Amplification of thymosin beta 10 and AKAP13 genes in metastatic and aggressive papillary thyroid carcinomas.

Papillary thyroid carcinoma (PTC) is the most common well-differentiated thyroid cancer. Although the great majority of the cases exhibit an indolent clinical course, some of them develop local invasion with distant metastasis, and a few cases transform into undifferentiated/anaplastic thyroid carcinoma with a rapidly lethal course. To identify gene copy number alterations predictive of metastatic potential or aggressive transformation, array-based comparative genomic hybridization (CGH-array) was performed in 43 PTC cases. Formalin-fixed and paraffin-embedded samples from primary tumours of 16 cases without metastasis, 14 cases with only regional lymph node metastasis, and 13 cases with distant metastasis, recurrence or extrathyroid extension were analysed. The CGH-array and confirmatory quantitative real-time PCR results identified the deletion of the EIF4EBP3 and TRAK2 gene loci, while amplification of thymosin beta 10 (TB10) and Tre-2 oncogene regions were observed as general markers for PTC. Although there have been several studies implicating TB10 as a specific marker based on gene expression data, our study is the first to report on genomic amplification. Although no significant difference could be detected between the good and bad prognosis cases in the A-kinase anchor protein 13 (AKAP13) gene region, it was discriminative markers for metastasis. Amplification in the AKAP13 region was demonstrated in 42.9% and 15.4% of the cases with local or with distant metastasis, respectively, while no amplification was detected in non-metastatic cases. AKAP13 and TB10 regions may represent potential new genomic markers for PTC and cancer progression.

[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.

[Significance of the intraductal component in local recurrence after breast-conserving surgery]. / Az intraductalis komponens jelentôsége az emlôrák emlômegtartó mûtétei után fellépô lokális recidívák létrejöttében.

Several predictors of local recurrence (LR) after breast conservation in early stage (stage I and II) breast cancer have been reported in the literature, but the importance of the individual factors does not appear to be clear. The presence of intraductal component (IC) is one of those factors; some authors regard it to be a predictor of LR, while others do not, or the latter have found a relationship with LR only if IC and certain other factors were present simultaneously. The authors investigated the impact of the presence of IC of various degrees on LR rate in various tumour sizes and degrees of histological anaplasia. Between 1996 and 2002, 701 patients with early stage breast cancer underwent breast conserving surgery. Based on the presence of IC, the tumours were divided into three groups: IC negative, MIC (IC < 25%) and EIC (IC > 25%). During the 65-month mean follow-up period, LR was discovered in 13.5% of the patients. Local recurrence in tumours without IC was found in 8.7% (recurrence rate: 0.017, 95% CI: 0.012-0.012). The relevant figures in MIC and EIC were 16.8% (recurrence rate 0.032, 95% CI: 0.021-0.047) and 25.6% (recurrence rate: 0.046, 95% CI: 0.033-0.064), respectively (p = 0.0001). If the size of the tumour was T1, the above figures were found to be 6.4%, 11% and 24.3%, while in size T2 tumours they were 11.5%, 22.9% and 27% (p < 0.005). If EIC was associated with G3 degree of differentiation, in IC-free tumours of size T1, the LR rate elevated from 6.1% to 31% (p = 0.008), while in size T2 the elevation was from 15.7% to 33.% (p = 0.02). Based on the above results, the authors concluded that the presence of the intraductal component predicts a greater risk to develop LR. This risk increases significantly if EIC is associated with G3 histological grade. Physicians must consider this fact in designing individually tailored adjuvant therapy for their patients. Special attention should also be paid to the follow-up of this group of patients.

[Incidence of local recurrence after breast preserving surgery]. / A lokális recidíva elofordulása emlo-megtartásos mutéteink után.

Breast preserving surgery combined with adjuvant radiotherapy became more frequent in the last 20 years in the surgical treatment of early stage (Std. I-II) breast cancer in Hungary. Those who refuse this method usually allude to the frequent multifocality and the high recurrence rate of breast cancer. In the 1st Department of Surgery, Medical and Health Science Center, University of Debrecen, 825 patients underwent breast preserving surgery with a recurrence rate of 9.1% between January 1996 and December 2003. The time of appearance of recurrence varied between 5 and 102 months after surgery. There was no difference between the premenopausal and postmenopausal group. The 6.7% rate in pT1N0 tumors elevated to 16.7% in patients with pT2N1. According to histological grade the Grade 1 tumors had a recurrence rate of 2.3%, in Grade 2 we found 6.2% and in Grade 3 as high as 15.8%. Other unfavorable histo-morphological signs are the absence of estrogen receptors, the presence of extensive intraductal component and vessel invasion. Their opinion is that in case of local recurrence with favorable prognostic factors excision should be performed if acceptable cosmetic result can be achieved.

[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.

[The effect of mammographic screening on tumor size, axillary node status and the degree of histologic anaplasia]. / A mammográfiás emlorákszurés hatása a tumorméretre, a hónalji nyirokcsomó státuszra és a szövettani anaplázia fokára.

UNLABELLED: Breast cancer is the most frequent malignant tumor in women in Hungary. Significant reduction of mortality has been brought about not only by the increasing efficiency of complex therapy but also by regular mammographic screening. Of the histopathological data of 633 patients operated with primary breast tumor at the 1st Surgical Clinic of the Debrecen Medical University between January 1st 2000 and December 31st 2004, the authors analyzed tumor diameter, axillary node status and the degree of histologic anaplasia and compared them with the data of mammographic screening. RESULTS: Of the "screened"patients, 70.7% were diagnosed with T1 size tumors, 28.5% with T2 size, and 0.8% with tumors bigger than that. In the "unscreened" patients, our findings were 44.3%, 45.9% and 9.8% respectively. Within T1 tumors, Tla tumors were found in 11%, TIb in 37.6% and T1c in 51.4% in the "screened" group of patients, while the "unscreened" group's results were 2.3%, 12.6% and 85% respectively. 72.7% of the "screened" patients and 56.2% of the "unscreened" patients were found to be axillary node-negative. A study of the degree of histologic anaplasia showed G-I tumors in 15.6%, G-IIs in 62.1% and G-IIIs in 22.3% of the "screened" patients. The corresponding values for the "unscreened" patients were 6.1%, 53.8% and 40.1%, respectively. The differences were highly significant (p < 0.001) in all the parameters investigated. The authors have found a significant increase in the proportion of node-negative patients and patients with smaller tumors even after the first round of mammographic screening and at less than 50% participation. It is to be hoped that a 20% reduction in mortality can be achieved by further increasing the rate of participation.

[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.

[Clinical significance of HNPCC, surgical aspects of early recognition]. / A HNPCC klinikai jelentosége, korai felismerésének sebészi vonatkozásai.

A hereditary background may be demonstrated in approximately 15-20% of colorectal carcinomas. Familial adenomatous polyposis syndrome (FAP) constitutes about 1% of this patient population whereas hereditary non-polyposis colorectal carcinoma (HNPCC) makes up a further 3-6% of colorectal malignancies. The clinical features of HNPCC are dominant right colon localization, early age of onset, high prevalence of synchronous and metachronous tumors. Germline mutations of the so-called mismatch repair genes can be demonstrated in the genetic background of HNPCC. Screening and careful follow-up of these families are essential since the lifetime occurrence of colorectal carcinomas and HNPCC associated tumors has an 80-85% prevalence. The recognition of the affected families may be accomplished by taking a thorough family history, spanning several generations based on the Amsterdam and Bethesda Criteria, immunohistological investigations of the removed specimens and finally the exact identification of the pathologic MMR gene mutations. Radical surgical intervention is advised in cases of proven mutation carriers who are suffering from CRC. The index persons and their family members must be under regular control for their lifetime, with one-to-two year intervals to prevent fatal disease. The initiation of a national HNPCC register would further decrease the mortality and morbidity of the disease.

[The role of ileostomy in the prevention and treatment of complications of deep rectal anastomoses]. / Az ileostoma értéke a mély rectum anastomosisok szövódményeinek megelózésében és kezelésében.

The authors analyzed their data of the last three and a half years about patients with temporary loop ileostomy. We formed 18 ileostomies in patients with rectum carcinoma where the anastomosis was performed in the mid or lower rectum. Ten ileostomies were formed because of anastomotic leak, eight to protect the anastomosis, although there were no signs of insufficiency at the time of the intraoperative testing. Sixteen of the 18 patients had no complications. There were two complications in connection with ileostomies, these stomas were closed earlier than usual. Two other patients needed permanent stomas. Fourteen ileostomies were reversed without complications after 6-8 weeks. Two patients with local septic complications, following the closure, were treated conservatively. No reoperations were needed because of anal incontinence or anastomotic stenosis. We consider loop ileostomy safe with low morbidity, it can prevent diffuse peritonitis and/or a permanent stoma. Its routine use is recommended in patients with "ultra low" anastomoses and in cases where the intraoperative air test is positive.

[Changes in calcium metabolism after parathyroidectomy in primary hyperparathyroidism]. / Primer hyperparathyreosis miatt végzett mútéteket követó kalciumanyagcsere-változások.

INTRODUCTION: Primary hyperparathyroidism causes elevated serum calcium level and osteopenia in most patients. AIMS: The authors measured the changes of calcium and bone mineral metabolism after parathyroidectomy in patients with primary hyperparathyroidism. PATIENTS: From 1995 to 2000, osteopenia was detected in 34 patients with primary hyperparathyroidism before surgery. There were 26 females (16 women were post-menopausal) and 8 males. The mean age of the patients was 54 years (range 19 to 64). The serum levels of calcium, phosphorus, alkaline phosphatase and the parathyroid hormone were measured before the operation and every year thereafter. Bone densitometry was performed at the lumbar spine (L II-IV) during the same period. RESULTS: The mean levels of calcium and parathyroid hormone rapidly decreased and varied in the normal range after the operation. The mean alkaline phosphatase concentrations also decreased after surgery, but in most cases the difference was not statistically significant. Bone densitometry showed increased bone mineral density at the lumbar spine (L II-IV) after the parathyroidectomy. One, 2, 3, 4 and 5 years after surgery the bone mineral density increased with 8.5%, 12.5%, 14.1%, 13.5% and 11.3% compared to the preoperative value respectively. The changes in bone mineral density values were not statistically significant 1 year after parathyroidectomy. The increase in the bone mineral density was significant two years after the operation. Nine patients had T-scores less than -2.5 before parathyroidectomy. CONCLUSION: The authors conclude, that the serum levels of calcium and parathyroid hormone significantly decreased after the parathyroidectomy in primary hyperparathyroidism. After successful surgical treatment the bone mineral density significantly increases and the osteopenia decreases or resolves.