Improved Accuracy of Lymph Node Staging and Long-Term Survival Benefit in Colorectal Cancer With Ex Vivo Arterial Methylene Blue Infiltration.

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 from the National Health Insurance Fund of Hungary. Results: A total of 162 specimens, 82 in the control and 80 in the MB groups, were included for analysis. Baseline characteristics were equally distributed among study groups, except for specimen length. Both the median of total number of lymph nodes retrieved (control 11 ± 8 [0-33] nodes vs. MB 14 ± 6 [0-42] nodes; p < 0.01), and the ratio of cases with at least 12 removed lymph nodes (36/82, 43.9% vs. 53/80, 66.3%; p < 0.01) were higher in the MB group. The rate of accurate lymph node staging was non-significantly improved. As for rectal cancer, nodal staging accuracy (16/31, 51.6% vs. 23/30, 76.7%; p = 0.04) and the proportion with minimum 12 lymph node retrieval (7/31, 22.6%, vs. 18/30, 60%; p < 0.01) was improved by MB injection. In Mantel-Cox regression, a statistically significant survival benefit with methylene blue injection at 5 years post-surgery was proven (51.2% vs. 68.8%; p = 0.04). Conclusion: In our experience, postoperative ex vivo arterial methylene blue injection appears to be an uncomplicated technique, improving lymph node yield and decreasing the chance of insufficient nodal staging. The technique might also associate with a 5-year overall survival benefit.

[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.

Decreased functional activity of multidrug resistance protein in primary colorectal cancer.

BACKGROUND: The ATP-Binding Cassette (ABC)-transporter MultiDrug Resistance Protein 1 (MDR1) and Multidrug Resistance Related Protein 1 (MRP1) are expressed on the surface of enterocytes, which has led to the belief that these high capacity transporters are responsible for modulating chemosensitvity of colorectal cancer. Several immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) studies have provided controversial results in regards to the expression levels of these two ABC-transporters in colorectal cancer. Our study was designed to determine the yet uninvestigated functional activity of MDR1 and MRP1 transporters in normal human enterocytes compared to colorectal cancer cells from surgical biopsies. METHODS: 100 colorectal cancer and 28 adjacent healthy mucosa samples were obtained by intraoperative surgical sampling. Activity of MDR1 and MRP1 of viable epithelial and cancer cells were determined separately with the modified calcein-assay for multidrug resistance activity and sufficient data of 73 cancer and 11 healthy mucosa was analyzed statistically. RESULTS: Significantly decreased mean MDR1 activity was found in primary colorectal cancer samples compared to normal mucosa, while mean MRP1 activity showed no significant change. Functional activity was not affected by gender, age, stage or grade and localization of the tumor. CONCLUSION: We found lower MDR activity in cancer cells versus adjacent, apparently, healthy control tissue, thus, contrary to general belief, MDR activity seems not to play a major role in primary drug resistance, but might rather explain preferential/selective activity of Irinotecan and/or Oxaliplatin. Still, this picture might be more complex since chemotherapy by itself might alter MDR activity, and furthermore, today limited data is available about MDR activity of cancer stem cells in colorectal cancers. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1675739129145824.

[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.

[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.

[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.

[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.

Binding of trastuzumab to ErbB2 is inhibited by a high pericellular density of hyaluronan.

Although trastuzumab is an efficient drug, primary and acquired resistance is a challenging problem. The authors have previously shown in mouse xenograft experiments that masking ErbB2 by hyaluronan leads to diminished binding of the antibody and consequent resistance. In the current work, they correlated trastuzumab binding with the pericellular density of hyaluronan in ErbB2-overexpressing human breast cancer samples. A method for quantifying the relative binding of trastuzumab was developed involving constant and low-frequency background subtraction, segmenting the image to membrane and background pixels followed by evaluation of trastuzumab fluorescence, normalized with the expression level of ErbB2, only in the membrane. The normalized binding of trastuzumab showed a negative correlation with the pericellular density of hyaluronan (r = -0.52) with the effect being the most pronounced in the extreme cases (i.e., low and high hyaluronan densities predicted strong and weak binding of trastuzumab, respectively). Removal of hyaluronan by hyaluronidase digestion unmasked the trastuzumab binding epitope of ErbB2 demonstrated by a significantly increased normalized binding of the antibody. The results show that the accumulation of pericellular hyaluronan plays a crucial role in masking ErbB2.

Expression of tight junction molecules in breast carcinomas analysed by array PCR and immunohistochemistry.

In the past few decades an enormous amount of data became known to clarify the molecular composition and architecture of tight junctions (TJs). Despite the efforts, the expression and function of several TJ genes and proteins in breast carcinoma are still not known and some of the data are contradictory. The expression of forty-four TJ associated genes was examined at mRNA level in eighteen invasive ductal breast carcinoma samples and corresponding normal breast tissues by using low density array PCR. Expressions of claudins (CLDNs) 5, 10, 16, 17, and 18, and ZO-1, ZO-2 were evaluated by immunohistochemistry as well. Using immunohistochemical phenotype as a surrogate for the genetic subtype, 11 luminal A, 3 luminal B, 3 triple negative and one HER2+ cases were included. Ten genes were significantly downregulated in tumors compared with normal breast tissues (CLDNs 5, 10, 16, 18, 19, CTNNAL1, JAM-B, ZO-1, ZO-2 and PARD3), whereas one gene (CLDN17) was significantly up-regulated in tumors when compared with normal breast. At protein level CLDNs 5, 10, 16, 18, ZO-1 and ZO-2 were downregulated in tumors as compared with normal breast tissue. CLDN17 showed variable expression in tumor tissues in comparison to normal breast. In the single HER2+ tumor when compared with the other subtypes CLDNs 5, 16, 17, 18, CTNNAL1, JAM-B, ZO-1, ZO-2 and PARD3 genes were found to be upregulated. We found altered TJ genes and proteins whose expression has not yet been associated with breast carcinoma. Our findings show a tendency of TJ genes and proteins to be downregulated in breast cancer. Further studies are necessary to examine whether the downregulation of the above mentioned TJ associated genes and proteins may contribute to the malignant progression of invasive ductal breast carcinomas.

[From project-based sample collection to biobank]. / Projektalapú mintagyujtéstol a biobankig.

The research group takes samples for molecular genetical examinations from tumors removed during operations within ischemic time interval. Samples are stored in liquid nitrogen. Clinical data of these patients are recorded in an informatics system developed by the group. Patients are followed in an out-patient clinic set up for this purpose not financed by the National Health Insurance Fund. Tissue samples and follow up data are used to cooperate with molecular genetical laboratories.

[Laparoscopic or open appendectomy?]. / Laparoszkópos vagy nyílt appendectomia?

UNLABELLED: Despite the fact that laparoscopic appendectomy was one of the first performed minimally invasive surgical procedures, the benefits and indications of its use are still controversial. METHODS: Data of patients with the diagnosis of appendicitis operated either with laparoscopic (LA) or open (OA) appendectomy were collected and analyzed. PATIENTS: This study involved 273 consecutive patients who had undergone appendectomy with the diagnosis of acute appendicitis at the Uzsoki Teaching Hospital, Department of Surgery between January 2005 and December 2007. 185 patients (68%) operated with the laparoscopic, 88 (32%) with the open technique, in the third year 89% of the cases underwent laparoscopic appendectomy. RESULTS: The conversion rate was 27%, the reason of the conversion was the progression of the disease in 35 patients (70%) and technical in 15 cases (30%). The wound infection rate was 8% in the LA and 18% in the OA group ( p = 0.022). No significant difference was found in the reoperation rate and in the hospital readmission rate between the two groups. There was one insufficiency which was treated with conservative therapy. The hospital stay was significantly lower in the laparoscopic group ( p = 0.031). CONCLUSIONS: This study demonstrated that laparoscopic appendectomy has significant advantages over open appendectomy. In our practice, laparoscopic appendectomy is the first choice of procedure in acute appendicitis.

[The role of laparoscopy assessing the resectability of hepatic malignancies]. / A laparoscopia szerepe a májdaganatok resecabilitasának megítélésében.

INTRODUCTION: Regarding the prognosis of hepatic malignancies, surgical resection can provide a 40% 5-year survival, however liver transplantation (OLTX) shows even better results. Unfortunately, many patients have non-resectable disease due to either the number and the position of the tumours or its distant spread. It is relatively frequent that it turns out only at the time of the surgical exploration that the patient is inoperable. Hence, in addition to preoperative clinical evaluation and imaging, laparoscopy can be valuable in further staging and assessment of resectability in selected cases. METHODS AND PATIENTS: 310 patients underwent hepatic resection between 1 January 2000 and 31 March 2006. A retrospective analysis was carried out of 39 patients, who underwent laparoscopy prior to the planned hepatectomy. 22 patients (56%) were diagnosed with hepatocellular carcinoma (HCC), while 17 patients (44%) had hepatic metastases. RESULTS: Altogether 70% of the patients were found to have non-resectable tumour on laparoscopy. However, when these patients underwent laparotomy, non-resectable disease was found in 50% of them. Laparoscopy was helpful to demonstrate non-resectability of the tumour when carcinosis peritonei or multifocal lesions were present, but central or venous invasion could not be assessed adequately with this technique. CONCLUSION: Laparoscopy can be an important component of the preoperative staging of malignant hepatic tumours. Further, it can help to avoid unnecessary laparotomies. However, this procedure is recommended in selected patients only, and its general use is not indicated.

Functional evaluation of multidrug resistance transporter activity in surgical samples of solid tumors.

Determination of multidrug resistance (MDR) activity of tumor cells could provide important information for the personalized therapy of cancer patients. The functional calcein assay (MultiDrug Quant Assay, Solvo Biotechnology, Budaörs, Hungary) has been proven to be clinically valuable in hematological malignancies by determining the transporter activity of MDR protein 1 (MDR1, ATP-binding cassette protein [ABC] B1, P-glycoprotein-170) and MDR-related protein 1 (MRP1, ABCC1). In this study, we evaluated if the same functional test was adaptable for the analysis of MDR activity in solid tumors. For this purpose, tissue specimens of human colorectal cancer samples were subjected to limited enzymatic digestion by collagenase to provide a single-cell suspension; dead cells were excluded by 7-aminoactinomycin D staining, and epithelial cancer cells were detected by Cy5-conjugated anti-BerEP4 monoclonal antibody. The transporter functions of MDR1 and MRP1 in viable epithelial cells were assessed by flow cytometry detecting the intracellular accumulation of calcein dye after exposing cells to various MDR inhibitors. Collagenase disintegration preserved the MDR activity and the antigenicity of tumor cells. Thus using the extended calcein assay provided sufficient viable and functionally active tumor cells from surgical biopsies to determine the functional MDR activity. In conclusion, the newly described modified calcein assay may be applicable for evaluating the MDR phenotype in solid tissue specimens from colorectal forceps biopsy to surgical samples.

[Hemobilia as a rare vascular complication of chronic pancreatitis]. / Erózios vérzéssel szövodött krónikus pancreatitis mint a hemobilia egy különleges esete.

Hemobilia is one of the possible causes of upper GI tract bleeding of unknown origin. However hemobilia is usually iatrogenic or traumatic, it can originate as a result of inflammation or may be caused by tumors. Authors present the case of a 46-year-old man, who developed hemobilia as a vascular complication of chronic pancreatitis. Diagnosis was proved on angiography and surgical intervention was necessary because of the life-threatening hemorrhage. Cholecystectomy, T-drainage and cystoduodenostomy were performed. We describe symptoms, diagnostic and therapeutic approches and compare it to recent literature.

[Surgery of the thymus]. / A thymus sebészete.

On the occasion of the 50th anniversary of Gyula Sebestény's death, an overview was prepared on the surgery of the thymic gland that was closely connected to his thoracic surgical activity. His results with thymectomy in myasthenia gravis were published as the second study on this topic in Europe and the first in Hungary. The early thymic surgery was based on pathological observations. Myasthenia gravis, a well-known disease for long, occurred frequently with pathological lesions of the thymus. Autopsies suggested potential causative relationship. The early period of thymic surgery was characterised by sporadic interventions and high mortality. The new period of the thymic surgery started with the American Blalock's 20 operations, and accomplished by the operative activity of Keynes including 281 thymectomies. They were followed by many European, American and Asian surgeons. Even today, there are many hotly debated topics, like indication and type of operation, prognostic factors, perioperative care, diagnosis, treatment and pathology of the thymic tumor. With fine-tuning the indication, the development of operation techniques, neurology, anaesthesiology and intensive care, imaging techniques and oncology and with introduction of new drugs the early and late results are improving. Thanks to Dr. Sebestény, Hungarian thoracic surgeons joined early the international thoracic surgical activities. Currently in Hungary there are two major centers for myasthenia gravis surgery, and all important thoracic surgical departments in the country treat thymic tumor cases.

[Change of attitude in the surgical treatment of lung metastases]. / Szemléletünk alakulása a tüdoáttétek sebészi kezelésében.

There has been no major change in surgical technique of lung metastasectomy till the last decades. In the latest years the variety of diagnostic tools and methods grew significantly. There are more chemotherapy possibilities and more palliative surgical techniques (VATS, ITP, RFTA) to treat certain types of lung metastases. Based on data of the International Registry of Lung Metastases the most important prognostic factor for metastasectomy is how radical the procedure was (clear resection margin). The more aggressive approach (even pneumonectomy for R0 resection) is becoming more popular.

[Effect of imatinib treatment of gastrointestinal stromal tumors]. / Az imatinibkezelés hatása gastrointestinalis stroma eredetú daganatokban.

INTRODUCTION: Advanced malignant gastrointestinal stromal tumours are practically resistant to further radio- or chemotherapy. These tumours are characterized by the presence of C-KIT (a transmembrane tyrosin kinase) mutation which can be specified by CD117 expression. Imatinib (2-fenilaminopirimidine) is a selective inhibitor of the mutated C-KIT. AIM: The purpose of our study was to determine the potential antitumour effect of imatinib in patients with gastrointestinal stroma tumour patients. MATERIALS AND METHODS: An open, non-randomized trial was performed involving 38 patients each of which had received/metastatic disease associated with CD117 positivity. Consecutively daily doses of 400-600 mg imatinib was administered orally to the patients. The evaluation was carried out on 37 patients in a form of an interim analysis. RESULTS: After a 3-18 months observation period 1 complete, 19 partial remissions and 10 static diseases could be registered (78%), in association of only grade 1-2 toxicity. CONCLUSIONS: The imatinib treatment improved the quality of life of the patients with gastrointestinal stroma tumour and their life expectancy became considerably prolonged. Further follow-up of the patients as well as design of a prospective, randomized trial on a larger patient material is urgently needed.