Colorectal cancer (CRC) has a high incidence and is one of the leading causes of cancer-related d... more Colorectal cancer (CRC) has a high incidence and is one of the leading causes of cancer-related death. The accumulation of cancer-associated fibroblasts (CAF) induces an aggressive, stem-like phenotype in tumor cells, and it indicates a poor prognosis. However, cellular heterogeneity among CAFs and the targeting of both stromal and CRC cells are not yet well resolved. Here, we identified CD142high fibroblasts with a higher stimulating effect on CRC cell proliferation via secreting more hepatocyte growth factor (HGF) compared to CD142low CAFs. We also found that combinations of inhibitors that had either a promising effect in other cancer types or are more active in CRC compared to normal colonic epithelium acted synergistically in CRC cells. Importantly, heat shock protein 90 (HSP90) inhibitor selected against CD142high fibroblasts, and both CRC cells and CAFs were sensitive to a BCL-xL inhibitor. However, targeting mitogen-activated protein kinase kinase (MEK) was ineffective in fi...
Introduction:Ex vivo methylene blue (MB) injection into the main supplying arteries of the colore... more Introduction:Ex vivo methylene blue (MB) injection into the main supplying arteries of the colorectal specimen after surgical removal is an uncomplicated technique to support lymph node harvest during pathological evaluation. The primary aim of this randomized, interventional, bicentric trial was to evaluate the impact of MB injection on lymph node yield, with secondary aims assessing the accuracy of lymph node staging and the effect on 5-year overall survival for patients undergoing resection of colorectal cancer.Methods: In the study period between December 2013 and August 2015, 200 colorectal resections were performed at two independent onco-surgery centers of Hungary. Following surgical resection, each specimen was randomly assigned either to the control (standard pathological work-up) or to the MB staining group before formaldehyde fixation. Patient-level surgical and clinical data were retrieved from routinely collected clinical datasets. Survival status data were obtained fro...
Extracellular vesicles (EV) are released by virtually all cells and they transport biologically i... more Extracellular vesicles (EV) are released by virtually all cells and they transport biologically important molecules from the release site to target cells. Colorectal cancer (CRC) is a leading cause of cancer-related death cases, thus, it represents a major health issue. Although the EV cargo may reflect the molecular composition of the releasing cells and thus, EVs may hold a great promise for tumor diagnostics, the impact of intratumoral heterogeneity on the intensity of EV release is still largely unknown. By using CRC patient-derived organoids that maintain the cellular and molecular heterogeneity of the original epithelial tumor tissue, we proved that CD44high cells produce more organoids with a higher proliferation intensity, as compared to CD44low cells. Interestingly, we detected an increased EV release by CD44high CRC cells. In addition, we found that the miRNA cargos of CD44high and CD44low cell derived EVs largely overlapped and only four miRNAs were specific for one of th...
EREDETI KÖZLEMÉNY kockázatúnak tekinthetők, ezért rendszeres surveillanceuk javasolt. Az ajánlás ... more EREDETI KÖZLEMÉNY kockázatúnak tekinthetők, ezért rendszeres surveillanceuk javasolt. Az ajánlás foka: erős ajánlás, teljes egyetértés Az ajánlás alapjául szolgáló irodalom: [3-5] 1.1.2. Kérdés: A cirrhoticus, Child-Pugh C-stádiumú, transzplantációs listán nem lévő betegek HCC surveillance-a a várható alacsony túlélés miatt javasolt-e? Megállapítás: Cirrhoticus Child-Pugh C-stádiumú, transzplantációs listán nem lévő betegek HCC-surveillance-a a várható alacsony túlélés miatt nem javasolt, rendszeres követésük azonban feltétlenül szükséges. Az ajánlás foka: erős ajánlás, teljes egyetértés Az ajánlás alapjául szolgáló irodalom: [6] 1.1.3. Kérdés: Nem cirrhoticus, közepes-nagy kockázatú HBV-fertőzöttek surveillance-a a PAGE-Bscore ≥10 pont (etnikum, életkor, HBV-kópiaszám, nem) alapján javasolt-e? Megállapítás: A közepes-nagy kockázatú (PAGE-B-score ≥10 pont) nem cirrhoticus HBV-fertőzöttek surveillance-a javasolt. Az ajánlás foka: közepes ajánlás, teljes egyetértés Az ajánlás alapjául szolgáló irodalom: [7-9] 1.1.4. Kérdés: A cirrhosis nélküli bridging fibrosisos (F3) idült HCV-fertőzöttek HCC-surveillance-a indokolt-e? Megállapítás: A bridging fibrosisos (F3) HCV-fertőzöttek surveillance-a indokolt. Irodalmi adatok alapján, a HCV-fertőzött betegek HCC-kockázata a krónikus fertőzést, valamint az eradikációt követően is fennáll. Kérdés: Ezen betegcsoport esetén hogyan történjék a fibrosis meghatározása? Megállapítás: Az elasztográfia az ajánlott és nagyszámú vizsgálattal alátámasztott vizsgálómódszer a HBV-, HCV-fertőzöttek, NAFLD/NASH betegek fibrosisstádiumának meghatározására. Az ajánlás foka: közepes ajánlás, teljes egyetértés Az ajánlás alapjául szolgáló irodalom: [10-14] 1.1.5. Kérdés: Fibrosis nélküli NAFLD/NASH betegek HCC-szűrése javasolt-e? Megállapítás: A fibrosis nélküli NAFLD/NASH betegek általános szűrése nem javasolt, mivel a HCC incidenciája ebben a betegcsoportban alacsony. Egyedi mérlegelés alapján indokolt lehet a szűrés fokozott kockázat (férfinem, morbid obesitas és diabetes együttállása) esetén. Az ajánlás foka: közepes ajánlás, teljes egyetértés Az ajánlás alapjául szolgáló irodalom: [15, 16] 1.1.6. Kérdés: A metabolikus szindrómában szenvedő, elhízott egyének rendszeres HCC-szűrése alátámasztott-e? Megállapítás: A metabolikus szindrómában szenvedő, elhízott egyének esetében a rendszeres HCC-szűrés csak cirrhosisban indokolt. Az ajánlás foka: közepes ajánlás, teljes egyetértés Az ajánlás alapjául szolgáló irodalom: [17, 18] ORVOSI HETILAP 6 EREDETI KÖZLEMÉNY Az ajánlás foka: közepes ajánlás, teljes egyetértés Az ajánlás alapjául szolgáló irodalom: [14] ORVOSI HETILAP 2021 ■ 162. évfolyam, Szupplementum 2 A cikk a Creative Commons Attribution-NonCommercial 4.0 International License () feltételei szerint publikált Open Access közlemény, melynek szellemében a cikk nem kereskedelmi célból bármilyen médiumban szabadon felhasználható, megosztható és újraközölhető, feltéve, hogy az eredeti szerző és a közlés helye, illetve a CC License linkje és az esetlegesen végrehajtott módosítások feltüntetésre kerülnek.
Extracellular vesicles (EV) are considered as a potential tool for early disease diagnosis; howev... more Extracellular vesicles (EV) are considered as a potential tool for early disease diagnosis; however, factors modifying EV release remain partially unknown. By using patient-derived organoids that capture the cellular heterogeneity of epithelial tissues, here we studied the connection between the Wnt-producing microniche and EV secretion in multiple tissues. Although nearly all cells in pancreatic ductal (PD) and pancreatic ductal adenocarcinoma (PDAC) samples expressed porcupine (PORCN), an enzyme critical for Wnt secretion, only a subpopulation of lung bronchiolar (NL) and lung adenocarcinoma (LUAD) organoid cells produced active Wnt. The microniche for proliferating cells was shaped not only by PORCN + cells in NL and LUAD organoids but also by fibroblast-derived EVs. This effect could be blocked by using Wnt secretion inhibitors. Whereas inhibiting Wnt secretion in PD NL or LUAD organoids critically changed both cell proliferation and EV release, these were uncoupled from each ot...
The pancreatic ductal adenocarcinoma (PDAC) is responsible for 95% of pancreatic malignancies. It... more The pancreatic ductal adenocarcinoma (PDAC) is responsible for 95% of pancreatic malignancies. It is the 12th most common cancer and is the 7th leading cause of cancer deaths worldwide. The incidence of PDAC is increasing in the USA and in Europe (including Hungary), while mortality rate is not changing too much. The only curative therapeutic possibility is R0 surgical resection. The mortality of pancreatic resections has been decreasing in recent years and can be kept below 5% in HPB centers. The limits of surgical radicality have been extended and the en bloc resection of greater veins around the pancreas is now accepted. The survival could be improved by R0 resection of early cancers without lymph node spread and results can be augmented by combined oncologic therapies.
Therapy for breast cancer today is characterised by ever more precise diagnostic methods and ever... more Therapy for breast cancer today is characterised by ever more precise diagnostic methods and ever more effective oncological treatments, a trend which will certainly continue in the future. Breast preservation and the application of oncoplastic principles are increasingly popular. A sentinel lymph node biopsy in the surgical treatment of the axilla is primary, with the indication for axillary block dissection (ABD) narrowing and radiation therapy becoming an alternative to ABD in certain cases. This publication summarises our recommendations on the surgical treatment of breast cancer based on the content of the 2nd Breast Cancer Consensus Conference and considering the latest international studies and professional recommendations.
Extracellular vesicles (EV) are considered as a promising diagnostic tool for pancreatic ductal a... more Extracellular vesicles (EV) are considered as a promising diagnostic tool for pancreatic ductal adenocarcinoma (PDAC), a disease with a poor 5-year survival that has not improved in the past years. PDAC patient-derived 3D organoids maintain the intratumoral cellular heterogeneity, characteristic for the tumor in vivo.Thus, they represent an ideal in vitro model system to study human cancers. Here we show that the miRNA cargo of EVs from PDAC organoids largely differs among patients. However, we detected a common set of EV miRNAs that were present in matched organoids and blood plasma samples of individual patients. Importantly, the levels of EV miR-21 and miR-195 were higher in PDAC blood EV preparations than in healthy controls, albeit we found no difference compared to chronic pancreatitis (CP) samples. In addition, here we report that the accumulation of collagen I, a characteristic change in the extracellular matrix (ECM) in both CP and PDAC, largely increases EV release from pa...
Background There is no consensus regarding the role of mechanical bowel preparation (MBP) and ora... more Background There is no consensus regarding the role of mechanical bowel preparation (MBP) and oral antibiotic prophylaxis (OABP) in reducing postoperative complications in colorectal surgery. The aim of this study was to examine the effect of OABP given in addition to MBP in the setting of a prospective randomized trial. Methods Patients awaiting elective colorectal surgery in four Hungarian colorectal centres were included in this multicentre, prospective, randomized, assessor-blinded study. Patients were randomized to receive MBP with or without OABP (OABP+ and OABP– groups respectively). The primary endpoints were surgical-site infection (SSI) and postoperative ileus. Secondary endpoints were anastomotic leak, mortality, and hospital readmission within 30 days. Results Of 839 patients assessed for eligibility between November 2016 and June 2018, 600 were randomized and 529 were analysed. Trial participation was discontinued owing to adverse events in seven patients in the OABP+ g...
Extracellular vesicles (EV) are membrane-surrounded vesicles that represent a novel way of interc... more Extracellular vesicles (EV) are membrane-surrounded vesicles that represent a novel way of intercellular communication by carrying biologically important molecules in a concentrated and protected form. The intestinal epithelium is continuously renewed by a small proliferating intestinal stem cell (ISC) population, residing at the bottom of the intestinal crypts in a specific microenvironment, the stem cell niche. By using 3D mouse and human intestinal organoids, we show that intestinal fibroblast-derived EVs are involved in forming the ISC niche by transmitting Wnt and epidermal growth factor (EGF) activity. With a mouse model that expresses EGFP in the Lgr5+ ISCs, we prove that loss in ISC number in the absence of EGF is prevented by fibroblast-derived EVs. Furthermore, we demonstrate that intestinal fibroblast-derived EVs carry EGF family members, such as amphiregulin. Mechanistically, blocking EV-bound amphiregulin inhibited the EV-induced survival of organoids. In contrast, EVs ...
Extracellular vesicles (EVs) are membrane-surrounded structures that transmit biologically import... more Extracellular vesicles (EVs) are membrane-surrounded structures that transmit biologically important molecules from the releasing to target cells, thus providing a novel intercellular communication mechanism. Since EVs carry their cargo in a protected form and their secretion is generally increased in tumorigenesis, EVs hold a great potential for early cancer diagnosis. By 3D culturing, we provide evidence that colorectal cancer (CRC) patient-derived organoids, representing a stateof-the-art established and essential approach for studying human CRC, is a suitable model for EV analysis. When testing the effects of major factors promoting CRC progression on EV release in the organoid model, we observed that Apc mutation, leading to uncontrolled Wnt activation and thus to tumorigenesis in the vast majority in CRC patients, critically induces EV release by activating the Wnt pathway. Furthermore, the extracellular matrix component collagen, known to accumulate in tumorigenesis, enhances EV secretion as well. Importantly, we show that fibroblast-derived EVs induce colony formation of CRC organoid cells under hypoxia. In contrast, there was no major effect of tumor cell-derived EVs on the activation of fibroblasts. Collectively, our results with CRC and Apc-mutant adenoma organoids identify Apc mutation and collagen deposition as critical factors for increasing EV release from tumors. Furthermore, we provide evidence that stromal fibroblastderived EVs contribute to tumorigenesis under unfavorable conditions in CRC. Exosome • Adenoma • Cancer patient-derived organoid • Stroma • Tumor • Collagen Cellular and Molecular Life Sciences
AimThere is little evidence to support choice of technique and configuration for stapled anastomo... more AimThere is little evidence to support choice of technique and configuration for stapled anastomoses after right hemicolectomy and ileocaecal resection. This study aimed to determine the relationship between stapling technique and anastomotic failure.MethodAny unit performing gastrointestinal surgery was invited to contribute data on consecutive adult patients undergoing right hemicolectomy or ileocolic resection to this prospective, observational, international, multicentre study. Patients undergoing stapled, side‐to‐side ileocolic anastomoses were identified and multilevel, multivariable logistic regression analyses were performed to explore factors associated with anastomotic leak.ResultsOne thousand three hundred and forty‐seven patients were included from 200 centres in 32 countries. The overall anastomotic leak rate was 8.3%. Upon multivariate analysis there was no difference in leak rate with use of a cutting stapler for apical closure compared with a noncutting stapler (8.4%...
Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland, 2018
The mainstay of management for locally advanced rectal cancer is chemoradiotherapy followed by su... more The mainstay of management for locally advanced rectal cancer is chemoradiotherapy followed by surgical resection. Following chemoradiotherapy, a complete response may be detected clinically and radiologically (cCR) prior to surgery or pathologically after surgery (pCR). We aim to report the overall complete pathological response (pCR) rate and the reliability of detecting a cCR by conventional pre-operative imaging. A pre-planned analysis of the European Society of Coloproctology (ESCP) 2017 audit was performed. Patients treated by elective rectal resection were included. A pCR was defined as a ypT0 N0 EMVI negative primary tumour; a partial response represented any regression from baseline staging following chemoradiotherapy. The primary endpoint was the pCR rate. The secondary endpoint was agreement between post-treatment MRI restaging (yMRI) and final pathological staging. Of 2572 patients undergoing rectal cancer surgery in 277 participating centres across 44 countries, 673 (26...
Introduction: Besides clinicopathological parameters, molecular markers can be very important, an... more Introduction: Besides clinicopathological parameters, molecular markers can be very important, and further characterize colorectal carcinomas into chromosomally unstable, microsatellite instable and “CqG-island methylator phenotype” groups. Aim: To study the frequency of microsatellite instability using immunohistochemical evaluation of MLH1, MSH2, MSH6 and PMS2 proteins in colorectal carcinoma. Method: 122 colorectal carcinomas as well as in 69 paired liver metastases were evaluated. Additionally, prognostic and predictive potential of mismatch repair status was tested. Results: Microsatellite instable phenotype was identified in 11.5% (14/122) of the tumours. There were no differences regarding staining intensity of tumour regions. Mismatch repair status was discordant in primaries vs. metastases in 20.2%. There was no difference in progression free- and overall survival according to mismatch repair status. The mismatch repair status was not predictive for survival within systemic...
Retroperitoneal sarcomas make up 0.15% of all solid tumors. The mainstay of their treatment is su... more Retroperitoneal sarcomas make up 0.15% of all solid tumors. The mainstay of their treatment is surgical resection, though the removal of the often sizable tumors may pose serious challenge to surgeons. There is no clear-cut recommendation for neoadjuvant, nor for adjuvant treatment so far. We collected the data and recommendations concerning the attributes and the treatment options for retroperitoneal sarcomas. Mainly we focused on the possibilities and the recent change in tactics of surgery. There is no prospective randomized study dealing with surgical treatment of retroperitoneal sarcomas. According to data in the literature the en-block R0 resection along with all the possibly involved neighboring organs offers the best chance for cure. The greatest problem is to define the required resection margin which is needed for R0 resection. Radio- and/or chemotherapy can be used for diminishing the possibility of tumor recurrence. The greatest risk factors for recurrence are incomplete...
Gliceril-trinitrát lokális alkalmazásának szerepe a végbélrepedés kezelésében
Magyar Sebészet (Hungarian Journal of Surgery), 2008
Absztrakt A végbélrepedés az analis nyálkahártya ischaemiás fekélye, mely leggyakrabban a hátsó c... more Absztrakt A végbélrepedés az analis nyálkahártya ischaemiás fekélye, mely leggyakrabban a hátsó comissurában alakul ki. A kezelésére választandó eljárást az elváltozás nagysága, valamint fennállásának ideje határozza meg. Az első lépés minden esetben a beteg ellátása az életmódjára vonatkozó utasításokkal. A lokális gyógyszeres kezelés (gliceril-trinitrát, botulinum-toxin), valamint a sebészi kezelés célja egyaránt a belső analis sphincter tónusfokozódásának a csökkentése. Igazi “farmakológiai sphincterotomia” csak a gliceril-trinitrát tartalmú kenőcsök lokális alkalmazásával, valamint a botulinum-toxin-injekcióval érhető el. A nitrogén-oxid neurotranszmitterként a belső analis sphincter relaxációját mediálja. A gliceril-trinitrát nitrogén-oxid-donorként viselkedve izomrelaxációt okoz. Gyakori mellékhatása a fejfájás az agyi erek kitágulásának következményeként, de ez gyógyszeresen jól csillapítható.
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