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My scientific breakthroughs

Some of my research papers have made substantial impact on overall scientific literature and knowledge in the field of endocrinology and diabetology. I have discovered several new clinical entities and diseases, described new endocrinological test and offered new treatment modalities. Excellence in science is closely related to excellence in clinical practice due to two main reasons:

  1. Each new discovery is preceded by thorough knowledge of entire current knowledge
  2. Competent use of scientific methodology and biostatistics enables me to read other scholar’s papers with criticism and to implement their findings into my own clinical practice

References stated below are the guarantee of success in elucidating your problem and finding the most suitable solution.

Pituitary gland

Pituitary surgery for prolactinomas may enhance response to dopamine agonists

Prolactinomas are usually treated with drugs called dopamine agonists (bromocriptine and cabergoline), which act on tumor cells in a similar fashion as chemotherapy, by killing viable tumors cells and suppressing prolactin hypersecretion. Pituitary surgery is rarely needed due to good overall effects of medicamentous treatment. However, patients with large prolactinomas usually need higher doses of cabergoline, which is often associated with high treatment costs in the setting of a low-income health care system. The purpose of this paper was to investigate whether pituitary surgery can improve the efficacy of dopamine agonists and potentially to reduce the dose required to control the disease. We compared outcomes between the two patient groups: patients with small prolactinomas (<1 cm) treated initially with dopamine agonists and patients with large residual tumors who were initially treated with pituitary surgery followed by treatment with dopamine agonists. Despite the fact that residual prolactinomas were approximately two-fold larger than microprolactinomas, similar patterns of the decrease in serum prolactin levels were observed with similar dopamine agonist dose. Consequently, this research has indirectly suggested that pituitary surgery may improve the efficacy of dopamine agonists. It was published in „International Journal of Endocrinology“, while the entire paper can be accessed through this link: https://www.hindawi.com/journals/ije/2015/697065/

Infarction of a pituitary metastasis caused by low blood thrombocyte levels

In this paper, I described a case of ischemic pituitary apoplexy after heparin-induced thrombocytopenia. Pituitary apoplexy is a rare clinical condition caused by hemorrhage or infarction within the pituitary tumor, leading to the sudden increase of the tumor volume located in the scanty sellar region, possessing live-threating potential. Increased blood pressure and blood sugar, head traumas and several other factors may precipitate pituitary apoplexy. This paper was first to report that pituitary apoplexy may be caused by low blood thrombocyte levels. Moreover, the fact that this rare condition occurred in a patient with pituitary metastasis (represent <1% of all pituitary tumors) makes this case rather bizarre. The paper was published in a renowned journal „Endocrine Pathology“, the abstract can be accessed at: https://www.ncbi.nlm.nih.gov/pubmed/23129546

Thyroid gland

Research paper cited by the American Thyroid Association

This research analyzed patients with hyperthyroidism (Graves’ disease). There were two different aims of the study. First aim was to analyze efficacy and side-effects of the unique thyrostatic regimen, which consisted of initially high methimazole doses that were tapered to lower doses in short time intervals. Second aim was to analyze whether rapid normalization of thyroid hormones with high-dose methimazole therapy was associated with long-term remission of Graves’ disease. Research has shown that the aforementioned protocol was associated with high rates of side-effects with similar efficacy when compared with standard low-dose regimen. Moreover, we have found that early normalization of thyroid hormones was not associated with long-term remission of the disease.

This was the first paper that analyzed the efficacy and safety of high-dose methimazole regimen in the treatment of Graves’ disease. Moreover, it was fist to find that early restoration of euthyroidism was not associated  with long-term remission. The paper was cited in official guidelines of the American thyroid association and published in „Endocrine Research“. Details can be accessed through this link:
https://www.ncbi.nlm.nih.gov/pubmed/24833206

Finding the right dose (activity) of radioactive iodine in treatment of patients with thyroid carcinoma 

Both tumor cells and normal thyroid tissue acumulate radioactive iodine, while the radiation induces death of tumor cells. Hence, patients who underwent total thyoroidectomy for well-differentiated thyroid carcinoma must receive profilactic treatment with radioactive iodine after the surgery. This procedure is called radioablation and it kills all tumor cells or normal thyroid cells that may have remained after the surgery in the majority of patients. This can be documented by undetectable serum thyroglobulin levels, while thyroglobulin can be used as a tumor marker during patient follow-up. Increased serum thyroglobulin levels after radioablation can be seen in the minority of patients and knowledge regarding radioablation failure is insufficient. This research included the largest number of patients with radioablation failure to date. The aim of this study was to evaluate the efficacy of different radioactive iodine activities used for re-ablation, to compare various combinations of treatment activities, and to identify predictors of re-ablation failure in low- and intermediate-risk differentiated thyroid carcinoma patients. The study have found that re-ablation was successful in 113 out of 128 patients (88.3 %). There was no association found between the first, second, and cumulative activity with re-ablation treatment outcome. Treatment failure was associated with higher thyroglobulin levels prior to re-ablation and the presence of lymph node metastases. We have conluded that the re-ablation success was high in all subgroups of patients and radioactive iodine activity did not influence treatment outcome. Thyroglobulin may serve as a good predictor of re-ablation failure. The paper was published in a renowned journal “Endocrine”, while details can be accessed through this link: https://www.ncbi.nlm.nih.gov/pubmed/26732041


Parathyroid gland and osteoporosis

The impact of metabolic hormones on mortality after hip fracture in patients with osteoporosis

It has been well known that metabolic hormones are associated with cardiovascular mortality. However, these hormones have important role on the bone, which has been poorly understood. This study investigated the impact of anthropometric parameters, adiponectin, leptin, homeostatic model assessment for insulin resistance (HOMA-IR), beta-cross laps and routine biochemical tests on one-year mortality in hip fracture patients. This prospective study included 236 patients of all ages with non-traumatic hip fractures.  We have found that male gender, high β-CTX, adiponectin, and leptin were independently associated with increased mortality. Thus, we constructed a nomogram that included all the latter variables in addition to age. Patients with nomogram score <9.2 had a mortality of 10.1%, while those with >9.2 had a mortality of 49.2%. The authors concluded that male patients with high adiponectin, leptin, and β-CTX levels have a 5-fold increase in all-cause one-year mortality after hip fracture. The paper was published in a prestigious journal „Osteoporosis International“, details can be accessed via this link: https://www.ncbi.nlm.nih.gov/pubmed/28501890

Presentation of a unique case an intrathyroid parathyroid carcinoma published in a journal of the Japanese Society of oncology

This was the case report of unique patient with extremely rare malignancy: parathyroid carcinoma. What makes this case unique is the fact that the parathyroid carcinoma was localized within the thyroid gland and had metastasized in the contralateral thyroid lobe. This was the first case report that described such remarkable clinical constellation in world’s literature. The paper warns clinicians of possible traps and difficulties in diagnostics and treatment of parathyroid carcinoma. My paper was first to highlight that entire thyroid should be removed in case of parathyroid carcinoma, unlike the previous guidelines that suggested only removal of the thyroid lobe leaning towards the tumor. The full paper can be accessed through this link:  https://academic.oup.com/jjco/article/41/9/1142/839036


Neuroendocrine tumors

New dynamic test which dramatically increases the diagnostic accuracy of chromogranin A in detecting neuroendocrine tumors

Serum chromogranin A (CgA) is routinely used as a biomarker in patients with neuroendocrine neoplasms (NENs). Several conditions and comorbidities may be associated with falsely elevated CgA, often leading to extensive diagnostic evaluation, which may be costly and harmful. The aim of this study was to analyze the effectiveness of the acute octreotide suppression test (AOST) in differentiating falsely elevated serum CgA. Our prospective study enrolled 45 patients from two different patient cohorts: (1) 29 patients with suspicion or presence of NENs (extensive workup and subsequent biopsy confirmed 16 NENs); (2) 16 consecutive patients admitted via the Emergency Department without NENs (non-NENs). AOST was performed after an overnight fast. Baseline CgA was measured, after which 0.25 mg of octreotide was administered subcutaneously. CgA was measured 3 and 6 h after administration. Baseline CgA levels were similar in NENs and non-NENs. At the end of the AOST, CgA decreased by a median of 83.3% (41.0-127.4) in non-NENs and 13.8% (0.0-43.6) in NENs (p < 0.001). In patients with increased baseline CgA, a decrease in CgA at the 6th hour of < 51.3% had 89.0% diagnostic accuracy in detecting NENs. In patients with normal baseline serum CgA, a decrease in CgA at the 3rd hour of < 17.6% had 82.0% diagnostic accuracy in detecting patients with NENs. The diagnostic accuracy of the AOST in the entire study population was 86.7%. The authors concluded that the AOST is a promising tool to increase the diagnostic accuracy of serum CgA. Eventually, it has been implemented in everyday clinical practice and can be performed in UHC Sestre milosrdnice and Center of endocrinoly at Solmed Clinic Ltd. The paper was published in world’s leading journal for neuroendocrine tumors „Neuroendocrinology“, details can be accessed at: https://www.ncbi.nlm.nih.gov/pubmed/30114698


Research in collaboration with the head of ENETS Center of excellence at Charite Clinic in Berlin

Chromogranin A (CgA) is a valuable biomarker for detection and follow-up of patients with neuroendocrine neoplasms (NENs). However, various comorbidities may influence serum CgA, which decreases its diagnostic accuracy. We aimed to investigate which laboratory parameters are independently associated with increased CgA in real-life setting and to develop a scoring system, which could improve the diagnostic accuracy of CgA in detecting patients with NENs. This retrospective study included 55 treatment naïve patients with NENs and160 patients with various comorbidities but without NEN (nonNENs). Scoring system (CgA-score) was developed based on z-scores obtained from receiver operating curve analysis for each parameter that was associated with elevated serum CgA in nonNENs. CgA correlated positively with serum blood-urea-nitrogen, creatinine, α2-globulin, red-cell distribution width, erythrocyte sedimentation rate, plasma glucose and correlated inversely with hemoglobin, thrombocytes and serum albumin. Serum CgA was also associated with the presence of chronic renal failure, arterial hypertension and diabetes and the use of proton pump inhibitors. In the entire study population, CgA showed an area under the curve of 0.656 (diagnostic accuracy of 66%). Aforementioned parameters were used to develop a CgA-score. In a cohort of patients with CgA-score <12.0 (N = 87), serum CgA >156.5 ng/ml had 84.7% diagnostic accuracy in detecting NENs. Serum CgA had no diagnostic value in detecting NENs in patients with CgA-score >12.0. The authors concluded that CgA-score encompasses a wide range of comorbidities and represents a promising tool that could improve diagnostic performance of CgA in everyday clinical practice. This paper has additional value because it has been conducted in collaboration with Dr. Ulrich-Frank Pape, the head of ENETS Center of excellence at Charite Clinic in Berlin. Dr. Pape is an outstanding scientist and clinician in the field of neuroendocrine tumors and is coauthor of European guidelines for the diagnostics and treatment of neuroendocrine tumors. Therefore, it was a great privilege to collaborate with him and to have him as a coauthor. The paper can be accessed here: https://www.ncbi.nlm.nih.gov/pubmed/29633144

Adrenal gland

Case presentation of a patient with exceedingly rare MEN-2 syndrome published in „American Journal of Medicine“

In this paper, I have described an unique patient with multiple endocrine neoplasia syndrome type 2b caused by mutation of RET-protooncogene. The MEN-2b syndrome presents with medullary thyroid carcinoma and pheochromocytoma (tumor within the adrenal medulla). Moreover, patients with MEN-2b syndrome have typical appearance characterized as marfanoid phenotype (tall, skinny, long thin fingers). This case is unique because the patient had malignant pheochromocytoma, which secreted adrenalin and noradrenalin as usual, but it also secreted ACTH causing Cushing’s disease. Cushing’s disease has not been reported previously in patients with MEN-2b syndrome. Therefore, this paper was first to describe specific appearance, symptoms and laboratory findings of a patient with coexisting MEN-2b syndrome and Cushing’s disease. In respect to the patient’s privacy and journal’s authorship policy, the full paper will not be presented on this website.

Diabetes mellitus

Results from my PhD thesis published in “Endocrine”

Increased plasma or urine ketone bodies in patients with type 1 diabetes usually mean that the patient is at high risk for development of diabetic ketoacidosis, a life-threatening complication which requires hospitalization in intensive care unit. However, little is know about the significance of increased ketone bodies in patients with type 2 diabetes. Moreover, evidence exists thatpatients with type 2 diabetes mellitus have impaired ketogenesis due to high serum insulin and low growth hormone levels and that normal synthesis of ketone bodies might improve kidney and cardiac function. In theory, improved ketogenesis in diabetics may have positive effects. We aimed to assess the impact of diabetic ketosis on all-cause mortality in patients with type 2 diabetes mellitus presenting with hyperglycemic crisis. We analyzed 486 patients with diabetic ketosis and 486 age and sex-matched patients with non-ketotic hyperglycemia presenting to the emergency department. Cox proportional hazard models were used to analyze the link between patient characteristics and mortality. During an observation time of 33.4 months, death of any cause occurred in 40.9 % of the non-ketotic hyperglycemia group and 30.2 % of the DK group (hazard ratio in the diabetic ketosis group, 0.63; 95 % confidence interval 0.48-0.82; P = 0.0005). Patients with diabetic ketosis had a lower incidence of symptomatic heart failure and had improved renal function. They used less furosemide and antihypertensive drugs, more metformin and lower insulin doses, all of which was independently associated with decreased mortality. Plasma glucose and glycated hemoglobin levels were similar in both groups. To date, this is the first study that found that the patients with hyperglycemic crisis and diabetic ketosis have decreased all-cause mortality when compared to those with non-ketotic hyperglycemia. Hence, diabetic ketosis might be a compensatory mechanism rather than a complication in patients with hyperglycemic crises, but further prospective studies are warranted. More details can be accessed through this link: https://www.ncbi.nlm.nih.gov/pubmed/27592119


Obesity

Can metabolic hormones predict successful weight loss after bariatric surgery?

Although various metabolic hormones have been implicated in bariatric-related weight loss, their use as predictors of weight loss is unknown. Our study evaluates changes in metabolic hormones after bariatric surgery, and their role as predictors of weight loss. This nonrandomized study included 51 patients, 21 underwent laporascopic adjustable gastric banding (LAGB), 15 laparoscopic sleeve gastrectomy (LSG) and 15 Roux-en Y gastric bypass (RYGB). Serum ghrelin, leptin, insulin, growth hormone, HOMA-IR and HOMA-β was recorded at baseline and 1, 3, 6 and 12 months, and correlated with weight loss. Successful weight loss was defined as excess weight loss >50% at 12 months for all groups. Weight loss pattern was similar in all groups. Ghrelin increased only in the LAGB group (P = 0·016). However, baseline ghrelin concentrations >664·6 pg/mL in the LSG group predicted successful weight loss with 81·8% sensitivity and 100·0% specificity, and ghrelin >969·8 pg/mL in the 1st postoperative month predicted success with 83·3% sensitivity and 83·3% specificity in the LAGB group. Insulin and HOMA-IR decreased significantly in the LSG and RYGB group, HOMA-β increased in the LAGB and LSG group. Serum leptin decreased and GH increased in all groups (P < 0·001 for all changes). Changes in insulin, leptin and growth hormone were not predictors, but a consequence of weight loss. Authors concluded that LSG is the most effective procedure for improvement of beta-cell function. High baseline ghrelin in the LSG group and an adequate 1st month increase in the LAGB group are associated with greater weight loss. Validation studies are required to confirm the role of ghrelin in predicting weight loss after bariatric surgery, but also in selecting candidates for specific bariatric procedures.

This paper was published in prestigious journal »Clinical Endocrinology«, an official journal of the British endocrine society. Details can be accessed through this link: https://www.ncbi.nlm.nih.gov/pubmed/27439154


Polycystic ovary syndrome and infertility

Letter to the editor of the world’s most prestigious medical journal “The New England Journal of Medicine”

The aim of this paper was to give an overview on potential mechanism of action of letrozole, a new drug for treating infertility in patients with polycystic ovary syndrome (PCOS). I assumed that letrozole may decrease serum prolactin levels that are often seen in patients with PCOS and may have independent negative effects on conception. This letter has set a new hypothesis regarding the letrozole’s mechanism of action. The value of this short letter lies in the fact that the innovative opinion of one young from Croatia deserves to be published in world’s most prestigious medical journal.

Rare diseases

Case report of an exceedingly rare disease: hypothalamic Langerhans cell histiocytosis

The aim of this paper was to present a rare case of multysystemic Langerhans cell histiocytosis (LCH) which had infiltrated and destroyed hypothalamus. LCH is a disease of uncertain etiology in which granulomas consisting of malignantly altered inflammatory cells called histiocytes can appear in almost all parts of the body. In this patient, granulomas had first infiltrated pituitary stalk and caused hypopituitarism (insufficient secretion of hormones from the anterior lobe of the pituitary gland) and diabetes insipidus (insufficient secretion of desmopressin from the posterior pituitary lobe). Since the volume of a granuloma in the pituitary stalk had increased, it destroyed the hypothalamus and the patient consequently lost the sense of thirst and gained an augmented sense of hunger. Due to the fact that the patient had not drank any fluid and had eaten massive amount of food, she developed a hyperosmolar coma. After the recovery of a hyperosmolar state in an intensive care unit, the patient was treated with chemotherapy after which all granulomas in her body had disappeared. This is the first paper in world’s literature which described that histicytosis can completely destroy hypothalamus and cause such severe metabolic complication. The paper was published in a prestigious journal „Endocrine“.

Paper published in the most prestigious journal in the field of nuclear medicine

This paper addressed treatment modalities in aforementioned rare disease: Langerhans cell histiocytosis (LCH). Optimal treatment of adult patients with LCH is largely unknown. After extensive search for international scientists and doctors with experience in treatment of this disease in adults, I have come across the work of Professor Imashuku, Kyoto, Japan. Professor invented the unique chemotherapy protocol, which had been used to treat four patients. My colleague hematologist initiated the chemotherapy and after only two months of treatment all tumors in the patient had disappeared. The complete response was documented on PET/CT, which had never been used for this purpose previously. Eventually, Professor Imashuku agreed to be a coauthor of this paper, which was published in a prestigious journal “Clinical Nuclear Medicine”.