2011, who were treated at the Department of Endocrinology, University Hospital Center Zagreb. After the operation, 63.8% of patients had residual adenoma. In the minority of patients (12/60 patients, 20%) with residual adenoma we detected increase in size. In patients with complete adenoma resection, only few patienst had recurrence (3/34 patients, 8.8%). The analysis showed that the adenoma size had a significant prognostic value for residual tumor (p=0.027). In majority of adenoma samples (74.5%) expression of Ki-67 was less than 3%, 26.1% had positive p53 while only 9.6% had mitotic activity. Functional adenomas had significantly higher expression of Ki-67 compared to nonfunctional adenomas (p=0.012). The expression of the Ki-67 in the pituitary adenoma correlated positively with the recurrence of adenoma as well as the increase in residual adenoma (p<0.001). On the other hand, the expression of p53 and mitotic activity in adenoma tissue did not correlate with the recurrence or increase of residual adenoma (p=0.201 and p=0.26, respectively). Cut-off value of Ki-67 ≥3% was significant for the time of residual adenoma progression or adenoma recurrence after complete removal (p=0.007). All patients with residual adenoma, regardless of the clinical outcome, had a significantly higher expression of Ki-67 compared to patients without residue (p=0.009). Patients with residual adenomas had significantly larger and more invasive adenomas (p<0.001 and p=0.002, respectively). In patients with enlargement of residual adenoma or recurrence after complete removal, the expression of Ki-67 was higher compared to patients with stable residue or complete adenoma removal (p<0.001). Patients with increased residue size and recurrent adenomas had significantly larger initial size of the adenoma (p=0.045). Moreover, these patients had higher expression of Ki-67 compared only to the group of patients with stable residue (p=0.005). Based on this study we can conclude that patients with larger adenoma size and higher expression of proliferative marker Ki-67 should be monitored more closely because they have an increased chance of progression of residual adenoma or recurrence after complete removal

Predictors of clinical behavior of pituitary adenomas

Cilj ovog istraživanja bio je ispitivanje ekspresije histoloških markera Ki-67, p53 i mitotske aktivnosti u adenomima hipofize te njihova korelacija s učestalošću recidiva odnosno progresije veličine ostatnog adenoma. Dodatni cilj bio je analiza kliničkog tijeka nakon operativnog liječenja tih bolesnika u razdoblju od pet godina te analiza proliferacijskih markera ovisno o tipu i kliničkom ponašanju adenoma hipofize. U istraživanje je uključeno 94 bolesnika operiranih zbog adenoma hipofize u razdoblju od 2005. do 2011. godine koji su praćeni najmanje pet godina u Zavodu za endokrinologiju KBC Zagreb. Neurokirurškim zahvatom u 63,8% bolesnika nije bilo moguće odstraniti adenom u cijelosti i zaostaje rezidua. Kod manjine bolesnika s rezidualnim adenomom (12/60 bolesnika, 20%) došlo je do porasta veličine rezidue. Kod bolesnika kojima je adenom ostranjen u cjelosti vrlo rijetko su se tijekom petogodišnjeg praćenja javljali recidivi (3/34 bolesnika, 8,8%). Pokazano je da veličina adenoma ima prognostičku važnost za postojanje rezidue nakon operativnog zahvata (p=0,027). U većine adenoma hipofize (74,5%) ekspresija Ki-67 je bila manja od 3%. Manjina adenoma hipofize (26,1%) pokazivala je pozitivitet na p53, a mitotska je aktivnost bila vidljiva u 9,6% adenoma. Funkcionalni adenomi hipofize imali su značajno veću ekspresiju proliferacijskog markera Ki-67 u usporedbi s nefunkcionalnim adenomima (p=0,012). Ekspresija proliferacijskog markera Ki-67 u adenomu hipofize je pozitivno korelirala s pojavom recidiva adenoma kao i s porastom veličine rezidualnog adenoma (p<0,001). S druge strane, ekspresija histološkog markera p53 kao i mitotska aktivnost u tkivu adenoma nisu korelirale s pojavom recidiva niti s porastom rezidualnog adenoma (p=0,201 i p=0,26). U ovom istraživanju je pokazano da kod prijelomne vrijednosti Ki-67 ≥3% postoji razlika u vremenu do progresije rezidue odnosno pojave recidiva adenoma (p=0,007). Svi bolesnici s rezidualnim adenomom, neovisno o kliničkom tijeku rezidue, su tijekom praćenja imali značajno veću ekspresiju proliferacijskog markera Ki-67 u usporedbi s bolesnicima bez rezidue (p=0,009). Bolesnici s reziduom su imali značajno veći i invazivniji adenom (p<0,001 i p=0,002). U bolesnika kod kojih je došlo do porasta rezidualnog adenoma ili se pojavio recidiv tijekom praćenja, ekspresija Ki-67 je bila veća nego kod bolesnika sa stabilnom reziduom i bez rezidue (p<0,001). Bolesnici s rastućom reziduom i recidivom adenoma su pri postavljanju dijagnoze imali značajno veći adenom (p=0,045). Ovi bolesnici su, također, imali veću ekspresiju Ki-67 u usporedbi samo s bolesnicima sa stabilnim rezidualnim adenomom (p=0,005). Na temelju ovog istraživanja možemo zaključiti da bolesnike s većim adenomom hipofize i većom ekspresijom proliferacijskog markera Ki-67 treba pomnije pratiti jer imaju povećanu šansu za progresiju rezidualnog adenoma ili pojavu recidiva nakon kompletnog odstranjenja.The aim of this study was to investigate the expression of histological markers Ki-67, p53 and mitotic activity in pituitary adenomas and their correlation with the frequency of recurrence and progression of residual adenoma. Additional purpose of the study was the analysis of clinical course after operative treatment for a period of at least five years, and analysis of proliferative markers depending on the type and clinical behavior of pituitary adenoma. The study comprised 94 patients operated due to pituitary adenoma in the period from 2005 to 2011, who were treated at the Department of Endocrinology, University Hospital Center Zagreb. After the operation, 63.8% of patients had residual adenoma. In the minority of patients (12/60 patients, 20%) with residual adenoma we detected increase in size. In patients with complete adenoma resection, only few patienst had recurrence (3/34 patients, 8.8%). The analysis showed that the adenoma size had a significant prognostic value for residual tumor (p=0.027). In majority of adenoma samples (74.5%) expression of Ki-67 was less than 3%, 26.1% had positive p53 while only 9.6% had mitotic activity. Functional adenomas had significantly higher expression of Ki-67 compared to nonfunctional adenomas (p=0.012). The expression of the Ki-67 in the pituitary adenoma correlated positively with the recurrence of adenoma as well as the increase in residual adenoma (p<0.001). On the other hand, the expression of p53 and mitotic activity in adenoma tissue did not correlate with the recurrence or increase of residual adenoma (p=0.201 and p=0.26, respectively). Cut-off value of Ki-67 ≥3% was significant for the time of residual adenoma progression or adenoma recurrence after complete removal (p=0.007). All patients with residual adenoma, regardless of the clinical outcome, had a significantly higher expression of Ki-67 compared to patients without residue (p=0.009). Patients with residual adenomas had significantly larger and more invasive adenomas (p<0.001 and p=0.002, respectively). In patients with enlargement of residual adenoma or recurrence after complete removal, the expression of Ki-67 was higher compared to patients with stable residue or complete adenoma removal (p<0.001). Patients with increased residue size and recurrent adenomas had significantly larger initial size of the adenoma (p=0.045). Moreover, these patients had higher expression of Ki-67 compared only to the group of patients with stable residue (p=0.005). Based on this study we can conclude that patients with larger adenoma size and higher expression of proliferative marker Ki-67 should be monitored more closely because they have an increased chance of progression of residual adenoma or recurrence after complete removal

A rapid biochemical and radiological response to the concomitant therapy with temozolomide and radiotherapy in an aggressive ACTH pituitary adenoma

Background and Importance: In the last eight years temozolomide (TMZ) has been used as the last-line treatment modality for aggressive pituitary tumors to be applied after the failure of surgery, medical therapy, and radiotherapy. The objective was to achieve a rapid control of tumor growth and hormone normalization with concurrent chemoradiotherapy in a patient with very aggressive ACTH pituitary adenoma. ----- Clinical Presentation: We describe a patient with an aggressive ACTH-producing adenoma treated with concurrent temozolomide and radiotherapy. The patient suffered from an aggressive ACTH adenoma resistant to surgical and medical treatment. After two months of concurrent temozolomide and radiotherapy, cortisol normalization and significant tumor shrinkage were observed. After 22 months of follow-up, there is still no evidence of tumor recurrence. ----- Conclusion: Concurrent treatment with temozolomide and irradiation appears to be highly effective in the achievement of the tumor volume control as well as in the control of ACTH secretion in aggressive ACTH adenoma