High CD142 Level Marks Tumor-Promoting Fibroblasts with Targeting Potential in Colorectal Cancer.

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 fibroblasts, and an epigenetic inhibitor selected for a tumor cell population with markers of aggressive behavior. Thus, we suggest BCL-xL and HSP90 inhibitors to eliminate cancer cells and decrease the tumor-promoting CD142high CAF population. This may be the basis of a strategy to target both CRC cells and stromal fibroblasts, resulting in the inhibition of tumor relapse.

IFITM1 expression determines extracellular vesicle uptake in colorectal cancer.

The majority of colorectal cancer (CRC) patients carry mutations in the APC gene, which lead to the unregulated activation of the Wnt pathway. Extracellular vesicles (EV) are considered potential therapeutic tools. Although CRC is a genetically heterogeneous disease, the significance of the intra-tumor heterogeneity in EV uptake of CRC cells is not yet known. By using mouse and patient-derived organoids, the currently available best model of capturing cellular heterogeneity, we found that Apc mutation induced the expression of interferon-induced transmembrane protein 1 (Ifitm1), a membrane protein that plays a major role in cellular antiviral responses. Importantly, organoids derived from IFITM1high CRC cells contained more proliferating cells and they had a markedly reduced uptake of fibroblast EVs as compared to IFITM1low/- cells. In contrast, there was no difference in the intensity of EV release between CRC subpopulations with high and low IFITM1 levels. Importantly, the difference in cell proliferation between these two subpopulations disappeared in the presence of fibroblast-derived EVs, proving the functional relevance of the enhanced EV uptake by IFITM1low CRC cells. Furthermore, inactivating IFITM1 resulted in an enhanced EV uptake, highlighting the importance of this molecule in establishing the cellular difference for EV effects. Collectively, we identified CRC cells with functional difference in their EV uptake ability that must be taken into consideration when using EVs as therapeutic tools for targeting cancer cells.

Shared extracellular vesicle miRNA profiles of matched ductal pancreatic adenocarcinoma organoids and blood plasma samples show the power of organoid technology.

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 pancreatic ductal organoids. This provides a possible explanation why both CP and PDAC patient-derived plasma samples have an elevated amount of CD63 + EVs. Collectively, we show that PDAC patient-derived organoids represent a highly relevant model to analyze the cargo of tumor cell-derived EVs. Furthermore, we provide evidence that not only driver mutations, but also changes in the ECM may critically modify EV release from pancreatic ductal cells.

CD44 Expression Intensity Marks Colorectal Cancer Cell Subpopulations with Different Extracellular Vesicle Release Capacity.

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 the above subpopulations. We observed that EVs released by CD44high cells induced the proliferation and activation of colon fibroblasts more strongly than CD44low cells. However, this effect was due to the higher EV number rather than to the miRNA cargo of EVs. Collectively, we identified CRC subpopulations with different EV releasing capabilities and we proved that CRC cell-released EVs have a miRNA-independent effect on fibroblast proliferation and activation.

Extracellular vesicles transmit epithelial growth factor activity in the intestinal stem cell niche.

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 have no role in transporting R-Spondin, a critical niche factor amplifying Wnt signaling. Collectively, we prove the important role of fibroblast-derived EVs as a novel transmission mechanism of factors in the normal ISC niche.

Short-term advantages of ELAPE over APR.

INTRODUCTION: Conventional abdominoperineal resection (APR) has a high rate of local recurrence. Extralevator abdominoperineal excision (ELAPE) can potentially diminish the rate of intraoperative tumour perforation (IOTP) and can provide wider circumferential resection margins (CRM) but at the price of higher perineal complication rate. The aim of our study was to compare the short term results of conventional APR to ELAPE. MATERIALS AND METHODS: Thirty-five consecutively operated APRs compared to 38 also consecutively operated ELAPEs. Prospectively collected short-term outcome data were analysed retrospectively. RESULTS: There was no difference in demographics, disease stage or tumour location between groups. IOTP rate and CRM positivity rates were similar between the two groups (p = .608). No difference was found in major (Clavien-Dindo III-V) complications, but we found statistically significant difference in minor (Clavien-Dindo I-II) complications (p = .01) in favour of the ELAPE group. Frequency of perineal SSI was lower in ELAPE group, but the difference was not significant (p = .320). Intraoperative iatrogenic complications occurred at significantly lower rate in ELAPE group (p = .035). Also, postoperative morbidity connected with the dissection in the perineal phase (e.g. urine incontinence, urinary retention) was significantly lower (p = .018) after ELAPE. DISCUSSION AND CONCLUSIONS: In our experience ELAPE operations may diminish the rate of Clavien-Dindo I-II complications compared to conventional APR. This effect is ensuing from the decrease of intraoperative iatrogenic complications and from the decrease of minor postoperative complications.

Extracellular vesicle release from intestinal organoids is modulated by Apc mutation and other colorectal cancer progression factors.

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 state-of-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 fibroblast-derived EVs contribute to tumorigenesis under unfavorable conditions in CRC.

[Is preoperative systemic chemotherapy recommended for resectable colorectal liver metastases? Oncosurgical aspects]. / Reszekábilis colorectalis eredetu májáttét esetén javasolt-e a preoperatív szisztémás kezelés? Onkosebészeti nézopont.

Surgical resection is still the only curative treatment for colorectal liver metastases, but this is one part of a complex therapy. Nowadays a patient with colorectal liver metastasis is not treated only by a surgeon or by an oncologist or even only by an invasive radiologist. Collective decisions, complement treatments give the only chance to treat these patients for longer time. Patients with colorectal liver metastases could be regarded as patients with chronic disease. Specially interesting are the various treatment options of resectable colorectal liver metastases. The efficiency and necessity of preoperative chemotherapy are still a hot spot in the treatment of resectable liver metastases. In this study, we try to summarize the international and local experiences and the current evidence of the use of preoperative chemotherapy in the treatment of colorectal liver metastases. Orv Hetil. 2018; 159(21): 823-830.

[New perspectives in rectal cancer surgery: Transanal total mesorectal excision. Initial experiences]. / Új távlatok a végbélrák sebészetében: Transanalis teljes mesorectum excisio. Kezdeti eredményeink.

INTRODUCTION: Colorectal cancer is the second most frequent cause of oncologic mortality. Its key prognostic factors are operability and surgical quality. Total mesorectal excision is the gold standard of rectal cancer surgery, however, it is hardly achievable with the laparoscopic technique in a number of cases due to anatomical issues. Transanal total mesorectal excision (TaTME) is a new operative concept, which may address this technical problem. AIM: We aimed to present the initial Hungarian experiences with the new technique. METHOD: Retrospective analysis of clinical data of the first year case series at two Hungarian centers initiating the technique. RESULTS: A total of 17 transanal total mesorectal excision (TaTME) operations were performed at two centers. Major perioperative complications happened in two cases. There was no 30-day mortality. CONCLUSIONS: Early Hungarian experiences with transanal total mesorectal excision (TaTME) give hope of a brand new era of rectal cancer surgery. Orv Hetil. 2018; 159(1): 16-22.

[Advantages of transanal approach in low rectal cancer resections]. / A transanalis megközelítés elonye a mély rectumdaganatok mutéteinél.

Laparoscopic surgery is proven equal technique to open rectal surgery. Despite advantages, some problems in case of low rectal surgery are existing: visualization of the pelvis, securing safe distal resection margin, preparing single stapled rectal stump with safe conjunction to the colorectal anastomosis. Approximately 500 procedures have been performed worldwide until today by applying Transanal Total Mesorectal Excision (TaTME) technique, which evolved from a combination of laparoscopy and transanal approach. TaTME presents a solution to the low and mid-level rectal cases. The transanal path provides a better opportunity for preparing safe distal resection margin, an easier way for making a secure distal stump closure, and also offers perfect visualization even in the most difficult area, supporting the aim of nerve-sparing. We present a case, where we performed a synchronous laparoscopic and transanal TaTME resection of a down-sized low rectal tumor at 5 cm, after neoadjuvant radio-chemotherapy. To the best of our knowledge, this was the first case in Hungary, when TaTME was administered in a synchronous way.

[Laparoscopic resection of a liver metastasis from segment VII. Case report]. / A máj VII-es szegmentumában igazolt áttéti daganat laparoszkópos reszekciója.

The technique and clinical results of liver surgery are constantly evolving in recent years, and this development felt most intensely in the field of laparoscopic liver surgery. Based on the results of comparative studies reported to date, laparoscopic surgery is not inferior to open surgery. Although a very small percentage of liver resections are performed with laparoscopic technique, clearly it has a role in oncological surgery. The minor, major, anatomical, or even multi-stage liver resections can be performed with laparoscopy. The previously general recommendation, that lesions in the front segments of the liver are recommended for the minimally invasive technique is currently outdated. The authors present the history of a 70-year-old female, who underwent complex oncosurgical treatment of a locally advanced rectum carcinoma and a pure laparoscopic resection of a solitary hepatic metastasis of segment VII. With this case report the authors want to underline that malignant lesions in the posterior segments of the liver can be removed safely with laparoscopy.

[Modern surgical treatment of breast cancer. 3rd Breast Cancer Consensus Conference]. / Az emlorák korszeru sebészi kezelése. III. Emlorák-konszenzuskonferencia.

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 into 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 3rd Breast Cancer Consensus Conference and considering the latest international studies and professional recommendations.

[3rd Hungarian Breast Cancer Consensus Conference - Surgery Guidelines]. / III. Emlõrák Konszenzus Konferencia - Az emlõrák korszerû sebészi kezelése.

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.

[Occurrence, intratumoral heterogeneity, prognostic and predictive potential of microsatellite instability following surgical resection of primary colorectal carcinomas and corresponding liver metastases]. / Mikroszatellita-instabilitás elofordulása, intratumoralis heterogenitása, prognosztikus és prediktív potenciálja primer colorectalis carcinomák és párosított májáttéteik sebészi kezelését követoen.

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 therapy regimen groups. CONCLUSIONS: The subgroups of colorectal carcinomas could be evaluated in a larger and homogenised patient cohort to predict prognosis and response to therapy.

[Autoimmune pancreatitis mimicking pancreatic tumor]. / Pancreastumort utánzó autoimmun pancreatitis.

Autoimmune pancreatitis (AIP) is a rare disease of unknown pathomechanism. AIP belongs to the IgG4-related disease family and responds well to steroids, although the relapse rate can reach up to 20-30%. Differentiation of AIP from the more common pancreatic cancer can be very challenging. About 20% of autoimmune pancreatitis is diagnosed postoperatively during final histological examination. While each of diagnostic investigations provide some additional information towards definitive diagnosis, the question still remains whether it is possible to prevent unnecessary pancreatic resection. We demonstrate the differential diagnostic opportunities when we present our case as well as discuss the literature data of this condition. In conclusion, we think that in case of a focal pancreatic lesion AIP should always be considered.

[Surgical treatment of retroperitoneal sarcomas]. / A retroperitoneális sarcomák sebészi kezelése.

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 resection, high grade tumor, and non-liposarcoma type histology. Survival depends on local recurrence rather than on distant metastases. Retroperitoneal sarcomas are ideally treated in sarcoma centers, where multidisciplinary consultation is available and complex treatment plans can be set. Complete recovery can be achieved with radical surgical excision. The chance for R0 resection is enhanced by chemo- and radiotherapy.

[Evolution of sentinel lymph node biopsy in breast cancer--axillary staging in the past 15 years at the Uzsoki Street Hospital]. / Hová tartasz sentinelbiopszia, avagy az elmúlt 15 év gyakorlata az axilla ellátásában az Uzsoki Utcai Kórházban.

INTRODUCTION: Sentinel biopsy technique was performed in Europe in 1996.It was a great improvement in the surgical treatment of breast cancer, it decreased the number of patients suffering from early and late morbidity following axillary lymph node dissection (ALND). In our paper we demonstrate the evolution of sentinel biopsy technique (SLNB), as well as the changes in our policy on axillary treatment in line with the European trends. METHODS: The authors of this article give an overview and analyse the relevant literature concerning sentinel lymph node biopsy and data of patients on whom sentinel lymph node biopsy was performed from 01/01/2001 to 31/12/2012. RESULTS: Between 2001 and 2013 we performed 3756 breast operations, 2742 of those were done for malignant disease. Altogether we performed 744 sentinel lymph node biopsies in the Uzsoki teaching Hospital. The proportion of SLNB patients is increasing, it was 24.6% between 2001-2006 and 29.2% between 2007-2012, respectively. The indication of SLNB is widening, there might be justification of the technique even by multifocal or multilocular disease, in male patients, after former breats surgery or even in pregnant patients. CONCLUSION: Histological examination of sentinel lymph node and its effect on complex treatment of breats cancer may place the role of surgical axillary staging in a brand new aspect in the near future perhaps.

[Laparoscopic appendicectomy in 2013--a barely tolerated procedure turning into a gold standard operation?]. / Laparoscopos appendectomia 2013-ban - hogyan vált egy megturt mutét gold standard beavatkozássá?

INTRODUCTION: Laparoscopic appendectomy is one of the first developed minimally invasive surgical procedures, nevertheless its judgement is contradictory up to the present day as far as its advantages and indications are concerned. METHODS: The authors of this article give an overview and analyse the relevant literature concerning laparoscopic appendectomy and the data of patients on whom appendectomy was performed from 01/01/2005 to 30/09/2013 with laparoscopic and open technique. RESULTS: At the Surgical Department of the Uzsoki Hospital 1214 patients had appendectomy because of acute appendicitis from 01/01/2005 to 30/09/2013. The applied surgical procedure was laparoscopy with 1065 patients (87.73%) and the open technique with 149 patients (12.27%). Since January 2006 our main principle has been that in case of appendicitis the primary technique to be applied is laparoscopic appendectomy. We were forced to conversion with 16.5% of patients and as the operational experience of the department grows, the proportion of conversions tends to decrease. CONCLUSION: The advantages of laparoscopic appendectomy as opposed to open surgery have become obvious in the past decade, and the procedure may be recommended for all age groups. In case acute appendicitis is suspected the primary procedure to be applied in our department is the laparoscopic operation, the results of which are at least as good as that of open appendectomy. The routine application of laparoscopic appendectomy provides an excellent basis for the acquisition of advanced laparoscopic surgery thus appendectomy will not lose its training character due to the laparoscopic approach.

[Preoperative chemotherapy in the surgical treatment of colorectal liver metastases]. / Preoperatív kemoterápia a colorectalis májáttétes betegek sebészi kezelésében.

INTRODUCTION: The only curative treatment of colorectal liver metastases (CRLM) is surgical resection. Preoperative/neoadjuvant chemotherapy can be used for resectable, for borderline resectable or even for irresectable CRLM patients. PATIENTS: Data of CRLM patients treated with surgical resection at the Uzsoki Hospital were analysed. Patients were classified into two groups, (A) who received preoperative chemotherapy before hepatic resection, and (B) who received no chemotherapy before resection. RESULTS: Between 01.01.2007. and 31.12.2010. 128 CRLM patients were treated with hepatic resection. 68 patients (53%) received chemotherapy before hepatic resection, 60 patients (47%) were resected without neoadjuvant chemotherapy. There was no significant difference in the complications between the groups (p = 0.39). Median overall survival was 41 months. The progression free survival (PFS) at 3 and 5 years were 25%, the 3 and 5 year overall survival (OS) were 55% and 31%. Both PFS and OS were significantly worse in the chemotherapy group (p = 0.014, p = 0.015). The subgroup of patients receiving bevacizumab containing preoperative chemotherapy has significanly better PFS than patients receiving only cytotoxic chemotherapy (p = 0.004). CONCLUSION: Surgical resection of CRLM patients results good survival data even in non-selected patients, although the very long survival results reported in the literature couldn't have been reproduced in this patient population. When preoperative chemotherapy was combined with bevacizumab, survival was similar to the upfront resected patients.

[Latest indications for hanging manoeuvre in liver surgery]. / A hanging manover újabb indikációi a májsebészetben.

By definition the liver hanging manoeuvre (LHM) means that a slip is passed between the liver parenchyma and the inferior vena cava. It was first published by Belghiti in 200l, and several changes in the indication as well as in the method have been published since then. In parallel, the anatomical and histological basis has been clarified for LHM, too. According to general consensus LHM increases safety and radicality of liver surgery. Initially LHM was applied for removal of huge tumours infiltrating the diaphragm. Authors worked out two modifications for LHM. Tumours / primary or secondary / in segment IVA are sometimes located in close proximity to the median hepatic vein and inferior vena cava , and the resectability of these tumors can determined by the hanging manoeuvre. Tumors in segment VII can be removed by partial resection of vena cava facilitated by LHM. Four patients with LHM are discussed, and based on this limited experience as well as the latest observations from relevant literature the authors claim that LHM increases the safety of resections from segment IVA and VII. Vascular infiltration of the vena cava is always a technical challenge, which can be suspected on preoperative imaging modalities, but in borderline cases only the intraoperative ultrasound and surgical judgment together with LHM would lead to the exact diagnosis and makes the resection possible.