Neoadjuvant (preoperative) chemoradiotherapy of advanced rectal tumors / Elorehaladott végbéldaganatok neoadjuváns (preoperatív) kemoradioterápiája

Introduction: There have been significant changes in the treatment protocol for rectal tumors in recent decades, greatly reducing the rate of local recurrence and distant metastasis, thereby increasing overall survival. Method: We performed a retrospective processing and statistical analysis of the data of 362 patients with rectal cancer who underwent local neoadjuvant chemoradiotherapy and then underwent surgical treatment between 1 January 2010 and 31 December 2017 at the Institute of Surgery of the University of Debrecen. We compared the response rate and overall survival results of our patients with local neoadjuvant treatment to the outcomes of total neoadjuvant treatment reported by the recent large international studies. Results: We experienced complete pathological regression in 8.6% of our patients. After neoadjuvant therapy, 10.7% of our patients experienced distant metastasis at the time of the operation or within 3 months period thereafter. In our study, the rate of response to the neoadjuvant treatment was a prognostic factor independent of the stage at di-agnosis and recognition. The groups with better response produced significantly better survival results. Conclusion: The total neoadjuvant treatment doubled the number of patients with complete pathological response, and the incidence of distant metastasis was by 7% lower in both recent international studies compared to the local neoadjuvant group. 85% of our patients were T3-4N+ stage at the time of recognition. Given the 10.7% rate of dis- tant metastases detected at the time of surgery or within 3 months in our patient population, we can state that ap- proximately half of our patients would have benefited from the administration of total neoadjuvant therapy which produced better outcomes. Based on this conclusion, we decided to introduce the total neoadjuvant therapy protocol in our department for treatment of patients with advanced rectal tumors.

Follow-up Study of Microflora Changes in Crevicular Gingival Fluid in Obese Subjects After Bariatric Surgery.

The objective of our study was to investigate the effect of weight loss on the crevicular microflora following bariatric surgery. Crevicular fluid samples were taken from 57 subjects: 22 were in the normal control group; 18 in the obese control group; and 17 patients had had bariatric surgery, who underwent a repeat sampling 6 to 12 months after the operation. Crevicular fluid samples were analyzed by MALDI-TOF MS analysis. After surgery and weight loss, the mean germ count increased, albeit not significantly. Also, Candida albicans and non-albicans Candida species: C. dubliniensis, C. kefyr, and C. lusitaniae appeared after surgery (p < 0.05) in subjects where Neisseria was either absent throughout or eliminated after surgery. However, periodontitis did not develop during this time in our subjects.

Correction: Identification of Novel Pathogenic Sequence Variants of the Mismatch Repair Genes During Screening for Lynch Syndrome in a Single Centre of Eastern Hungary.

The original version of this article unfortunately contained a mistake. The variants listed in Table 3 of the original version of this article are not in line with the latest HGVS (Human Genome Variation Society) nomenclature (version 19.01).

Identification of Novel Pathogenic Sequence Variants of the Mismatch Repair Genes During Screening for Lynch Syndrome in a Single Centre of Eastern Hungary.

INTRODUCTION: Lynch syndrome is an autosomal dominant disorder, most frequent leading to colon cancer. Identification of patients with Lynch syndrome and screening of their family members are available prevention approach that can significantly decrease mortality. Unfortunately, routine screening still does not belong to standard of care in Hungary. In this study, we performed a comprehensive screening in order to identify patients with mismatch repair (MMR) mutation between the years of 2011 and 2014. Identified mutations were compared with those already published in the international databases. PATIENTS AND METHODS: Patients who underwent treatment for colorectal cancer at the Surgical Institute of the University of Debrecen were screened using the modified Amsterdam and Bethesda Criteria. Immunohistochemistry and microsatellite analyses were performed in order to identify possible mutation carrier cases. Suspicious cases underwent DNA sequencing to detect mutations in the mismatch repair genes (hMLH1, hMSH2). RESULTS: All together 760 colorectal cancer patients were screened. A total of 28 patients were identified as possible MMR mutation carrier and underwent further genetic evaluation. Pathogenic sequence variants of the MMR gene were found in 5 patients. Hypermethylation of the promoter region of the hMLH1 gene was identified in 2 patients. Two out of the 5 pathogenic sequence variants of the MMR gene were first identified by our group while other 2 mutations were previously published as possible founder mutations. CONCLUSION: Identification of families with Lynch syndrome, while challenging because of variable phenotypes at diagnosis, is feasible with available molecular biological technologies and crucial to reduce mortality caused by this syndrome.

[Significance of the monitoring and screening for hereditary nonpolyposis colorectal carcinoma syndrome patients by presenting a case of a family tree]. / A hereditaer nonpolyposus colorectalis carcinoma szindrómás betegek szurésének és szoros utánkövetésének fontossága egy családfa bemutatása kapcsán.

INTRODUCTION: Hereditary nonpolyposis colorectal carcinoma (HNPCC) is an autosomal dominant disease, which shows familial clustering. AIM: We would like to emphasize the importance of monitoring the HNPCC syndrome patients by presenting a case of a proven MMR gene mutation carrier and her family tree encompassing 10 years. MATERIALS AND METHOD: To screen a suspected HNPCC Hungarian family member we are taking thorough family histories. If the diagnosis of HNPCC was further supported by immunohistology and the microsatellite status, sequencing of the MMR genes was carried out. RESULTS: A novel mutation in exon 6 of the hMSH2 gene leading to the deletion of two nucleotide pairs [c.969-970delTC] was detected in our patient. During the 10-year follow-up period of our patient new HNPCC-associated tumors have developed in several family members. Conslusion: Close surveillance of the patient and its family members at risk was effective, although it requires compliance from the subjects. Orv Hetil. 2017; 158(30): 1182-1187.

Occurrence of bladder metastasis 10 years after surgical removal of a primary gastric cancer: a case report and review of the literature.

INTRODUCTION: Secondary bladder neoplasms are uncommon and they represent only 2% of all malignant bladder tumors. CASE PRESENTATION: The authors present a case of a 59-year-old Caucasian man with a primary gastric adenocarcinoma that had been surgically removed 10 years before he developed bladder metastasis. He presented with low abdominal pain after 10 years without any symptoms. Cystoscopy and an abdominal computed tomography scan showed a bladder tumor. A transurethral resection of the bladder tumor was performed. A histological examination revealed an adenocarcinoma, which turned out to be a metastasis of the primary gastric tumor. One year later, abdominal surgery revealed peritoneal metastases. CONCLUSION: This is the first known case in Europe where bladder metastasis occurred 10 years after surgical removal of a primary gastric neoplasm. There are only four cases in the literature where metastases of the peritoneum developed 11 years after surgical removal of a primary gastric tumor.

Q48P mutation in the hMLH1 gene associated with Lynch syndrome in three Hungarian families.

Lynch syndrome (Hereditary nonpolyposis colorectal cancer, HNPCC) is an inherited disease with variable phenotype causing the development of colon cancer and other malignancies. The basis of the disease is believed to be the mismatch repair gene mutations. Genetic screening has been performed among the patients who have undergone surgery for colon cancer at the University of Debrecen, Department of Surgery. Tumor samples of the screened patients were submitted to immunohistochemistry on hMLH1, hMSH2 and hMSH6 genes, microsatellite instability testing, followed by sequencing and multiple ligation dependent probe amplification. Three families were identified with the missense mutation c.143A>C (p.Q48P) of hMLH1 gene. In one of the families a segregation analysis of this particular variant was also accomplished. The segregation analysis revealed a clear correlation between the tumor cases and the occurrence of this mutation. However, none of the analyzed 100 healthy controls demonstrated the same aberration. There is only one published evidence in the literature about the presence of this rare variant in any population. The Gln to Pro switch in the ATPase domain, a conservative region of the hMLH1 gene, creates significant changes in the protein structure. These results indicate that this mutation is the abnormality responsible for the patients' phenotype and it is feasible that this particular aberration occurs more frequently among Hungarian Lynch syndrome patients.

Correlations between clinicopathological parameters and molecular signatures of primary tumors for patients with stage T3n0 colorectal adenocarcinomas: a single center retrospective study on 100 cases.

BACKGROUND/AIMS: To examine the clinical and protein expression characteristics of tumor tissues for prediction of prognosis in colorectal cancer (CRC). METHODOLOGY: We retrospectively analyzed the clinicopathological data of patients with stage T3N0 CRC, operated between 1997-2003 and the surgical materials for the relation between disease prognosis and p53, p21, p16, ß-catenin, E-cadherin, EGFR, hMLH1, hMSH2 and TS protein expressions. RESULTS: A significantly shorter 3-year disease free survival was observed in patients under the age of 50. The worst 5-year overall survival (OS) observed for patients over 70. Tumor localization and number of processed lymph nodes significantly affected prognosis. The EGFR, hMSH2 and TS expressions and the 5-fluorouracyl treatment were not found to be of prognostic value; p53 and p21 positivity had significantly worse survival. When ß-catenin membrane expression disappeared on tumor cells, the 5-year OS rate decreased and time to metastasis shortened significantly. Membrane ß-catenin expression, processed lymph nodes number and age were detected as independent prognostic markers. CONCLUSIONS: These results suggest that the evaluation of a clinicopathological profile, based on age, tumor localization, number of examined lymph nodes, p53, p21 and E-cadherin ß-catenin expression appears to be useful in identifying high risk patients.

Investigation of ß-catenin and E-cadherin expression in Dukes B2 stage colorectal cancer with tissue microarray method. Is it a marker of metastatic potential in rectal cancer?

ß-catenin and E cadherin are both membrane-associated proteins which are essential regulators and providers of cellular adhesion. In the metastatic cascade of malignant tumours, detachment of tumour cells from each other is a very important step. It has been shown in several tumour types, that reduced expression of these proteins is important. The aim of our study was to clarify the expression profile of these proteins, and correlate the findings with the metastasizing potential of early stage colon and rectal cancers. Formalin fixed and paraffin embedded samples from 79 Dukes B2 stage colorectal cancer were examined using a tissue microarray approach. The expression of ß-catenin and E-cadherin proteins was determined immunohistochemically. Our findings indicated that there is a tendency for metastatic spread in cases when membranous expression of ß-catenin is lost (p = 0.062). Similarly metastases in negative cases developed more rapidly, than in positive ones (p = 0.05). Survival rate was worse in the negative cases. The risk of metastasis in rectal cancer was significantly higher in the ß-catenin membranously negative than positive groups (p = 0.024) and in case of ß-catenin nuclear expression the risk was also higher (p = 0.047). Reduced E-cadherin expression also correlated with development of metastatic disease, but this association was statistically not significant. The immunohistochemical analysis of 79 cases shows that in Dukes B2 stage colorectal tumours clarification of ß-catenin and E-cadherin expression patterns is reliable for predicting the metastatic potential of early stage rectal cancer and hence the method may have relevant implications in the therapeutic management of these cancers.

Detection of internal tandem duplications in the FLT3 gene by different electrophoretic methods.

BACKGROUND: In acute myeloid leukemia (AML), the internal tandem duplication (ITD) in the juxtamembrane domain of the FLT3 (Fms-like tyrosine kinase 3) gene is one of the most frequent genetic alterations associated with poor prognosis. METHODS: A complex evaluation of the analytical properties of the three most frequently used detection methods--PCR followed by agarose (AGE), polyacrylamide (PAGE) or capillary electrophoresis (CE)--was performed on 95 DNA samples obtained from 73 AML patients. RESULTS: All the three methods verified the presence of a mutant allele in 20 samples from 18 patients. AGE and PAGE could detect the presence of 1%-2% mutant allele, while the detection limit of CE was 0.28%. However, acceptable reproducibility (inter-assay CV <25%) of the mutant allele rate determination was only achievable above 1.5% mutant/total allele rate. The reproducibility of the ITD size determination by CE was much better, but the ITD size calculated by PeakScanner or GeneScan analysis was 7% lower as compared to values obtained by DNA sequencing. The presence of multiple ITD was over-estimated by PAGE and AGE due to the formation of heteroduplexes. CONCLUSIONS: This study suggests the use of PCR+CE in the diagnostics and the follow-up of AML patients. The data further supports the importance of proper analytical evaluation of home-made molecular biological diagnostic tests.

[The role of preoperative investigation with 18-FDG-PET/CT in primary operable breast cancer]. / A preoperatív 18-FDG PET/CT-vizsgálat szerepe primer operábilis emlôrák esetén.

INTRODUCTION: The widespread use of PET/CT has a potential to change oncological diagnosis fundamentally. In our study we intended to clarify if preoperative PET/CT was able to assess axillary lymph node status, and the potential of these to modify preliminary treatment plans based on conventional diagnostic methods. PATIENTS AND METHODS: We carried out 18-FDG PET/CT before elective surgery in 52 primary operable breast cancer patients between February 2008 and February 2009 at the DEOEC Clinical Department of Surgery. Total body imaging was performed in all cases; scans were evaluated by two specialists first visually, then semi-quantitatively based on body mass-corrected lesion suvmax values. The assessments were compared with axillary ultrasound and final histological diagnosis. RESULTS: Two patients were excluded from the study due to failure to report for further treatment. Based on the results obtained from the remaining 50 patients, PET/CT showed a sensitivity of 80%, a specificity of 100%, positive and negative predictive values of 100% and 84.6% respectively for detecting axillary lymph node metastases. The same figures for axillary ultrasound, in respective order, were 30%, 81.8%, 60% and 56.2%. Prompted by the PET/CT results, we modified 9 patients' (18%) preliminary, conventional diagnosis-based treatment schemes. CONCLUSIONS: In case of a positive axillary PET/CT, it is unnecessary to perform SNB--axillary block dissection is called for with no further deliberation. Preoperative PET/CT can facilitate patient selection as regards possible benefit from neoadjuvant therapy. Preoperative PET/CT has a potential to modify the original management plan in about 15 to 20%. In case of a negative PET/CT scan, further studies are necessary to be able to spare the axilla from surgical intervention with confidence.

[Ki-67 -- new faces of an old player]. / Ki-67 -- egy régi játékos új arcai.

The Ki-67 protein was isolated twenty-five years ago and has become the first histological marker of proliferating cells until now. This molecule with a unique structure possesses such fundamental biological functions that are essential for normal cell proliferation. Since the Ki-67 protein is present in every dividing cell (G1, S, G2/M phase) but is absent from the resting cells (G0 phase) it is very much suitable for identifying the proliferating fraction of cells. Thus, it provides essential information concerning the malignancy of a tumor and about the prediction of response to a certain therapy. Based on its important role in cell proliferation, the Ki-67 protein might also play a role in tumor genesis. In their present work the authors discuss the history and the properties of Ki-67, its role in cell cycle regulation and its prognostic importance in different malignant disorders.

[Our experience with the incidence of hereditary non-polyposis colorectal cancer]. / Hereditaer Nonpolyposis Colorectalis Carcinoma elôfordulásával szerzett tapasztalataink.

INTRODUCTION: Hereditary Non-Polyposis Colorectal Cancer (HNPCC) is the most frequent genetic disease leading to colorectal malignancies. 3-5 percent of all colorectal cancer cases are related to Hereditary Non-Polyposis Colorectal Cancer. Currently there is no reliable data on the incidence of the disease in Hungary. METHODS: The family history of 809 patients with colorectal cancer was investigated between 1997 and 2006. Data collection was performed in a retrospective manner in the rst and in a prospective manner in the second phase of the study. Subsequent immunohistochemical and microsatellite instability analysis, and DNA sequencing was carried out to detect any underlying MMR gene mutation. Moreover, multiple ligation dependent probe amplication was applied for recognizing large deletions in MMR genes. RESULTS: During the investigation 10 pathogenic mutations and several polymorphisms were found. Seven mutations were detected in families fulfilling the Amsterdam Criteria, while the remaining three fulfilled the Bethesda Criteria. In the second phase of the study -- which better reflects the real population characteristics -- six percent of our patients fulfilled completely the Amsterdam Criteria and we managed to nd pathogenic MMR gene mutations in 1,7 percent of our patients. CONCLUSION: 8 out of 10 pathogenic mutations were novel and published rst time by ourselves. No repeatedly occurring mutations were found in our patients. It seems that these genetic alterations are located sporadically on different exons of the involved MMR genes. Our mutation detection rate was 77 percent in the Amsterdam positive patients who were completely examined, which appears to be better than the published data in the relevant literature. Importantly, 30 percent of the mutation carrier could be missed applying only this single criteria system. In order to detect the highest number of HNPCC patients, we suggest using both the Amsterdam as well as the Bethesda Criteria.

Two germline alterations in mismatch repair genes found in a HNPCC patient with poor family history.

The Bethesda guidelines may offer more useful criteria in patients' selection for germline mismatch repair gene mutation analysis than guidelines merely based on family background. An early onset double primary colorectal cancer patient with poor family history with MSI-H status was investigated for MLH1 promoter methylation, expression of the MLH1 and MSH2 gene by immunohistochemistry and mutations in the MLH1 and MSH2 genes. The index patient carried two germline alterations, the p.Val716Met in MLH1 and the c.2210+1G>C in MSH2 genes, and both tumors failed to express MLH1 and MSH2 proteins. After subsequent analysis of the whole family of the index patient, the p.Val716Met variant can be defined as a rare polymorphism with the possible contribution of pathogenicity to tumor formation and c.2210+1G>C as a true pathogenic mutation causing an out-of-frame deletion of exon 13.

[Increasing dominance of laparoscopic techniques in the surgery of the spleen in hematologic syndromes]. / A laparoszkópia elterjedése a lépsebészetben haematológiai kórképek esetén.

Parallel with the evolution of minimally invasive techniques more and more organs became the subject of different laparoscopic operations. The spleen was not an exception to this trend, the first laparoscopic splenectomy was performed in 1991. In the present publication the authors give an overview of their own initial experience with the technique. Between the time period of January 1996 and April 2005, 204 splenectomies were carried out at the 1st Dept. of Surgery, University of Debrecen. The indication was haematological in 113 cases, the choice of operation was laparoscopic splenectomy in 18 cases. The male-female ratio was 7 to 11, the mean age was 45.6 years (21-71). The average operation time lasted 106 minutes (60-200 min.), the mean hospital stay was 11.9 days (5-50 days). Laparoscopy had to be converted to open procedure in three cases, because of bleeding and adhesions. In one case, laparoscopic reoperation was necessary with the indication of subphrenic haematoma on the fifth postoperative day. One death occurred in this series from bilateral pneumonia. The authors conclude that laparoscopic splenectomy can be carried out safely, blood loss is limited, and the widely recognized advantages of laparoscopic techniques can be secured for the patients.

Pedigree and genetic analysis of a novel mutation carrier patient suffering from hereditary nonpolyposis colorectal cancer.

AIM: To screen a suspected Hungarian HNPCC family to find specific mutations and to evaluate their effect on the presentation of the disease. METHODS: The family was identified by applying the Amsterdam and Bethesda Criteria. Immunohistochemistry was performed, and DNA samples isolated from tumor tissue were evaluated for microsatellite instability. The identification of possible mutations was carried out by sequencing the hMLH1 and hMSH2 genes. RESULTS: Two different mutations were observed in the index patient and in his family members. The first mutation was located in exon 7, codon 422 of hMSH2, and caused a change from Glu to STOP codon. No other report of such a mutation has been published, as far as we could find in the international databases. The second mutation was found in exon 3 codon 127 of the hMSH2 gene, resulting in Asp-->Ser substitution. The second mutation was already published, as a non-pathogenic allelic variation. CONCLUSION: The pedigree analysis suggested that the newly detected nonsense mutation in exon 7 of the hMSH2 gene might be responsible for the development of colon cancers. In family members where the exon 7 mutation is not coupled with this missense mutation, colon cancer appears after the age of 40. The association of these two mutations seems to decrease the age of manifestation of the disease into the early thirties.

[Surgical treatment of morbid obesity]. / A kóros elhízás sebészeti kezelése.

Morbid obesity is a multicausal disease with great importance because of the life threatening associated co-morbidities. Its treatment has many different aspects and needs multidisciplinary collaborations. The most powerful way of treatment is the surgical intervention which demands thorough preoperative investigations and patient selection. The bariatric surgical procedures went through significant development and many of them have only historical importance. Different interventions can be classified to malabsorptive, restrictive and combined subgroups. In Europe the laparoscopic adjustable gastric banding seems to be the most widely applied procedure which is purely a restrictive intervention. Apart from the low rate of complications it has many advantages which were not characteristic of the formerly used procedures. These include: minimal invasiveness, reversibility, preservation of the gastrointestinal anatomy, adjustability for demands of care.

[Fenotypical diversity of hereditary non-polyposis colorectal carcinoma. Pedigree and genetical analysis of two mutation carrier patients]. / A herediter nonpolipózis kolorektális karcinóma fenotípusának sokszínuisége. Két, igazolt mutáció hordozó beteg családfa analízise.

INTRODUCTION: The phenotype of HNPCC shows great diversity. Investigation of the disease needs the application of both the Amsterdam and Bethesda Guidelines. The clinical diagnosis of HNPCC can be established by means of thorough family history containing more generations. The immunohistochemistry and MSI investigation of the tumorous tissue as well as the detection of mutations based on DNA sequencing could reinforce the existence of the possible hereditary tendency. PATIENTS AND METHODS: Two pedigrees were selected based on the above-mentioned protocol at the Surgical Institute of the University of Debrecen, Medical and Health Science Center. Amongst first-degree relatives of the 31-year old male patient suffering from colorectal carcinoma (1st patient), three other colorectal, one gastric, one breast and one lung tumors have been found. Two genetic alterations of hMSH2 gene were detected in this family, which were also detectable in other family members. The mutation of exon 7 was not at that time available in international databases, so it was detected by us for the first time. We were able to find alterations of both hMLH1 and hMSH2 genes in the case of the 25-year old patient with synchronous colorectal carcinomas (2nd patient). These alterations could be detected in other family members as well. The whole pedigree contains only one other case of colorectal carcinoma besides the index person. CONCLUSION: Several HNPCC families would be missed in case of considering the Amsterdam Criteria alone. The application of the Bethesda Guidelines is absolutely necessary for the detection of families with poor history at the first screening. The association of a polymorphism and a pathogen mutation in one person could lead to early onset of colorectal carcinoma.

[The role of positron emission tomography (PET) in the detection of local recurrence and metastases of colorectal cancer]. / A pozitronemissziós tomográfia (PET) szerepe a colorectalis carcinomák lokális recidívájának és metasztázisainak felismerésében.

We presented here the results of PET imaging of 12 patients, previously operated on for colorectal cancer and followed at the 1st Department of Surgery, University of Debrecen. The tests were carried out using 0.15 mCi/kg FDG injections. Whole body imaging was performed in eleven patients. The indication for PET was elevated tumor marker levels in three patients, although CT scan was negative. The PET scan showed lymph node, hepatic and disseminated lymph node metastases with liver involvement in these patients. Suspicious lesions were found on CT scan in the pelvis of four patients. Local recurrence was identified in three of them, PET was negative in the fourth case. Bone scan suggested rib metastasis in one patient, which was not supported at PET investigation. In one patient, the malignant nature of large retroperitoneal lymph nodes could not be determined by CT. PET imaging proved that they were malignant and detected a previously unknown pulmonary metastasis at the same time. In one patient both pulmonary and liver metastases were seen on CT, whereas PET confirmed only the latter. Similarly, CT failed to identify liver metastasis detected at ultrasound, while PET proved it. Finally, a pulmonary metastasis detected on X-ray, could be confirmed by PET only. Based on our experience, we recommend PET-scanning with FDG when conventional imaging is equivocal and/or elevated tumor marker levels are present during follow-up. FDG-PET is important in the detection of local recurrence and metastases as well. It is advisable to use PET more often in the evaluation of patients with recurrent colorectal cancer in order to diagnose recurrences in earlier stages, which helps to identify patients who will benefit from surgery.