RESUMEN

Elorehaladott szájüregi daganatok eltávolítása után kialakult kiterjedt szövethiányok helyreállítására funkciómegtartó céllal a leggyakrabban alkalmazott eljárás a mikrovaszkuláris technikával végzett szabad szövetátültetés. Hazánkban a felületes szájüregi hiányok helyreállítására a leggyakrabban választott szabadlebeny a radiális alkarlebeny. Elsosorban vastagabb vagy nagyobb kiterjedésu hiányokra alkalmazzuk az anterolateralis comblebenyt. Az alkarlebeny esetén azonban a donorterületi szövodményráta jóval magasabb. Vékonyított anterolateralis comblebeny a hátrányokat kiiktatva alkalmas lehet az alkarlebeny intraoralis alkalmazása helyett.A korábban nyelvtumor miatt operált, alkarlebennyel rekonstruált és besugarazott 69 éves nobetegnél a korábbi mutéti terület szélén a követéses kontrollvizsgálat során recidív tumort verifikáltunk. Az Onkoterápiás Bizottság döntését követoen a recidíva eltávolítását, tangencionális mandibula reszekciót és szabad lebenyes helyreállítást terveztünk tracheotomiás védelemben. Elozetes kézi dopplerrel és duplex ultrahanggal történo perforátor meghatározás után, a jobb combon a perforátorra centrálva 6 × 8 cm-es superficialis fascia rétegében vékonyított anterolateralis comblebenyt preparáltunk. A lebeny vastagsága 6-8 mm, az érnyél hossza 12 cm volt, mely az intraoralis hiányra ideális volt. A nyakon elkészített mikrosebészeti anasztomózis után a donorterületet primeren zártuk.A lebeny keringése mindvégig kielégíto volt. A tracheotomiát a posztoperatív 11. napon megszüntettük, perorális táplálkozása a posztoperatív 14. napon helyreállt.Az anterolateralis comblebeny sokrétusége az anatómiájában rejlik. A korábban csak nagyobb és vastagabb hiányokra használt anterolateralis comblebeny jó adaptálhatósága és megfelelo mérete miatt felületesebb hiányokra is alkalmas. A korábban alkarlebennyel helyreállított hiányok pótlására a hasonló tulajdonságokkal rendelkezo vékonyított anterolateralis comblebeny is alkalmazható azzal a jelentos elonyével együtt, hogy a donorhely morbiditása minimális az alkarlebennyel szemben.

Asunto(s)

RESUMEN

A korai és lokálisan elorehaladott colontumorok esetében a megfelelo onkológiai minoségu sebészi resectio a kezelés központi eleme. Jobb oldali vastagbél tumorok sebészi ellátásában - a kedvezobb hosszú távú onkológiai eredmények elérése céljából - egyre szélesebb körben elfogadott a Hohenberger által 2009-ben elsoként publikált "complett mesocolicus-excisio" (CME) és centrális érlekötés (CVL).Esetünkben egy 78 éves nobeteg jobb alhasi faeculens váladékozása miatt indult kivizsgálása során a hasfalat szélesen infiltráló coecum tumor igazolódott. Az Onkoterápiás Bizottság - tekintettel az egyértelmu távoli áttét hiányára, a beteg jó általános állapotára, a fennálló colo-cutan sipolyra és egyértelmu irresecabilitási jelek hiányára - mutétet javasolt. A kuratív intenció és kello radikalitás érdekében, komplett mesocolicus excisio és kiterjesztett hasfali resectio mellett döntöttünk. A mutét során a kialakult hasfali defektus rekonstrukciójához a jobb comb lateralis felszínérol tensor fasciae lateae musculocutan (TFL) lebenyt preparáltunk. A hasfali defektust, mind a fascia, mind a subcutis-cutis rétegében helyreállítottuk, a donor területet primeren zártuk. A posztoperatívumban a lebeny distalis végén vénás pangás jelei majd felületes necrosis mutatkozott. Sorozatos necrectomia és negatívnyomás-terápia (NPWT) mellett a hasfal végig intakt maradt és per secundam gyógyult.Megfelelo betegszelekció esetén, centrumokban elvégezve - onkosebész és helyreállító plasztikai sebész szoros együttmuködésével - a radikális mutét kiterjesztett hasfali resectiót igénylo jobb colonfél tumoroknál is biztonsággal elvégezheto.

Asunto(s)

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of all cancer types with a constant rise in global incidence. Therefore, better understanding of PDAC biology, in order to design more efficient diagnostic and treatment modalities, is a priority. Here we found that the expression levels of cystathionine ß-synthase (CBS), a transsulfuration enzyme, is markedly elevated in metastatic PDAC cells compared to cell lines isolated from non-metastatic primary tumors. On human immunohistochemical samples from PDAC patients we also found higher CBS staining in cancerous ductal cells compared to in non-tumor tissue, which was further elevated in the lymph node metastasis of the same patients. In mice, orthotopically injected CBS-silenced T3M4 cells induced fewer liver metastases compared to control cells indicating important roles for CBS in PDAC cancer cell invasion and malignant transformation. Wound healing and colony formation assays in cell culture confirmed that CBS-deficient metastatic T3M4 and non-metastatic BxPC3 primary tumor cells migrate slower and have impaired anchorage-independent growth capacities compared to control T3M4 cells. CBS silencing in T3M4 cells lowered WNT5a and SNAI1 gene expression down to levels that were observed in BxPC3 cells as well as resulted in an increase in E-cadherin and a decrease in Vimentin signals in mouse tumors when injected orthotopically. These observations suggested a primary role for the epithelial to mesenchymal transformation of cancer cells in CBS-mediated tumor aggressiveness. Under normal conditions, STAT3, an upstream regulator of Wnt signaling pathways, was less phosphorylated and more oxidized in shCBS T3M4 and BxPC3 compared to control T3M4 cells, which is consistent with decreased transcriptional activity at lower CBS levels due to less protection against oxidation. Sulfur metabolome analyses suggested that this CBS-mediated protection against oxidative modifications is likely to be related to persulfide/sulfide producing activities of the enzyme rather than its canonical function to produce cystathionine for cysteine synthesis. Taken together, CBS overexpression through regulation of the EMT plays a significant role in PDAC cancer cell invasion and metastasis.

RESUMEN

BACKGROUND: Discriminating between autoimmune pancreatitis (AIP), chronic pancreatitis (CP), and pancreatic ductal adenocarcinoma (PDAC) can be challenging. In this retrospective study, levels of serum and tissue cytokines were analyzed as part of the clinical strategy for the preoperative differentiation between AIP and PDAC. The identification of differential cytokine profiles may help to prevent unnecessary surgical resection and allow optimal treatment of these pathologies. METHODS: To compare the cytokine profiles of AIP, CP, and PDAC patients, serum and pancreatic tissue homogenates were subjected to multiplex analysis of 17 inflammatory mediators. In total, serum from 73 patients, composed of 29 AIP (14 AIP-1 and 15 AIP-2), 17 CP, and 27 PDAC, and pancreatic tissue from 36 patients, including 12 AIP (six AIP-1 and six AIP-2), 12 CP, and 12 PDAC, were analyzed. RESULTS: Comparing AIP and PDAC patients' serum, significantly higher concentrations were found in AIP for interleukins IL-1ß, IL-7, IL-13, and granulocyte colony-stimulating factor (G-CSF). G-CSF also allowed discrimination of AIP from CP. Furthermore, once AIP was divided into subtypes, significantly higher serum levels for IL-7 and G-CSF were measured in both subtypes of AIP and in AIP-2 for IL-1ß when compared to PDAC. G-CSF and TNF-α were also significantly differentially expressed in tissue homogenates between AIP-2 and PDAC. CONCLUSIONS: The cytokines IL-1ß, IL-7, and G-CSF can be routinely measured in patients' serum, providing an elegant and non-invasive approach for differential diagnosis. G-CSF is a good candidate to supplement the currently known serum markers in predictive tests for AIP and represents a basis for a combined blood test to differentiate AIP and particularly AIP-2 from PDAC, enhancing the possibility of appropriate treatment.

Asunto(s)

RESUMEN

BACKGROUND: Functionalized nanoparticles (NPs) are one promising tool for detecting specific molecular targets and combine molecular biology and nanotechnology aiming at modern imaging. We aimed at ligand-directed delivery with a suitable target-biomarker to detect early pancreatic ductal adenocarcinoma (PDAC). Promising targets are galectins (Gal), due to their strong expression in and on PDAC-cells and occurrence at early stages in cancer precursor lesions, but not in adjacent normal tissues. RESULTS: Molecular probes (10-29 AA long peptides) derived from human tissue plasminogen activator (t-PA) were selected as binding partners to galectins. Affinity constants between the synthesized t-PA peptides and Gal were determined by microscale thermophoresis. The 29 AA-long t-PA-peptide-1 with a lactose-functionalized serine revealed the strongest binding properties to Gal-1 which was 25-fold higher in comparison with the native t-PA protein and showed additional strong binding to Gal-3 and Gal-4, both also over-expressed in PDAC. t-PA-peptide-1 was selected as vector moiety and linked covalently onto the surface of biodegradable iron oxide nanoparticles (NPs). In particular, CAN-doped maghemite NPs (CAN-Mag), promising as contrast agent for magnetic resonance imaging (MRI), were selected as magnetic core and coated with different biocompatible polymers, such as chitosan (CAN-Mag-Chitosan NPs) or polylactic co glycolic acid (PLGA) obtaining polymeric nanoparticles (CAN-Mag@PNPs), already approved for drug delivery applications. The binding efficacy of t-PA-vectorized NPs determined by exposure to different pancreatic cell lines was up to 90%, as assessed by flow cytometry. The in vivo targeting and imaging efficacy of the vectorized NPs were evaluated by applying murine pancreatic tumor models and assessed by 1.5 T magnetic resonance imaging (MRI). The t-PA-vectorized NPs as well as the protease-activated NPs with outer shell decoration (CAN-Mag@PNPs-PEG-REGAcp-PEG/tPA-pep1Lac) showed clearly detectable drop of subcutaneous and orthotopic tumor staining-intensity indicating a considerable uptake of the injected NPs. Post mortem NP deposition in tumors and organs was confirmed by Fe staining of histopathology tissue sections. CONCLUSIONS: The targeted NPs indicate a fast and enhanced deposition of NPs in the murine tumor models. The CAN-Mag@PNPs-PEG-REGAcp-PEG/tPA-pep1Lac interlocking steps strategy of NPs delivery and deposition in pancreatic tumor is promising.

Asunto(s)

RESUMEN

BACKGROUND: Diabetes mellitus is linked to pancreatic cancer. We hypothesized a role for pancreatic stellate cells (PSC) in the hyperglycemia induced deterioration of pancreatic cancer and therefore studied two human cell lines (RLT-PSC, T3M4) in hyperglycemic environment. METHODOLOGY/PRINCIPAL FINDINGS: The effect of chronic hyperglycemia (CHG) on PSCs was studied using mRNA expression array with real-time PCR validation and bioinformatic pathway analysis, and confirmatory protein studies. The stress fiber formation (IC: αSMA) indicated that PSCs tend to transdifferentiate to a myofibroblast-like state after exposure to CHG. The phosphorylation of p38 and ERK1/2 was increased with a consecutive upregulation of CDC25, SP1, cFOS and p21, and with downregulation of PPARγ after PSCs were exposed to chronic hyperglycemia. CXCL12 levels increased significantly in PSC supernatant after CHG exposure independently from TGF-ß1 treatment (3.09-fold with a 2.73-fold without TGF-ß1, p<0.05). The upregualtion of the SP1 transcription factor in PSCs after CHG exposure may be implicated in the increased CXCL12 and IGFBP2 production. In cancer cells, hyperglycemia induced an increased expression of CXCR4, a CXCL12 receptor that was also induced by PSC's conditioned medium. The receptor-ligand interaction increased the phosphorylation of ERK1/2 and p38 resulting in activation of MAP kinase pathway, one of the most powerful stimuli for cell proliferation. Certainly, conditioned medium of PSC increased pancreatic cancer cell proliferation and this effect could be partially inhibited by a CXCR4 inhibitor. As the PSC conditioned medium (normal glucose concentration) increased the ERK1/2 and p38 phosphorylation, we concluded that PSCs produce other factor(s) that influence(s) pancreatic cancer behaviour. CONCLUSIONS: Hyperglycemia induces increased CXCL12 production by the PSCs, and its receptor, CXCR4 on cancer cells. The ligand-receptor interaction activates MAP kinase signaling that causes increased cancer cell proliferation and migration.

Asunto(s)