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

Monoklonska protutijela u liječenju ne-Hodgkinovih limfoma

Monoclonal antibodies are an exciting advance in the treatment of lymphoma. They are safe and well-tolerated, and exhibit little cross-resistance with conventional chemotherapeutic agents. In indolent lymphomas, antibody has shown useful response rates both as first line therapy and in relapsed disease. Follicular lymphomas appear to be particularly sensitive to rituximab, and chronic lymphocytic leukaemia to alemtuzumab. In aggressive lymphomas, the addition of rituximab to CHOP chemotherapy significantly prolongs disease-free and overall survival compared to CHOP alone as first-line therapy. Novel agents, including radiolabelled antibodies are showing promise in phase I and II trials in a variety of clinical settings.Monoklonska protutijela su velik korak naprijed u liječenju limfoma. Sigurna su i dobro se podnose, a s konvencionalnim kemoterapijskim lijekovima izazivaju vrlo malu unakrsnu rezistenciju. Kod indolentnih limfoma protutijela su pokazala korisnu stopu odgovora kad su primjenjivani kao terapija prvoga reda i kao terapija kod relapsa bolesti. Folikularni limfomi su osobito osjetljivi na rituksimab, a kronična limfocitna leukemija na alemtuzumab. Dodavanjem rituksimaba kemoterapiji po shemi CHOP u liječenju agresivnih limfoma znatno se produljuje razdoblje bez bolesti i sveukupno preživljenje usporedimo li rezultate primjene samo kemoterapije CHOP kao terapije prvoga reda. Novi lijekovi među kojima su radioaktivno obilježena protutijela u kliničkim ispitivanjima I. i II. faze pokazuju obećavajuće rezultate u različitim kliničkim situacijama

Monoklonska protutijela u liječenju ne-Hodgkinovih limfoma

Monoclonal antibodies are an exciting advance in the treatment of lymphoma. They are safe and well-tolerated, and exhibit little cross-resistance with conventional chemotherapeutic agents. In indolent lymphomas, antibody has shown useful response rates both as first line therapy and in relapsed disease. Follicular lymphomas appear to be particularly sensitive to rituximab, and chronic lymphocytic leukaemia to alemtuzumab. In aggressive lymphomas, the addition of rituximab to CHOP chemotherapy significantly prolongs disease-free and overall survival compared to CHOP alone as first-line therapy. Novel agents, including radiolabelled antibodies are showing promise in phase I and II trials in a variety of clinical settings.Monoklonska protutijela su velik korak naprijed u liječenju limfoma. Sigurna su i dobro se podnose, a s konvencionalnim kemoterapijskim lijekovima izazivaju vrlo malu unakrsnu rezistenciju. Kod indolentnih limfoma protutijela su pokazala korisnu stopu odgovora kad su primjenjivani kao terapija prvoga reda i kao terapija kod relapsa bolesti. Folikularni limfomi su osobito osjetljivi na rituksimab, a kronična limfocitna leukemija na alemtuzumab. Dodavanjem rituksimaba kemoterapiji po shemi CHOP u liječenju agresivnih limfoma znatno se produljuje razdoblje bez bolesti i sveukupno preživljenje usporedimo li rezultate primjene samo kemoterapije CHOP kao terapije prvoga reda. Novi lijekovi među kojima su radioaktivno obilježena protutijela u kliničkim ispitivanjima I. i II. faze pokazuju obećavajuće rezultate u različitim kliničkim situacijama

Primarni limfomi središnjeg živčanog sustava

Primary central nervous system lymphoma (PCNSL) is a distinct form of aggressive non-Hodgkin’s lymphoma (NHL) confined to the central nervous system. PCNSL typically affects older population. Individuals with HIV infection are especially at risk of PCNSL development and their outcome is extremely poor. Due to the presence of the blood brain barrier, PCNSL is treated differently from other extranodal NHLs. The mainstay of treatment is the high-dose methotrexate (MTX). Despite the treatment, local relapses are frequent and almost inevitably fatal. Intensification of treatment is possible in patients younger than 60 years. Radiotherapy is effective but complicated with significant delayed neurotoxicity, especially in the elderly. There are no curative treatment options in older patients who represent the majority of patients. Novel less toxic agents have modest activity. Prospective multicentric trials are needed to establish the optimal treatment for PCNSL.Primarni limfom središnjeg živčanog sustava (PLSZŠ) je poseban oblik agresivnog ne-Hodgkinovog limfoma (NHL) lokaliziran u središnjem živčanom sustavu. PLSZŠ tipično zahvaća stariju populaciju. Za razvoj PLSZŠ-a posebno su rizične osobe s HIV infekcijom čija je prognoza ekstremno loša. Zbog krvno-moždane barijere, PLSZŠ se liječi drugačije od ostalih ekstranodalnih NHL. Temelj liječenja su visoke doze metotreksata. Unatoč liječenju, lokalni relapsi su česti i gotovo uvijek fatalni. Radioterapija je učinkovita, ali komplicirana značajnom kasnom neurotoksičnosti, posebno u starijih. U starijih bolesnika, koji čine većinu, nema terapijskih opcija koje bi dovele do izlječenja. Noviji, manje toksični lijekovi, skromnog su djelovanja. Potrebne su prospektivne multicentrične studije kako bi se definiralo optimalno liječenje PLSZŠ-a

Hematological abnormalities in rheumatic diseases

Hematološke promjene se javljaju u 25-70% bolesnika s upalnim reumatskim bolestima. Najčešći hematološki poremećaj je anemija kronične bolesti uzrokovana upalnim citokinima koji izazivaju promjene u metabolizmu željeza, proizvodnji eritropoetina, proliferaciji prethodnih stanica crvene loze i dužini života eritrocita. Glavni regulator prometa željeza u organizmu je hepcidin koji koči apsorpciju željeza kroz crijevni epitel i oslobađanje željeza iz stanica monocitno - makrofagnog sustava. Liječenje anemije kronične bolesti uspješno se provodi rekombinantnim eritropoetinom i željezom. Znatno su rjeđi poremećaji drugih krvnih loza na razini koštane srži ili periferne krvi koji se očituju smanjenjem ili povećanjem broja leukocita i trombocita. Ostali hematološki poremećaji mogu se smatrati dijelom osnovnog autoimunog zbivanja. Trajna antigena stimulacija može biti poticaj na limfomagenezu te je učestalost limfoma u bolesnika s upalnim reumatskim bolestima 5-6 puta veća nego u običnoj populaciji.Haematological abnormalities are present in 25-50% patients with rheumatic diseases. The most common finding is anaemia of chronic disease which is driven by inflammatory cytokines. Hepcidin plays key role in iron homeostasis. It reduces iron absorption from duodenum and iron release from reticuloendothelial cells. Anaemia of chronic disease could be successfully treated by recombinant erythropoietin in combination with iron supplementation. Various abnormalities can be observed in the leukocyte and platelets counts. Other haematological disturbances are considered as part of autoimmune disease. Prolonged antigen stimulation can induce lymphomagenesis and lymphoma incidence in patients with rheumatic diseases is 5 to 6-fold increased compared to normal population

FNA based diagnosis of head and neck nodal lymphoma [Citomorfološka dijagnoza limfoma u području glave i vrata]

Fine-needle aspiration (FNA) biopsy has become a well established technique in the diagnosis, staging, and follow-up of patients with head and neck lesions. As in lymphoma diagnostics, FNA serves as a screening method in evaluating potentially affected lymph node for open or core biopsy. According to the World Health Organization classification of lymphoid neoplasms, today it is important to recognize cell morphology and reveal its phenotype, then combine it with different genotypic information and clinical data to provide appropriate therapy. The aim of this study was to assess the efficacy of FNA and immunocytochemistry based lymphoma diagnostic in head and neck region. We conducted a retrospective study during a period of three years where cases with either FNA diagnosis or clinical suspicion of newly recognized or relapsing lymphoma were reviewed. In the study were included patients that were referred to our laboratory from hematology department, in whom head and neck lymphadenopathia was found and lymph node FNA preceded other procedures. Two hundred eighty-five aspirations from 248 patients fulfilled study criteria. Adequate specimens were diagnosed as lymphoma in 100 cases (36%), in 65 male and 35 female patients, 76 in patients with newly discovered disease and 24 in patients with prior lymphoma diagnosis. Overall sensitivity of FNA specimens in the diagnosis of head and neck lymphomas was 90%, specificity 88%, predictive value of a positive result 97%, and predictive value of negative result 61%. Based on our results FNA corroborated with immunophenotyping by immunocytochemistry can be method of choice in primary lymphoma diagnosis as a method complementary to histopathology in lymphoma diagnostics

Treatment of patients with advanced Hodgkin’s lymphoma with escalated BEACOPP

Cilj: Svrha rada je pokazati rezultate, kao i nuspojave, u bolesnika s Hodgkinovim limfomom stadija III ili IV, koji su liječeni s 4 ciklusa eBEACOPP-a i 4 ciklusa sBEACOPP-a. Metode: U razdoblju od listopada 2003. do ožujka 2011. godine liječeno je 15 bolesnika. Medijan dobi bio je 28 godina (19 – 47), s medijanom praćenja od 14 mjeseci (1 – 90). Svi su bolesnici liječeni s 4 ciklusa eBEACOPP-a, 11 bolesnika liječenje je nastavilo s 4 ciklusa sBEACOPP-a, kod 3 bolesnika, zbog značajnih nuspojava, primijenjen je program ABVD, dok je jedan bolesnik (plućna toksičnost) liječen programom COPP. Rezultati: U 10 bolesnika liječenjem je postignuta kompletna remisija bolesti, a u 5 bolesnika parcijalna remisija bolesti; ukupan odgovor na terapiju bio je 100 %. U 5 bolesnika koji su postigli parcijalnu remisiju bolesti provedena je radioterapija. Nakon praćenja od 14 mjeseci, preživljenje bez znakova bolesti, kao i ukupno preživljenje, iznosi 100 %. Kod većine bolesnika primijećena je ozbiljna hematotoksičnost, a 5 bolesnika (33 %) je zbog febrilne neutropenije liječeno bolnički. Rasprava i zaključak: Ova preliminarna studija potvrđuje da je program liječenja eBEACOPP-om izrazito učinkovit, a rezultati su u skladu s rezultatima dosad provedenih studija. Radi se o malom uzorku bolesnika s kratkim razdobljem praćenja. Treba naglasiti da za sada nisu zamijećeni rani relapsi bolesti. Toksičnost je značajna, naročito hematotoksičnost uz neutropenijske vrućice.Aim: We present the outcome and toxicity of intensive chemotherapy protocol escalated BEACOPP (eBEACOPP 4 cycles) followed by standard BEACOPP (sBEACOPP 4 cycles). Methods: From October 2003 untill March 2011, 15 patients were treated with eBEACOPP. The median age was 28 years with a range of 19 to 47 years; median follow-up was 14 months (range 1 to 90 months). All patients received 4 cycles of eBEACOPP; 11 patients continued their therapy with 4 cycles of sBEACOPP; in 3 patients ABVD was given because of severe toxicity, while in one patient with lung toxicity COPP was the therapy of choice after eBEACOPP. Results: Complete remission and partial remission has been achieved in 10 and 5 patients, respectively. The response to treatment was 100 %. In 5 patients with PR, radiotherapy was given after chemotherapy. After the median of 14 months follow-up the probability of progression-free survival and overall survival is 100 %. The majority of patients experienced serious hematological toxicity and 5 patients (33 %) had to be admitted to hospital because of febrile neutropenia. Discussion and conclusion: This study confirms the efficacy of eBEACOPP protocol, and the results are similar with the reported data. However, the number of patients and relatively short follow-up is the weakness of this study. It has to be stressed out that relapse of Hodgkin lymphoma was not reported. Toxicity is a serious problem, especially hematological toxicity with febrile neutropenia

FNA Based Diagnosis of Head and Neck Nodal Lymphoma

Fine-needle aspiration (FNA) biopsy has become a well established technique in the diagnosis, staging, and follow-up of patients with head and neck lesions. As in lymphoma diagnostics, FNA serves as a screening method in evaluating potentially affected lymph node for open or core biopsy. According to the World Health Organization classification of lymphoid neoplasms, today it is important to recognize cell morphology and reveal its phenotype, then combine it with different genotypic information and clinical data to provide appropriate therapy. The aim of this study was to assess the efficacy of FNA and immunocytochemistry based lymphoma diagnostic in head and neck region. We conducted a retrospective study during a period of three years where cases with either FNA diagnosis or clinical suspicion of newly recognized or relapsing lymphoma were reviewed. In the study were included patients that were referred to our laboratory from hematology department, in whom head and neck lymphadenopathia was found and lymph node FNA preceded other procedures. Two hundred eighty-five aspirations from 248 patients fulfilled study criteria. Adequate specimens were diagnosed as lymphoma in 100 cases (36%), in 65 male and 35 female patients, 76 in patients with newly discovered disease and 24 in patients with prior lymphoma diagnosis. Overall sensitivity of FNA specimens in the diagnosis of head and neck lymphomas was 90%, specificity 88%, predictive value of a positive result 97%, and predictive value of negative result 61%. Based on our results FNA corroborated with immunophenotyping by immunocytochemistry can be method of choice in primary lymphoma diagnosis as a method complementary to histopathology in lymphoma diagnostics

High-dose ifosfamide and mitoxantrone (HDIM) in patients with relapsed or refractory Hodgkin's lymphoma

Relapsed/refractory Hodgkin's lymphoma (HL) is treated with salvage chemotherapy and autologous stem cell transplantation (ASCT). Optimal chemotherapy is unknown. We retrospectively analyzed outcomes of 58 patients treated with 2 cycles of high-dose ifosfamide and mitoxantrone (HDIM). HDIM consisted of ifosfamide 5 g/m(2)/day and MESNA 5 g/m(2)/day in continuous 24-h infusion (days 1 and 2), MESNA 2.5 g/m(2) over 12 h (day 3), and mitoxantrone 20 mg/m(2) (day 1) administered every 2 weeks. Stem cells were collected after the first cycle. Responding patients proceeded to ASCT. Toxicity was acceptable. Stem cell mobilization was successful in 96 % of patients. Overall response rate was 74 % (89 % in relapsing and 45 % in refractory patients) with 31 % complete remissions. After a median follow-up of 54 months, 5-year event-free survival was 56 % (69 % for relapsing and 35 % for refractory patients), and 5-year overall survival was 67 % (73 % for relapsing and 55 % for refractory patients). Significant adverse prognostic factors were refractoriness to previous therapy and HDIM failure. No differences in outcomes were noted between patients with early and late relapses or between complete and partial responders. HDIM is a well-tolerated and effective regimen for relapsed and refractory HL with excellent stem cell mobilizing properties. Patients failing HDIM may still benefit from other salvage options

Immunoglobulin heavy/light chain analysis enhances the detection of residual disease and monitoring of multiple myeloma patients

Aim To evaluate the clinical utility of incorporating a novel heavy/light chain immunoassay (HLC) into the existing methods for the assessment of multiple myeloma (MM) patients. Methods Convenience sera samples from 90 previously treated IgG and IgA MM patients in different disease stages were analyzed. The study was conducted in Clinical Hospital Center Zagreb between 2011 and 2013. The collected sera were analyzed by standard laboratory techniques (serum protein electrophoresis, quantification of total immunoglobulins, serum immunofixation, serum free light chain [FLC] assay) and HLC assay. Results HLC ratios outside the normal range were found in 58 of 90 patients, including 28 out of 61 patients with total immunoglobulin measurements within the normal range and 5 out of 23 patients in complete response. Both elevated HLC isotype level and abnormal HLC ratio correlated with the parameters of tumor burden, including percentage of plasma cells in the bone marrow (P < 0.001 and P = 0.002, respectively) and an abnormal serum FLC ratio (for both P < 0.001). In addition, abnormal HLC isotype level correlated with serum beta-2-microglobulin level (P = 0.038). In terms of prognosis, abnormal HLC isotype level and abnormal HLC ratio were significantly associated with shorter overall survival (P < 0.001 and P = 0.002, respectively). Interestingly, suppression of the uninvolved (polyclonal) isotype pair, but not other non-myeloma immunoglobulin isotypes, was also associated with a shorter overall survival (P = 0.021). In a multivariate analysis, an abnormal HLC ratio and β2-microglobulin level >3.5mg/L were independent risk factors for survival. Conclusion The new HLC assay has greater sensitivity in detecting monoclonal protein, correlates with tumor burden markers, and affects patients’ outcome