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Maligni pleuralni mezoteliom rijetka je i agresivna primarna novotvorina mezotelnih stanica pleure. Glavni rizični čimbenik je izloženost azbestu, najčešće uz latenciju od 30–50 godina. Unatoč terapiji medijan preživljenja je od 4 do 18 mjeseci, ovisno o izvoru. Cilj istraživanja bio je odrediti karakteristike bolesnika oboljelih od malignoga pleuralnog mezotelioma te ishode njihova liječenja na KBC Zagreb u razdoblju od 1999. do 2012. godine. Ispitane su karakteristike 101 bolesnika dijagnosticiranog i liječenog na KBC Zagreb u razdoblju od rujna 1999. do rujna 2012. Analizirali smo ukupno preživljenje (OS), preživljenje bez progresije bolesti (PFS) te preživljenje ovisno o histološkom podtipu tumora, dobi, kliničkom stadiju, pleurodezi talkom i modalitetu liječenja. Koristili smo Kaplan- Meierovu metodu za izradu krivulje preživljenja. 89 bolesnika bilo je muškog, 12 ženskog spola, a medijan dobi 62 godine. Prema TNM klasifikaciji stadij IV je utvrđen kod 69, 3%, stadij III kod 26, 73%, te stadij II kod samo 3, 96% bolesnika. 73, 26% bolesnika imalo je epiteloidni, 4, 95% sarkomatoidni, 1% mješoviti te 20, 79% NOS (nespecifirani) histološki podtip bolesti. Kirurški je liječeno 14, 85% bolesnika, kemoterapijom 55, 44%, dok je radioterapija primijenjena kod 9, 9% bolesnika. Medijan OS iznosi 11 mjeseci, dok je PFS 10 mjeseci. Prema histološkom podtipu medijan OS iznosio je 11 mjeseci za epiteloidni, 12, 5 za NOS te 5, 5 za sarkomatoidni, a prema kliničkom stadiju 7 mjeseci za stadij II, 17, 5 mjeseci za stadij III te 11 mjeseci za stadij IV. Medijan OS bio je dulji u skupini bolesnika mlađoj od 65 godina (12 naspram 8, 5 mjeseci, p=0.28), skupini sa učinjenom pleurodezom (13 naspram 7, 5 mjeseci, p=0.06) te u skupini liječenoj kemoterapijom (12, 5 naspram 7, 5 mjeseci, p=0.10). Očekivano preživljenje bolesnika oboljelih od malignoga pleuralnog mezotelioma u Republici Hrvatskoj u skladu je s podatcima iz literature. Ispitane metode liječenja relativno skromno utječu na preživljenje bolesnika.

BACKGROUND Recently, as a possible therapy resolving solution, pentadecapeptide BPC 157 therapy, has been used in alleviating various vascular occlusion disturbances. BPC 157 was previously reviewed as novel mediator of Robert cytoprotection and endothelium protection in the stomach, and gut- brain axis, beneficial therapy in gastrointestinal tract, with particular reference to vascular recruitment, ulcerative colitis and tumor cachexia, and other tissues healing. Here we raised new hypothesis about BPC 157 therapy in the Budd- Chiari syndrome in rats, rapid bypassing of the suprahepatic inferior caval vein occlusion, and rats recovery with the active and effective pharmacotherapy treatment. AIM To investigate Budd-Chiari syndrome model (inferior caval vein suprahepatic occlusion) resolution, since BPC 157 resolves various rat vascular occlusion. METHODS We assessed the activated bypassing pathways between the inferior and superior caval veins and portocaval shunt, counteracted caval/portal hypertension, aortal hypotension, venous/arterial thrombosis, electrocardiogram disturbances, liver and gastrointestinal lesions (i.e., stomach and duodenum hemorrhages, in particular, congestion). Rats with suprahepatic occlusion of the inferior vena cava by ligation were medicated at 1 min, 15 min, 24 h, or 48 h post-ligation. Medication consisted of 10 µg/kg BPC 157, 10 ng BPC 157 or 5 mL/kg saline, administered once as an abdominal bath or intragastric application. Gross and microscopic observations were made, in addition to assessments of electricalactivity of the heart (electrocardiogram), portal and caval hypertension, aortal hypotension, thrombosis, hepatomegaly, splenomegaly and venography. Furthermore, levels of nitric oxide, malondialdehyde in the liver and serum enzymes were determined. RESULTS BPC 157 counteracted increased P wave amplitude, tachycardia and ST- elevation, i.e., right heart failure from acute thrombotic coronary occlusion. The bypassing pathway of the inferior vena cava-azygos (hemiazygos) vein-superior vena cava and portocaval shunt occurred rapidly. Even with severe caval portal hypertension, BPC 157 antagonized portal and caval hypertension and aortal hypotension, and also reduced refractory ascites. Thrombosis of portal vein tributaries, inferior vena cava, and hepatic and coronary arteries was attenuated. In addition, there was reduced pathology of the lungs (severe capillary congestion) and liver (dilated central veins and terminal portal venules), decreased intestine hemorrhagic lesions (substantial capillary congestion, submucosal edema and architecture loss), and increased liver and spleen weight. During the period of ligation, nitric oxide- and malondialdehyde-levels in the liver remained within normal healthy values, and increases in serum enzymes were markedly reduced. CONCLUSION BPC 157 counteracts Budd Chiari syndrome in rats.

Background & Aims The guidelines of the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition allow for diagnosis of celiac disease without biopsies in children with symptoms and levels of immunoglobulin A against tissue-transglutaminase (TGA-IgA) 10-fold or more the upper limit of normal (ULN), confirmed by detection of endomysium antibodies (EMA) and positivity for HLA-DQ2/DQ8. We performed a large, international prospective study to validate this approach. Methods We collected data from consecutive pediatric patients (18 years or younger) on a gluten-containing diet who tested positive for TGA-IgA from November 2011 through May 2014, seen at 33 pediatric gastroenterology units in 21 countries. Local centers recorded symptoms; measurements of total IgA, TGA, and EMA; and histopathology findings from duodenal biopsies. Children were considered to have malabsorption if they had chronic diarrhea, weight loss (or insufficient gain), growth failure, or anemia. We directly compared central findings from 16 antibody tests (8 for TGA-IgA, 1 for TGA-IgG, 6 for IgG against deamidated gliadin peptides, and 1 for EMA, from 5 different manufacturers), 2 HLA-DQ2/DQ8 tests from 2 manufacturers, and histopathology findings from the reference pathologist. Final diagnoses were based on local and central results. If all local and central results were concordant for celiac disease, cases were classified as proven celiac disease. Patients with only a low level of TGA-IgA (threefold or less the ULN) but no other results indicating celiac disease were classified as no celiac disease. Central histo-morphometry analyses were performed on all other biopsies and cases were carefully reviewed in a blinded manner. Inconclusive cases were regarded as not having celiac disease for calculation of diagnostic accuracy. The primary aim was to determine whether the nonbiopsy approach identifies children with celiac disease with a positive predictive value (PPV) above 99% in clinical practice. Secondary aims included comparing performance of different serological tests and to determine whether the suggested criteria can be simplified. Results Of 803 children recruited for the study, 96 were excluded due to incomplete data, low level of IgA, or poor-quality biopsies. In the remaining 707 children (65.1% girls; median age, 6.2 years), 645 were diagnosed with celiac disease, 46 were found not to have celiac disease, and 16 had inconclusive results. Findings from local laboratories of TGA-IgA 10-fold or more the ULN, a positive result from the test for EMA, and any symptom identified children with celiac disease (n = 399) with a PPV of 99.75 (95% confidence interval [CI], 98.61–99.99); the PPV was 100.00 (95% CI, 98.68–100.00) when only malabsorption symptoms were used instead of any symptom (n = 278). Inclusion of HLA analyses did not increase accuracy. Findings from central laboratories differed greatly for patients with lower levels of antibodies, but when levels of TGA-IgA were 10-fold or more the ULN, PPVs ranged from 99.63 (95% CI, 98.67–99.96) to 100.00 (95% CI, 99.23–100.00). Conclusions Children can be accurately diagnosed with celiac disease without biopsy analysis. Diagnosis based on level of TGA-IgA 10-fold or more the ULN, a positive result from the EMA tests in a second blood sample, and the presence of at least 1 symptom could avoid risks and costs of endoscopy for more than half the children with celiac disease worldwide. HLA analysis is not required for accurate diagnosis. Clinical Trial Registration no: DRKS00003555. © 2017 AGA Institute

First Experience with Osimertinib in Patients with Newly Developed T790M Mutation Previously Treated with EGFR – TKIs in Croatia

Osimertinib u liječenju pacijenata s T790M mutacijom.

Srčano zatajivanje se ubraja među vodeće uzroke smrti u razvijenim zemljama. Obećavajući eksperimentalni pristupi uključuju poticanje regeneracije srca transplantiranim matičnim stanicama ili poticanje diobe i umnažanja postojećih kardiomiocita. Unatoč nedovoljno ohrabrujućim rezultatima pojedinih kliničkih studija, prvenstveno baziranih na terapiji matičnim stanicama, znanstveno-klinički interes za razvijanjem i poboljšanjem ovakvih potencijalnih terapijskih pristupa ne jenjava. Naš rad uključuje izradu i primjenu genskih biljega za obilježavanje i praćenje živih kardiomiocita diferenciranih iz matičnih stanica, te istraživanje genskih biljega koji omogućuju promatranje napredovanja kardiomiogene diferencijacije. Usmjerena, in vitro kardiomiogena diferencijacija pluripotentnih matičnih stanica je postignuta primjenom kombinacije čimbenika rasta, aktivina A (50 ng/ml) i koštanog morfogenetskog proteina-4 (10 ng/ml) u RPMI/B27 staničnom mediju. Pojava sveobuhvatnih područja spontanih i ritmičnih kontrakcija upućivala je na nazočnost diferenciranih kardiomiocita, što je potvrđeno različitim metodama detekcije izražaja gena i elektrofiziološkim metodama. Praćenje živih kardiomiocita nakon in vitro diferencijacije omogućila nam je izrada lentivirusnog vektora koji je posredovao prijenos reporterskog gena za pojačani zeleni fluorescentni protein koji je bio pod transkripcijskom kontrolom promotora gena lakog lanca miozina-2v. Vektor je proizveden podkloniranjem reporterskog konstrukta u lentivirusni transfer plazmid pHR(+)c.Ub.MCSoligo.R(-)W(+). Primjenom ovog načina označavanja kardiomiocita potvrđena je visoka učinkovitost kardiomiogene diferencijacije, koja iznosi 65-85%, ovisno o staničnoj liniji, uz učinkovitost transdukcije od 98%. Sam tijek in vitro diferencijacije različitih pluripotentnih staničnih linija je praćen uz pomoć kvantitativnog PCR-a, pri čemu je određivan izražaj skupa gena karakterističnih za pojedine stadije kardiomiogeneze, i to: OCT4 (genski biljeg pluripotentnosti), brachyury (T ; biljeg mezendoderma), MESP1, NKX2.5 i ISL1 (biljezi rane faze indukcije kardiomiogeneze), GATA4, MEF2C, TNNT2 i MYL7 (biljezi kasne faze diferencijacije) te HCN4, SCN5A, CACNA1C, KCNH2, KCNJ2 i KCND3 (ionski kanali u kardiomiocitima). Analizom je utvrđeno da se vremenski obrazac izražaja ovih genskih biljega podudara s pojedinim fazama kardiomiogene diferencijacije. U zaključku, primjena ovih pristupa genskog obilježavanja kardiomiocita predstavlja platformu za razvoj znanstveno-dijagnostičkih pomagala uz pomoć kojih bi se mogla pratiti terapijska regeneracija srca koju bismo mogli očekivati u budućnosti.

The sphincters failure is a part of NSAIDs-toxicity that can be accordingly counteracted. We used a safe stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419), LD1 not achieved, since successful in inflammatory bowel disease trials, and counteracts esophagitis, sphincters failure, gastrointestinal ulcer and skin ulcer, external and internal fistulas in rats, and particularly counteracts all NSAIDs-lesions. We assessed lower esophageal sphincter and pyloric sphincter pressure (cmH

SUBUNGUAL EXOSTOSIS OF THE THUMB - CASE REPORT IN AN EIGHT YEAR OLD GIRL

New Cytoprotection/Adaptive Cytoprotection: Peroral Strong Alcohol in Rat to Resolve the Regular Eating/Drinking Habits and Mucosa Maintenance

It is indisputable that nowadays one of the hardest and most important tasks in medicine and especially in medical education, is the conversion of the extensive amount of available data, into medical experience, after a proper analysis. A project under the title “ICT (Information and Communication Technology) eModules on HistoPathology: a useful online tool for students, researchers and professionals – HIPON”, co-financed by the Lifelong Learning Program of the Education, Audiovisual and Culture Executive Agency (EACEA), The Commission of the European Union, has been launched at the beginning of 2013. HIPON’s purpose is not to provide just another pathology website atlas, but to convey professional experience and thinking in pathology. HIPON has resulted in a well-structured and user-friendly, open resource, multi-language, e-learning platform which, taking advantage of modern image technology, offers medical students, researchers, and professionals a valuable teaching instrument so that they can acquire professional experience in pathology. The mid-term report of HIPON has been favorably evaluated by the EACEA experts who appreciated the potential of our teaching tool in providing the opportunity and the means to acquire medical experience. Through the use of virtual slides, educative videos and microscopic, high resolution, marked images accompanied by relevant questions and answers, HIPON project aims to make end-users able to think as experienced pathologists and become highly efficient in correlating pathologic data with other clinical-laboratory information. © 2015 Riccioni et al.

While very rarely reported, duodenocutanenous fistula research might alter the duodenal ulcer disease background and therapy. Our research focused on rat duodenocutaneous fistulas, therapy, stable gastric pentadecapeptide BPC 157, an anti-ulcer peptide that healed other fistulas, nitric oxide synthase-substrate L- arginine, and nitric oxide synthase-inhibitor L-nitro-arginine methyl ester (L-NAME). The hypothesis was, duodenal ulcer-healing, like the skin ulcer, using the successful BPC 157, with nitric oxide-system involvement, the "wound healing-therapy", to heal the duodenal ulcer, the fistula-model that recently highlighted gastric and skin ulcer healing. Pressure in the lower esophageal and pyloric sphincters was simultaneously assessed. Duodenocutaneous fistula-rats received BPC 157 (10 μg/kg or 10 ng/kg, intraperitoneally or perorally (in drinking water)), L-NAME (5 mg/kg intraperitoneally), L-arginine (100 mg/kg intraperitoneally) alone and/or together, throughout 21 days. Duodenocutaneous fistula- rats maintained persistent defects, continuous fistula leakage, sphincter failure, mortality rate at 40% until the 4(th) day, all fully counteracted in all BPC 157-rats. The BPC 157- rats experienced rapidly improved complete presentation (maximal volume instilled already at 7(th) day). L-NAME further aggravated the duodenocutaneous fistula-course (mortality at 70% until the 4(th) day) ; L-arginine was beneficial (no mortality ; however, maximal volume instilled not before 21(st) day). L- NAME-worsening was counteracted to the control level with the L-arginine effect, and vice versa, while BPC 157 annulled the L-NAME effects (L-NAME + L-arginine ; L-NAME + BPC 157 ; L-NAME + L-arginine + BPC 157 brought below the level of the control). It is likely that duodenocutaneous fistulas, duodenal/skin defect simultaneous healing, reinstated sphincter function, are a new nitric oxide-system related phenomenon. In conclusion, resolving the duodenocutanenous fistulashealing, nitric oxide-system involvement, should illustrate further wound healing therapy to heal duodenal ulcers.

Atypical presentation of S1 radiculopathy in a 53- year-old man is presented. Patient noticed calf swelling associated with pain. Extensive radiological diagnostic procedure and muscle and bone biopsy were performed in order to exclude the presence of tumor. Electromyography of the muscles was diagnostic for radicular lesion of S1 segment. After surgical laminectomy, calf enlargement and pain remained. This case provides further evidence that chronic radiculopathy could be responsible for development of neurogenic muscle hypertrophy and focal myositis, and that careful diagnostic evaluation is needed to exclude asymmetric presentation of systemic neuromuscular condition or tumor. This is the first case describing PET/CT finding in focal myositis associated with lumbosacral radiculopathy.

Research Article Open Access Mortal Furosemide-Hypokalemia-Disturbances in Rats NO-System Related Shorten Survival by L-NAME. Therapy Benefit with BPC 157 Peptide More Than With L-Arginine