The cellular story of dishevelleds

Dishevelled (DVL) proteins, three of which have been identified in humans, are highly conserved components of canonical and noncanonical Wnt signaling pathways. These multifunctional proteins, originally discovered in the fruit fly, through their different domains mediate complex signal transduction: DIX (dishevelled, axin) and PDZ (postsynaptic density 95, discs large, zonula occludens-1) domains serve for canonical beta-catenin signaling, while PDZ and DEP (dishevelled, Egl-10, pleckstrin) domains serve for non-canonical signaling. In canonical or beta-catenin signaling, DVL forms large molecular supercomplexes at the plasma membrane consisting of Wnt-Fz-LRP5/6-DVLAXIN. This promotes the disassembly of the beta-catenin destruction machinery, beta-catenin accumulation, and consequent activation of Wnt signaling. Therefore, DVLs are considered to be key regulators that rescue cytoplasmic beta-catenin from degradation. The potential medical importance of DVLs is in both human degenerative disease and cancer. The overexpression of DVL has been shown to potentiate the activation of Wnt signaling and it is now apparent that up-regulation of DVLs is involved in several types of cancer

Extramedullary Plasmacytoma Imitating Neoplasm of the Gallbladder Fossa after Cholecystectomy

Extramedullary plasmacytomas are plasma cell tumors that arise outside of the bone marrow. They account for approximately 3% of plasma cell neoplasms and are most frequently located in the head and neck region. Five months after undergoing cholecystectomy, a 69-year-old patient presented with the pain under the right costal margin and a 12 kg weight loss. Computed tomography of the abdomen demonstrated irregular, vascular mass in the gallbladder fossa that dents towards the duodenum and the pylorus and lowers caudally to the hepatic flexure. His laboratory tests indicated normocytic anemia and showed elevated sedimentation rate. During operative procedure, a tumorous mass in the gallbladder fossa was found, inseparable of the peritoneum of the hepatoduodenal ligament and the IVb liver segment. Histopathological examination and immunohistochemical staining determined the diagnosis of the plasmacytoma. Total resection of the tumor was achieved and after 24-month follow-up patient showed no signs of local recurrence or dissemination of the disease

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

Prijetransfuzijsko ispitivanje i transfuzijsko liječenje pri primjeni monoklonskog protutijela anti-CD38

Daratumumab je prvo monoklonsko protutijelo anti-CD38 koje se primjenjuje u liječenju multiplog mijeloma. Njegova primjena uzrokuje panreaktivnost u testovima prijetransfuzijskog ispitivanja. Panreaktivnost je posljedica vezanja monoklonskog protutijela anti-CD38 na protein CD38 na površini eritrocita, što u standardnom testiranju onemogućuje otkrivanje antieritrocitnih aloprotutijela i osiguranje podudarne krvi za transfuzijsko liječenje. Cilj rada bila je retrospektivna analiza vlastitih iskustava u rješavanju smetnja prijetransfuzijskog ispitivanja uzrokovanih monoklonskim protutijelom anti-CD38 i u transfuzijskom liječenju tih bolesnika. Prikazani su postupci za prijetransfuzijsko ispitivanje i transfuzijsko liječenje bolesnika liječenih monoklonskim protutijelom anti-CD38 koji su provedeni u Kliničkome bolničkom centru Zagreb. U istraživanju je analizirano 10-ero bolesnika liječenih daratumumabom. Prije i poslije primjene daratumumaba pretražena su antieritrocitna protutijela i određen je direktan antiglobulinski test. Pri transfuzijskom liječenju napravljeni su test pretraživanja antieritrocitnih protutijela i križne reakcije standardnim testiranjem i specifičnim postupcima imunohematoloških ispitivanja za uklanjanje smetnja monoklonskog protutijela anti-CD38. Postupci su uključivali obradu eritrocita ditiotreitolom koncentracije 0,2 M i neutralizacijski test uz primjenu reagensa DaraEx. Kod svih bolesnika testovi pretraživanja antieritrocitnih protutijela i križne reakcije bili su nakon primjene daratumumaba pozitivni, dok je direktan antiglobulinski test zbog primjene daratumumaba bio pozitivan u gotovo polovine bolesnika. Nakon obrade eritrocita ditiotreitolom 0,2 M učestalost lažno pozitivnih rezultata testova pretraživanja antieritrocitnih protutijela i križnih reakcija iznosila je oko 40%, a poslije primjene reagensa DaraEx oko 20%. Oba specifična postupka, obrada eritrocita ditiotreitolom 0,2 M i neutralizacijski test primjenom reagensa DaraEx, nisu se pokazala dovoljno pouzdanima u rješavanju smetnja uzrokovanih monoklonskim protutijelom anti-CD38. Zato je za transfuzijsko liječenje tih bolesnika nužno osigurati eritrocitne pripravke podudarne prema klinički najvažnijim antigenima u sustavima krvnih grupa Rh, Kell, Kidd, Duffy i MNS. Dobra suradnja između odjela i transfuzijske službe te postojanje protokola za prijetransfuzijsko ispitivanje i transfuzijsko liječenje ostaju preduvjet za pravodobno i sigurno transfuzijsko liječenje te skupine bolesnika

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

Ulceracije gingive u bolesnice s akutnom mijeloidnom leukemijom: prikaz slučaja i pregled literature

A 40-year-old female patient was admitted to the Department of Oral Medicine due to oral ulcerations. Oral ulcerations were present on vestibular mucosa above teeth 21, 22, 25 and 26 and were 1 cm in diam-eter, and also around teeth 45 and 46. The patient had prolonged neutropenia due to therapy-related myelodysplastic syndrome that progressed to therapy-related acute myeloid leukemia. Initially, the pa-tient was successfully treated with polychemotherapy for non-Hodgkin lymphoma. Unfortunately, many toxic complications ensued, such as peripheral neuropathy, dilated cardiomyopathy and therapy-related myelodysplastic syndrome/therapy-related acute myeloid leukemia. The onset of therapy-related myelo-dysplastic syndrome was less than six months after initiation of chemotherapy treatment, which was ra-ther early, but cytogenetic changes (monosomy 5 and 7) were consistent with the diagnosis. Upon admis-sion to our Department, microbiological swabs were obtained and were all negative, while x-ray finding showed that ulcerations did not have dental cause. Biopsy was not obtained as the patient had severe neutropenia and thrombocytopenia. While viral and fungal swabs were negative, Stenotrophomonas maltophilia was cultured from the oral cavity. Thus, differential diagnoses are listed in this report. Neutro-penic ulcerations did not heal albeit extensive medicamentous oral and systemic treatments were applied and the patient died.Bolesnica u dobi od 40 godina primljena je na Zavod za oralnu medicinu zbog oralnih ulceracija. Oralne ulceracije promjera 1 cm bile su prisutne na vestibularnoj sluznici iznad zuba 21, 22, 25 i 26, a također i oko zuba 45 i 46. Bolesnica je imala produljenu neutropeniju uslijed mijelodisplastičnog sindroma povezanog s terapijom, koji je pro-gredirao u akutnu mijeloidnu leukemiju povezanu s terapijom. U početku je bolesnica uspješno liječena polikemote-rapijom za non-Hodgkinov limfom. Nažalost, uslijedile su mnoge toksične komplikacije poput periferne neuropatije, proširene kardiomiopatije i mijelodisplastičnog sindroma povezanog s terapijom/akutne mijeloidne leukemije pove-zane s terapijom. Terapijski mijelodisplastični sindrom pojavio se u manje od šest mjeseci nakon započinjanja liječenja kemoterapijom, što je bilo prilično rano, ali su citogenetske promjene (monosomija 5 i 7) bile u skladu s dijagnozom. Nakon dolaska na naš Zavod učinjeni su mikrobiološki brisevi i svi su bili negativni, a rendgenski nalaz je isključio odontogenu etiologiju ulceracija. Biopsija nije učinjena, jer je bolesnica imala tešku neutropeniju i trom-bocitopeniju. Iako su virusni i gljivični brisevi bili negativni, Stenotrophomonas maltophilia izolirana je iz usne šup-ljine. Stoga su u ovom prikazu navedene različite dijagnoze. Unatoč ekstenzivnim oralnim i sistemskim tretmanima neutropenične ulceracije nisu zacijelile, a bolesnica je preminula

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