Biosličan lijek u hematologiji i onkologiji Biosimilar drug in hematology and oncolog

Biološki lijek je onaj čija se djelatna tvar proizvodi ili izlučuje iz biološkog izvora (ljudskog, životinjskog ili mikrobiološkog). Zbog načina proizvodnje i njihovog porijekla, djelatne tvari bioloških lijekova značajno su složenije strukture od djelatnih tvari kemijskog porijekla. Neke od djelatnih tvari bioloških lijekova mogu se nalaziti i u ljudskom organizmu, poput inzulina, hormona rasta ili eritropoetina. Biosličan lijek biološki je lijek za koji je dokazana sličnost u odnosu na kakvoću, biološke aktivnosti, sigurnosti primjene i djelotvornosti s odobrenim izvornim biološkim lijekom. Zbog složene strukture djelatne tvari i načina proizvodnje bioloških lijekova, nije vjerojatno da je moguće proizvesti biološki lijek koji ima u cjelosti istovjetnu djelatne tvari koju ima izvorni biološki lijek. Stoga se standardni pristup razvoju i odobravanju generičkih kemijskih lijekova, koji se temelji na dokazu bioekvivalentnosti s izvornim lijekom, ne može primijeniti kod biosličnih lijekova, već je u postupku razvoja i davanja odobrenja biosličnih lijekova potrebno dodatnim ispitivanjima potvrditi njihovu sličnost s izvornim lijekom. Razvoj biosličnog lijeka započinje opsežnom karakterizacijom fizikalno-kemijskih i bioloških svojstava djelatne tvari te nekliničkim in vitro ispitivanjima, a podaci dobiveni u ovim ispitivanjima određuju opseg i vrstu nekliničkih in vivo ispitivanja i kliničkih ispitivanja na ljudima koja će se morati provesti u svrhu dokazivanja sličnosti. S obzirom na to da je izvorni biološki lijek odobren u Europskoj uniji niz godina te je njegova klinička korist dokazana, određena ispitivanja provedena na izvornom lijeku nije potrebno ponavljati u svrhu odobravanja biosličnog lijeka. Iz navedenih razloga, razvoj, opseg ispitivanja i podaci temeljem kojih se biosličan lijek odobrava, moraju se pojedinačno razmotriti. Bioslični lijekovi proizvode se prema istovjetno strogim standardima kao i svi drugi lijekovi, što se potvrđuje inspekcijskim nadzorima proizvođača od strane regulatornih tijela. Znanstvenu pouzdanost pristupa odobravanju biosličnih lijekova podupire dugogodišnje iskustvo na razini Europske unije kojim je do danas pacijentima omogućen pristup brojnim kvalitetnim, sigurnim i djelotvornim biosličnim lijekovima. Truxima je prvi bioslični rituksimab na hrvatskom tržištu. Nalazi se u jačinama 100 mg i 500 mg u obliku i. v. aplikacije. Prema smjernicama HZZO-a, Truxima je indicirana za: 1. Prva linija liječenja agresivnih non-Hodgkinovih limfoma, koji su prema nalazu imunohistokemije, imunocitokemije ili protočne citometrije CD20 pozitivni, u kliničkom stadiju II.-IV. ili stadiju I. s povišenim LDH-om ili velikom tumorskom masom. Odobravaju se 4 ciklusa liječenja u kombinaciji s kemoterapijom u dozi od 375 mg/(m)2 po ciklusu. U slučaju povoljnog učinka odobrava se primjena još 4 ciklusa terapije. 2. Prva linija liječenja bolesnika s neliječenim CD20 pozitivnim indolentnim non-Hodgkinovim limfomom. Odobrava se primjena osam ciklusa liječenja u dozi od 375 mg/(m)2 po ciklusu. 3. Liječenje bolesnika s indolentnim B-staničnim non-Hodgkinovim limfomom u relapsu, odnosno u bolesnika s kemorezistentnim tipom B-staničnog non-Hodgkinovog limfoma niskog stupnja malignosti u kojih je imunohistokemijski i/ili protočnom citometrijom dokazano da stanice na sebi imaju CD20 biljeg. Odobrava se primjena tri ciklusa liječenja uz obveznu reevaluaciju učinka nakon trećeg ciklusa terapije. U slučaju povoljnog učinka odobrava se primjena još tri ciklusa terapije. Liječenje odobrava Bolničko povjerenstvo za lijekove na prijedlog specijalista internista hematologa. Liječenje pod 1. i 2. odobrava se iz sredstava posebno skupih lijekova, a liječenje pod 3. iz sredstava bolničkog proračuna

KLINIČKO LABORATORIJSKE KORELACIJE I KOMUNIKACIJSKO DIJAGNOSTIČKI PROCES

Clinical-laboratory correlations are the most important part of everyday practice in the era of modern clinical medicine. It is based on the successful functioning of the patient-physician (clinician)-laboratory triangle. Laboratory or other diagnostic tests do not define specific clinical entity or disease; however, they are very useful to make decision related to complicated diagnostic procedures and therapies. Each clinical diagnostic process begins with medical history and physical examination where the doctor uses professional and communication skills. This is followed by setting of the working diagnosis and differential diagnosis. Finally, laboratory tests should help in successful diagnosis and treatment. Daily communication between clinicians and laboratory professionals is very important, and teamwork guidelines are based on modern technological achievements, which is the main postulate for effective diagnostic procedures and treatment. Translational medicine has been developed rapidly in the past ten years, representing a two-way communication between basic science and clinical practice. Discovery of biomarkers and different new molecular pathways in the pathogenesis of disease has enabled early detection of disease when it could not be detected by other standard diagnostic methods. This should lead to more successful diagnosis and treatment.U modernoj medicini kliničko laboratorijske korelacije dio su svakodnevne prakse i temelje se na uspješnom funkcioniranju trokuta bolesnik–liječnik– laboratorij. Laboratorijsko-dijagnostičke pretrage ne definiraju pojedini klinički entitet, ali pomažu kliničaru u donošenju daljnjih složenijih dijagnostičkih procedura i terapijskih odluka. Svaki kliničko-dijagnostički proces započinje anamnezom i fizikalnim pregledom gdje se liječnik koristi stručnim i komunikacijskim vještinama. Nakon stvaranja radne dijagnoze i diferencijalnih dijagnoza odabiru se laboratorijske pretrage koje trebaju pomoći u što bržem i uspješnijem dijagnosticiranju bolesnikovog problema – bolesti. Svakodnevna komunikacija kliničara i laboratorijskih stručnjaka, donošenje smjernica timskim radom utemeljenih na suvremenim tehnološkim dostignućima preduvjet su uspješnog dijagnostičkog procesa i liječenja. Translacijska medicina se razvija zadnjih desetak godina i predstavlja dvosmjernu komunikaciju između bazičnih znanosti i kliničkih struka. Otkriće biomarkera i molekularnih puteva u nastanku bolesti omogućava ranije otkrivanje bolesti kada se ne može otkriti standardnim metodama. To bi trebalo pripomoći u uspješnijem dijagnosticiranju bolesti i liječenju oboljelih

Violent deaths among composers (accidents, drownings and murders)

In this study, we described different accidents, drowning and murders as the main cause of death among 145 composers. We included accidents (48 composers), drowning (26 composers) and murders (71 composers) which were mainly fatal, and premature. Accidents are the third leading cause of deaths today. Murders were often during the wars and revolutions (World War I, II, French, Russian revolution). We mentioned all of the etiologies of these accidents, drowning and murders according to the chronological order of their occurrence. Accidents, drowning and murders caused chiefly a sudden interruption of the composer’s creative work. Composers involved in these accidents died prematurely at the average age of 46.7 years, whereas murdered composers died at the average age of. 44.4 years, and drowned 44,1 years. It is important to conclude that almost 15% of composers died from accidents, drowning and murders. Poisonings - intoxications and suicides were elaborated in previous publications

Psychoses in composers

In this article, we have described the pathographies of fifty composers who were suffering from psychotic disorders. A few of them committed suicide in younger age because of schizophrenia. Others suffered from paranoid personality disorder, or were likely to have a bipolar affective disorder. The vast majority of composers who attempted to commit suicide suffered from severe depressive episodes. Progressive paralysis-neurosyphilis, as well as alcoholic psychosis were previously mentioned and published in this Journal

Maligne bolesti kao uzrok smrti kod 92 skladatelja/glazbenika (uključujući ovisnosti)

This study shows malignant diseases as the main cause of death in composers. Pathographies are listed according to the chronological order of their occurrence. Composers in this study died of malignant diseases in the average age of 66.3 years, (median age 67, range 33-91 years). Unfortunately, one part of this heterogeneous group of composers lived too short, while most of them could realize their creative work. Nowadays many of these composers could be cured thanks to the development of medicine, better diagnostic procedures and treatment options, including more selective radiotherapy, chemotherapy, immunotherapy (monoclonal antibodies, specific target receptor or intracellular signal inhibitors).U ovom radu su prikazane maligne bolesti kao glavni uzrok smrti kod 92 skladatelja. Patografije su navedene kronološki. Prosječna dob smrti skladatelja u ovoj studiji je 66,3 godine (medijan dobi 67 godina, raspon 33-91 godine). Nažalost, značajan dio skladatelja nije mogao zbog malignih oboljenja dostići svoj stvaralački opus, dok je ipak većina dostigla stariju dob i stvaralački maksimum. U današnjici bi mnogi od ovih skladatelja mogli biti izliječeni zahvaljujući napretku suvremene medicine, boljim dijagnostičkim postupcima i terapijskim opcijama liječenja. To ponajprije podrazumijeva ciljanu terapiju poput selektivne kemoterapije, imunoterapije (monoklonska protutijela, specifično ciljani inhibitori staničnih receptora ili unutarstaničnih signalnih puteva)

A case report of acute inferior myocardial infarction in a patient with severe hemophilia A after recombinant factor VIII infusion

RATIONALE: The extent of protective effects of hemophilia against thrombotic events such as myocardial infarction (MI) and other acute coronary syndromes remains to be determined, as major risk factors for cardiovascular disease exist despite factor VIII (FVIII) deficiency. We present a case report of a 41-year-old male with severe hemophilia A and several cardiovascular risk factors. ----- PATIENT CONCERNS: This morbidly obese patient developed chest pressure, followed by chest pain and difficulty in breathing shortly after receiving on-demand treatment with intravenous recombinant FVIII (rFVIII) (turoctocog alfa) dosed per body weight. ----- DIAGNOSES: An electrocardiogram revealed a diagnosis of inferior ST-segment elevation MI. ----- INTERVENTIONS: The patient underwent an urgent coronary angiography using a radial artery approach. During the next 12 months, he received dual antiplatelet treatment, acetylsalicylic acid 100 mg, and clopidogrel 75 mg daily. His treatment for severe hemophilia A was changed to plasma-derived FVIII replacement therapy. -----OUTCOMES: During this 12-month period, he experienced several small bleeds in his elbows. ----- CONCLUSIONS: The temporal relationship between rFVIII infusion and onset of the MI suggests a possible association; however, apart from obesity, the patient also had other major risk factors for arterial thrombosis, such as hypertension and smoking. Furthermore, atherosclerotic disease and underlying atherosclerotic changes could not be excluded with certainty. This case highlights the importance of studies assessing the impact of excess body weight on rFVIII dosing

Fatal diseases of composers due to tobacco smoking and other addictions

In this article we are presenting about 40 tobacco-related pathographies among more than 1 000 general pathographies that we examined, dealing with composers who died of fatal diseases such as cancer, pneumonia and vascular episodes (stroke, heart attack-failure), which were all connected to their tobacco and other addictions

Opsežna duboka venska tromboza u mladog bolesnika kao prva manifestacija rijetke venske anomalije – dvostruke donje šuplje vene: prikaz slučaja

Although venous thromboembolism (VTE) including deep venous thrombosis (DVT) and pulmonary embolism is a major health problem in the world, it is an infrequent disease among young people. It is always mandatory to look at the underlying conditions for VTE, and in young patients, inherited prothrombotic factors should also be evaluated, especially in case of unprovoked VTE. Anomalies of inferior vena cava (IVC) are very rare in the general population. In this case report we describe rare occurrence of extensive DVT in a young male patient with rare anomaly of IVC – duplication of IVC – as a predisposition factor for DVT. Physicians need to be reminded of the IVC anomalies that should be considered in young patients with idiopathic DVT of lower extremity, which may require extended anticoagulant treatment.Iako su venske tromboembolije (VTE) koje uključuju duboku vensku trombozu (DVT) i plućnu emboliju značajan zdravstveni problem u svijetu, one su rijetke bolesti u mladih osoba. Uvijek je potrebno ispitati uzroke koji su doveli do nastanka VTE, a u mladih bolesnika potrebno je također evaluirati i nasljedne protrombotske čimbenike, osobito kod nastanka neprovocirane VTE. Anomalije donje šuplje vene su vrlo rijetke u općoj populaciji. U ovom prikazu slučaja opisujemo rijedak slučaj mladog bolesnika s opsežnom DVT i rijetkom anomalijom donje šuplje vene – dvostrukom donjom šupljom venom – kao čimbenikom rizika za nastanak DVT. Potrebno je podsjetiti liječnike na postojanje anomalija donje šuplje vene koje treba razmotriti u mladih bolesnika s idiopatskom DVT donjih ekstremiteta, što može zahtijevati dugotrajno antikoagulantno liječenje

Influence of blood count, cardiovascular risks, inherited thrombophilia, and JAK2 V617F burden allele on type of thrombosis in patients with Philadelphia chromosome negative myeloproliferative neoplasms

Introduction: Thrombosis is the most common complication in Philadelphia chromosome negative (Ph-) myeloproliferative neoplasms patients. ----- Patients and methods: In a cohort of 258 Ph- myeloproliferative neoplasm patients, the difference between patients with and without thrombosis was analyzed according to genetic thrombophilia factors, JAK2 V617F status and burden allele, blood count, cardiovascular risk factors and age. Patients were also divided in polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) subgroups as well as by the type of thrombosis. ----- Results: Analysis of cardiovascular risk factors regarding arterial thrombosis showed that PV patients with thrombosis had higher incidence of diabetes (P = .030), ET patients more often had hypertension (P = .003) and hyperlipidemia (P = .005), while PMF patients had hyperlipidemia (P = .046) and at least one cardiovascular risk factor (P = .044). Moreover, leukocytes > 18 × 109/L and V617F burden allele > 25.7% were statistically significantly different in PV patients (P = .019 and borderline significant at P = .055, respectively), while in ET patients leukocytes > 9.2 × 109/L (P 55 years were statistically significantly different (P = .002). PMF patients with V617F burden allele ≤ 34.8% were more prone to thrombosis (P = .032). When comparing patients with and without venous thrombosis, cutoff value of V617F burden allele > 90.4% was significant for PV patients with thrombosis (P = .036), as was > 56.7% for PMF patients with thrombosis (P = .046). Platelets ≤ 536 × 109/L and age at diagnosis > 54 years showed statistically significant difference for ET patients with thrombosis (P = .015 and P = .041, respectively). ----- Conclusion: On the basis of our results, a new scoring system for thrombosis risk in PV could be made, while PMF prognostic model may be expanded for better recognition of potential thrombotic risk factors