BRAFV600E mutations are found in approximately 10% of colorectal cancer patients and are associated with worse prognosis and poor outcomes with systemic therapies. The aim of this study was to ...identify novel druggable features of BRAFV600E-mutated colon cancer (CC) cells associated with the response and resistance to BRAFV600E inhibitor vemurafenib. Towards this aim, we carried out global proteomic profiling of BRAFV600E mutant vs. KRAS mutant/BRAF wild-type and double wild-type KRAS/BRAF CC cells followed by bioinformatics analyses. Validation of selected proteomic features was performed by immunohistochemistry and in silico using the TCGA database. We reveal an increased abundance and activity of nucleophosmin (NPM1) in BRAFV600E-mutated CC in vitro, in silico and in tumor tissues from colon adenocarcinoma patients and demonstrate the roles of NPM1 and its interaction partner c-Myc in conveying the resistance to vemurafenib. Pharmacological inhibition of NPM1 effectively restored the sensitivity of vemurafenib-resistant BRAF-mutated CC cells by down-regulating c-Myc expression and activity and consequently suppressing its transcriptional targets RanBP1 and phosphoserine phosphatase that regulate centrosome duplication and serine biosynthesis, respectively. Altogether, findings from this study suggest that the NPM1/c-Myc axis could represent a promising therapeutic target to thwart resistance to vemurafenib in BRAF-mutated CC.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We studied 115 cases of EEC diagnosed on hysterectomy specimens. Double immunohistochemical staining (D2-40/CD31) was performed in all 115 cases to show LVI and BVI on the same slide. MELF pattern ...invasion was present in 24/115 (21%) cases. MELF-positive tumors had a higher frequency of LVI than MELF-negative tumors (58% and 23%, respectively); the frequency of BVI was twice as high in MELF-positive tumors in comparison to MELF-negative tumors (25% and 12%, respectively). These differences were significant (p ˂ 0.0001). All tumors with positive BVI also had a concomitant LVI. The presence of MELF invasion had no impact on overall survival, confirming previous studies. 5-year survival rates were almost equal in cases with negative LVSI and cases with positive isolated LVI (98% vs. 97%). However, in cases where BVI was also present, the 5-year survival rate was significantly lower, 63% (p ˂ 0.0001). Furthermore, BVI proved to be an independent prognostic factor for overall survival, disease-free survival, and recurrence in the multivariate analysis. In conclusion, MELF pattern invasion is a good predictor of lymphatic and blood vessel invasion but has no prognostic value. Our results suggest that BVI in EEC has greater clinical value than isolated LVI or myometrial invasion patterns, and the therapeutic approach should be guided by BVI presence. Therefore, we hope this study will promote the routine evaluation of BVI in the context of EEC diagnostic procedures.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Kirurška patologija najznačajniji je i vremenski najzahtjevniji dio prakse većine patologa. Ima za cilj dati/isključiti definitivnu dijagnozu bolesti temeljeći se na uzorcima tkiva. Dva su glavna ...tipa tkivnih uzoraka za patološku analizu: biopsije i kirurške resekcije. Četiri su glavna dijela kirurške patologije koji se koriste u konačnoj dijagnostici tkivnih uzoraka: makroskopski pregled, patohistološki pregled koji se temelji na svjetlosnoj mikroskopiji, imunohistokemija i molekularne/citogenetske analize. Rezultat rada patologa je patohistološko izvješće. Ono sadrži makroskopski i mikroskopski opis lezije, dijagnozu ili diferencijalnu dijagnozu. Postoje situacije kada je potrebno dijagnozu postaviti za vrijeme kirurškog zahvata, dok je pacijent pod anestezijom. Tada se koristi hitna ili intraoperacijska biopsija, na smrznutim tkivnim rezovima. Hitna ili intraoperacijska biopsija je hitno stanje u patologiji koje zahtijeva dobru suradnju između kirurga i patologa te iskusnog i dobro educiranog patologa koji je svjestan mogućnosti, ali i ograničenja hitne biopsije. Resekcijski rubovi su rubovi ili površine koje je napravio kirurg. Udaljenost između tumora i resekcijskog ruba naziva se kirurški rub. Kirurški rubovi izuzetno su važni jer pozitivnost rubova korelira s recidivom bolesti. Definicija pozitivnog kirurškog ruba ovisi o vrsti tumora, njegovoj biologiji i lokalizaciji bolesti. Jedan od najvažnijih ciljeva kirurške patologije je dijagnostika malignih bolesti i procjena proširenosti bolesti, odnosno klasifikacija tumora, prema odrednicama Svjetske zdravstvene organizacije. Patološka klasifikacija (p) malignih bolesti označava se kao pTNM (primarni tumor – T, regionalni limfni čvorovi – N, udaljene metastaze – M). Ona se temelji na podacima dobivenim prije kirurškog liječenja uz modifikaciju proizašlu iz patohistološke analize tkiva.
Cilj istraživanja je bio utvrditi utjecaj pandemije COVID-19 na sveukupni rad patohistološkog i citološkog laboratorija u KBC-u Rijeka kao i na dijagnostiku nekih od najčešćih malignih bolesti.
...Retrospektivno su iz računalne baze podataka izvučeni i međusobno uspoređeni brojevi patohistoloških i citoloških nalaza, novodijagnosticiranih malignoma dojke, pluća, debelog crijeva, endometrija i prostate te molekularnih testova za analizu mutacije EGFR i HPV-infekcije za razdoblje od 1. ožujka do 30. rujna 2019. (prije pandemije) te od 1. ožujka do 30. rujna 2020. (za vrijeme pandemije COVID-19).
Ukupni broj izvršenih pretraga bio je statistički značajno manji za vrijeme pandemije COVID-19 u 2020. u odnosu na isto razdoblje 2019. (p<0,000), patohistološke dijagnostike za 24%, neginekoloških citoloških nalaza za 20%, ginekoloških za 13% te papa testova za 11% manje. Za vrijeme COVID-19 u odnosu na isto razdoblje prije pandemije broj novodijagnosticiranih malignih tumora značajno je smanjen za maligne novotvorine debelog crijeva (–25%, p<0,0001). Smanjenje novih slučajeva karcinoma dojke (–3%) i karcinoma prostate (–4%) bilo je manje izraženo, dok je povećanje evidentirano za karcinome pluća (+2%) i endometrija (+53%). Broj HPV-testova značajno je pao za vrijeme pandemije COVID-19, za 40% (p<0,0001).
Ovim radom smo potvrdili očekivano značajno smanjenje opsega rada tijekom prvog vala pandemije COVID-19 u 2020., i to od 11% do 40%, iako broj bolesnica/ka s novodijagnosticiranim karcinomima, osim s karcinomom debelog crijeva, nije značajno pao. Važno bi bilo formirati zajednički nacionalni registar koji bi prikupio ne samo dijagnostičke, već i terapijske postupke, posebno onkoloških bolesnica/ka, čime bi se dobio objektivniji uvid u probleme zdravstvenog sustava za vrijeme pandemije. Ovi podatci mogu poslužiti promišljanju mjera i strategije za što adekvatnije zbrinjavanje ne samo oboljelih od COVID-19, već i ostalih.
Simultaneous occurrence of T-cell and B-cell neoplasms is rare, and etiologic relationships between these 2 malignancies are poorly understood. We describe the case of a 66-year-old woman who was ...admitted to the hospital because of fever, hemoptysis, lymphadenopathy, and skin rash. Enlarged lymph nodes in axillary, pectoral, paratracheal, and periportal regions as well as slight hepatomegaly and splenomegaly were confirmed. A peripheral blood smear revealed rouleaux formation and numerous circulating plasma cells, with plasmacytoid lymphocytes. Immunofixation-electrophoresis detected a monoclonal band defined as immunoglobulin (IgG)-lambda light chains with broad-band polyclonal IgA. The patient died from abrupt splenic rupture before diagnostic work-up was finished. Postmortem examination revealed infiltration of atypical lymphoid cells exhibiting high proliferative activity admixed with typical and atypical plasma cells in several organs. Thus, plasma cell leukemia (IgG-lambda) as a rare and aggressive variant of plasma cell myeloma in the present case was associated with aggressive peripheral T-cell lymphoma and polyclonal (IgA) plasmacytosis.
Metabolic-associated fatty liver disease (MAFLD) is a spectrum of clinical manifestations ranging from benign steatosis to cirrhosis. A key event in the pathophysiology of MAFLD is the development of ...nonalcoholic steatohepatitis (NASH), which can potentially lead to fibrosis and hepatocellular carcinoma, but the triggers of MAFLD-associated inflammation are not well understood. We have observed that lipid accumulation in hepatocytes induces expression of ligands specific to the activating immune receptor NKG2D. Tissue-resident innate-like T cells, most notably γδ T cells, are activated through NKG2D and secrete IL-17A. IL-17A licenses hepatocytes to produce chemokines that recruit proinflammatory cells into the liver, which causes NASH and fibrosis. NKG2D-deficient mice did not develop fibrosis in dietary models of NASH and had a decreased incidence of hepatic tumors. The frequency of IL-17A
γδ T cells in the blood of patients with MAFLD correlated directly with liver pathology. Our findings identify a key molecular mechanism through which stressed hepatocytes trigger inflammation in the context of MAFLD.
Cilj: Prikazati bolesnika s hepatocelularnim karcinomom koji je izravno invadirao desni atrij, a inicijalno se prezentirao bezbolnom žuticom i kardijalnom insuficijencijom. Prikaz slučaja: Na Zavod ...za gastroenterologiju zaprimljen je sedamdesetsedmogodišnji bolesnik zbog bezbolne žutice i kardijalne insuficijencije. U fizikalnom statusu uočeni su edemi obiju potkoljenica i natkoljenica te hepatomegalija. Laboratorijskom analizom utvrđene su povišene vrijednosti kreatinina u serumu, ukupnog bilirubina, jetrenih enzima te produženo protrombinsko vrijeme i aktivirano parcijalno tromboplastinsko vrijeme. Nativna snimka abdomena pokazala je uredan nalaz. U daljnjoj obradi učinjen je ultrazvuk abdomena na kojem je prikazana uvećana jetra, nepravilnije površine, difuzno hiperehogena, inhomogena, bez vidljivih fokalnih lezija uz proširenje intrahepatičnih žučnih vodova. Test na markere hepatitisa B i C bio je negativan. Zbog razjašnjavanja uzroka bilijarne opstrukcije indicirana je magnetska rezonancija abdomena i magnetnorezonantna kolangiopankreatografija (MRCP). Otkrivena je infiltrativna tumorska tvorba koja opsežno zahvaća žučne vodove, invadira donju šuplju venu i direktno prodire u desni atrij. Širokoiglenom biopsijom i patohistološkom analizom dijagnosticiran je hepatocelularni karcinom (HCC). Tijekom hospitalizacije ordinirana je kardijalna terapija, niskomolekularni heparin, supstitucija albumina i antibiotska terapija zbog infekcije bakterijom Clostridium difficile. Usprkos intenzivnom liječenju pacijent je preminuo s kliničkom slikom višeorganskog zatajenja. Zaključak: Izravna penetracija HCC-a u desni atrij rijedak je entitet. U bolesnika koji se prezentiraju bezbolnom žuticom uz negativan nalaz ultrazvuka, potrebno je proširiti slikovnu dijagnostiku na magnetsku rezonanciju i MRCP zbog superiornosti u procjeni bilijarnog stabla. Iako je žutica rijetka prva manifestacija hepatocelularnog karcinoma, ne treba isključiti taj entitet, posebice u bolesnika s jetrenom cirozom.
Aim: To report a case of a patient with hepatocellular carcinoma that directly invaded the right atrium, initially manifested with painless jaundice and cardiac insufficiency. Case report: A seventy-seven-year-old patient was admitted to the Department of Gastroenterology due to painless jaundice and cardiac insufficiency. Edema of both lower legs and thighs and hepatomegaly were observed in the physical status. Laboratory analysis revealed elevated serum creatinine, total bilirubin, liver enzymes and prolonged prothrombin time and activated partial thromboplastin time. Radiographic tomography showed no pathological finding. In further procedure, abdominal ultrasound was performed which revealed the enlarged liver with irregular surface, diffusely hyperechoic, inhomogeneous, without visible focal lesions with dilation of the intrahepatic bile ducts The test for hepatitis B and C markers were negative. To clarify the cause of biliary obstruction, abdominal magnetic resonance imaging and magnetic resonance cholangiopancreatography (MRCP) were indicated. An infiltrative tumor was detected that extensively affected the bile ducts, invaded the inferior vena cava, and penetrates directly into the right atrium. Hepatocellular carcinoma (HCC) was confirmed by core needle biopsy and histopathological examination. During hospitalization, cardiac therapy, low molecular weight heparin, albumin substitution, and antibiotic therapy for Clostridium difficile infection were prescribed. Despite the efforts and treatment, the patient passed away because of multiple organ failure. Conclusion: The extension of hepatocellular carcinoma per continuitatem into the right atrium is a rare entity. In the case of painless jaundice and negative ultrasound findings, it is necessary to extend the imaging diagnostics to magnetic resonance imaging and MRCP which is superior in the assessment of the biliary tree. Although jaundice is a rare manifestation of hepatocellular carcinoma, this entity should not be ruled out, especially in patients with liver cirrhosis.
The aim of this study was to evaluate the expression of matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9) in prostate cancer in the main tumor mass and tumor cells at the ...positive margin as well as the influence of these biomarkers on the biochemical recurrence of the disease in prostatectomy patients. Tissue microarrays of 120 archival prostate carcinoma samples were immunohistochemically evaluated for MMP-2 and MMP-9 expression and compared with clinicopathological parameters. Tumors with positive surgical margins showed significantly higher overall expression of MMP-9 versus tumors with negative resection margins P = 0.0121 . MMP-9 expression was significantly elevated in tumors from patients who had biochemical recurrence P = 0.0207 . In the group of patients with negative margins, MMP-9 expression above the cut-off value was significantly associated with recurrence P = 0.0065 . Multivariate analysis indicated that MMP-9 is a good predictor of biochemical recurrence (odds ratio = 10.29; P = 0.0052 ). Expression of MMP-2 in tumor cells was significantly higher at the positive margins than in the main tumor mass P = 0.0301 . The present results highlight the potential value of MMP-2 and MMP-9 expression for predicting the behavior of prostate tumors after prostatectomy with both positive and negative surgical margins.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Burkitt lymphoma, a type of non-Hodgkin B-cell lymphoma, is the fastest growing human cancer, presenting pathologically with a 'starry sky' pattern. It is most often found in the abdomen and the jaw, ...however, localization in the abdomen other than the ileocecal area is very rare and described only in a handful of cases. Standard treatment consists of initial tumor cytoreduction followed by intense chemotherapy. Most of the relapses occur within one year of the diagnosis, while the 5-year survival is around 80%. We present two cases which are specific for unusual location of Burkitt lymphoma in the colon and stomach, in immunocompetent patients with negative Epstein-Barr virus tests. Also, one of the patients presented is one of the oldest ever reported with abdominal Burkitt lymphoma, while the other patient is an example of diagnostic difficulties in distinguishing Burkitt lymphoma from similar lymphomas. Due to the rapidly growing tumors and urgent need for cytoreductive surgery, it is crucial to consider the diagnosis of Burkitt lymphoma even in atypical localizations or absence of the common risk factors associated with Burkitt lymphoma.
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