[Systemic treatment of pancreatic cancer]. / A pankreászrák szisztémás kezelése.

Pancreatic cancer is a devastating disease, survival rates did not improve during the last decades. At the same time new drugs and chemotherapy regimens have been approved for systemic use lately, the results of targeted therapy and the precision medicine approach are also encouraging. Further progress is needed covering all treatment modalities (surgery, radiotherapy, systemic treatment) in order to improve outcome of patients suffering from pancreatic cancer.

Current therapy of advanced colorectal cancer according to RAS/RAF mutational status.

Colorectal cancer is a clinically and molecularly heterogeneous disease. Currently, extended RAS and BRAF mutation testing is obligatory in routine clinical practice before starting any treatment in the metastatic setting. Treatment decision making also includes assessment of the clinical condition of the patient, definition of the treatment goal, and consideration of the primary tumor site. Biological treatment is part of the first-line drug combination unless contraindicated. Mutational status is significantly associated with the outcome of patients and is strongly predictive for anti-EGFR-targeted therapy. The prognosis of RAS mutant CRC is clearly inferior to wild-type cases. RAS remains an elusive target, and specific treatment options are not yet available. Recently, promising results of a direct KRAS G12C inhibitor have been reported; however, further confirmation is needed. The biomarker landscape in mCRC is evolving; new promising markers are awaited with the chance of more precise targeted treatment.

The surgical removal of orbital foreign bodies: double case report / A szemgödörbe került idegen testek mutéti eltávolítása két eset kapcsán

The surgical procedure of orbital foreign bodies with its complications is not yet solved in Hungary. Despite the fact that many specialities are involved, until the present day, an orbital surgical centre was not developed. The main goal of this case report is to highlight the importance of these events, to develop a surgical approach, to recognize and solve the complications if they are present even in the cases of organic foreign bodies affecting more head and neck anatomical regions and structures. Orv Hetil. 2020; 161(21): 889-894.

Resection of pancreatic cancer in Europe and USA: an international large-scale study highlighting large variations.

OBJECTIVE: Resection can potentially cure resectable pancreatic cancer (PaC) and significantly prolong survival in some patients. This large-scale international study aimed to investigate variations in resection for PaC in Europe and USA and determinants for its utilisation. DESIGN: Data from six European population-based cancer registries and the US Surveillance, Epidemiology, and End Results Program database during 2003-2016 were analysed. Age-standardised resection rates for overall and stage I-II PaCs were computed. Associations between resection and demographic and clinical parameters were assessed using multivariable logistic regression models. RESULTS: A total of 153 698 records were analysed. In population-based registries in 2012-2014, resection rates ranged from 13.2% (Estonia) to 21.2% (Slovenia) overall and from 34.8% (Norway) to 68.7% (Denmark) for stage I-II tumours, with great international variations. During 2003-2014, resection rates only increased in USA, the Netherlands and Denmark. Resection was significantly less frequently performed with more advanced tumour stage (ORs for stage III and IV versus stage I-II tumours: 0.05-0.18 and 0.01-0.06 across countries) and increasing age (ORs for patients 70-79 and ≥80 versus those <60 years: 0.37-0.63 and 0.03-0.16 across countries). Patients with advanced-stage tumours (stage III-IV: 63.8%-81.2%) and at older ages (≥70 years: 52.6%-59.5%) receiving less frequently resection comprised the majority of diagnosed cases. Patient performance status, tumour location and size were also associated with resection application. CONCLUSION: Rates of PaC resection remain low in Europe and USA with great international variations. Further studies are warranted to explore reasons for these variations.

Pancreatic Cancer: Multicenter Prospective Data Collection and Analysis by the Hungarian Pancreatic Study Group.

BACKGROUND AND AIMS: Pancreatic cancer is a devastating disease with poor prognosis. There is very limited information available regarding the epidemiology and treatment strategies of pancreatic cancer in Central Europe. The purpose of the study was to prospectively collect and analyze data of pancreatic cancer in the Hungarian population. METHODS: The Hungarian Pancreatic Study Group (HPSG) organized prospective, uniform data collection. Altogether 354 patients were enrolled from 14 Hungarian centers. RESULTS: Chronic pancreatitis was present in 3.7% of the cases, while 33.7% of the patients had diabetes. Family history for pancreatic cancer was positive in 4.8%. The most frequent presenting symptoms included pain (63.8%), weight loss (63%) and jaundice (52.5%). The reported frequency of smoking and alcohol consumption was lower than expected (28.5% and 27.4%, respectively). The majority of patients (75.6%) were diagnosed with advanced disease. Most patients (83.6%) had a primary tumor located in the pancreatic head. The histological diagnosis was ductal adenocarcinoma in 90.7% of the cases, while neuroendocrine tumor was present in 5.3%. Biliary stent implantation was performed in 166 patients, 59.2% of them received metal stents. Primary tumor resection was performed in 60 (16.9%) patients. Enteral or biliary bypass was done in 35 and 49 patients, respectively. In a multivariate Cox-regression model, smoking status and presence of gemcitabine-based chemotherapy were identified as independent predictors for overall survival. CONCLUSION: We report the first data from a large cohort of Hungarian pancreatic cancer patients. We identified smoking status and chemotherapy as independent predictors in this cohort.

The behavior of matrix metalloproteinases and their inhibitors in colorectal cancer.

Matrix metalloproteinases (MMPs) play an important role in the degradation of extracellular matrix components crucial for tumor growth, invasion and metastasis. MMPs are controlled by natural inhibitors called tissue inhibitors of metalloproteinases (TIMPs). We and others have demonstrated that MMPs and TIMPs are especially important in the process of tumor invasion, progression and the metastasis of colorectal cancer (CRC). It has been proposed that MMPs and TIMPs might play a part not only in tumor invasion and initiation of metastasis but also in carcinogenesis from colorectal adenomas. Several recent studies demonstrated that high preoperative serum or plasma MMP-2, MMP-9 and TIMP-1 antigen levels are strong predictive factors for poor prognosis in patients with CRC and their determination might be useful for identification of patients with higher risk for cancer recurrence. MMP-9 and TIMP-1 have significant potential tumor marker impact in CRC. Their diagnostic sensitivity is consistently higher than those of conventional biomarkers. The pharmacological targeting of CRC by the development of a new generation of selective inhibitors of MMPs, that is highly specific for certain MMPs, is a promising and challenging area for the future.

The role of inflammation and proteinases in tumor progression.

Chronic inflammation is an important risk factor for the development of cancers. The link between chronic inflammation and the risk of developing cancer is now well established. At least 20% of all cancers arise in association with infection and chronic inflammation. Inflammation and cancer are linked both along intrinsic (driven by genetic events causing malignancy) and extrinsic (driven by inflammatory conditions predisposing to tumor) pathways. Proteinases are key contributors to the breakdown and reconstitution of extracellular matrix components in physiological processes and pathological conditions, including destructive diseases and tumor progression. Matrix metalloproteinases are especially essential in the complex process of coregulation between cellular components of the tumor environment, and they are considered as potential diagnostic and prognostic biomarkers in many types and stages of cancer. Although the link between chronic inflammation, proteinases and risk of developing cancer is now well established, several open questions remain. The most exciting challenge is to find the best approach to target cancer-associated inflammation in patients with cancer. With respect to matrix metalloproteinases, the development of a new generation of selective inhibitors is a promising area of research.

The impact of matrix metalloproteinases and their tissue inhibitors in inflammatory bowel diseases.

BACKGROUND: It has been suggested that matrix metalloproteinases (MMPs) may play a role in the pathogenesis of inflammatory bowel diseases (IBD). However, the impact of serum MMPs and their inhibitors [tissue inhibitors of metalloproteinases (TIMPs)] have scarcely been investigated in the same experimental setting in ulcerative colitis (UC) and Crohn's disease (CD) as well as their correlation with IBD activity. METHODS: MMP-2, MMP-7, MMP-9, TIMP-1 and TIMP-2 serum antigen levels were determined in 23 patients with UC, 25 patients with CD and 10 healthy control patients by enzyme-linked immunoassay technique. Statistical analysis with one-way ANOVA and Student's t tests was performed. A linear regression analysis or a Spearman's r test was used to assess correlation. Differences were considered significant with p < 0.05. RESULTS: Serum antigen concentrations of MMP-9, TIMP-1 and TIMP-2 were significantly higher in UC and CD patients compared to controls. MMP-7 was also significantly higher in CD compared with controls. Elevated MMP-9 and TIMP-1 antigen levels showed significant positive correlation with disease activity of IBD. MMP-2 and TIMP-2 levels inversely correlated with CD activity. Significant correlations were found between MMP-9/TIMP-1 and MMP-2/TIMP-2 antigen levels in both UC and CD. CONCLUSIONS: We demonstrated that serum antigen concentrations of MMP-9, TIMP-1 and TIMP-2 were significantly increased in patients with UC and CD compared to controls. Our results suggest that MMPs and TIMPs may contribute to the inflammatory and remodeling processes in IBD. Serum MMP-9 and TIMP-1 might be useful as additional biomarkers in the assessment of IBD activity.

The behavior of matrix metalloproteinase-9 in lymphocytic colitis, collagenous colitis and ulcerative colitis.

Matrix metalloproteinases play an important role in extracellular matrix remodelling. It has been proposed that matrix metalloproteinase-9 (MMP-9) is involved in epithelial damage in ulcerative colitis (UC). However, to our knowledge, no data are available in terms of MMP-9 expression in microscopic colitis. Determination of mucosal protein expression levels of MMP-9 in lymphocytic colitis (LC), collagenous colitis (CC) and UC. MMP-9 immunohistochemical expressions were analyzed in paraffin-embedded tissue samples by immunohistochemistry including patients with LC, CC, UC, active diverticulitis, inactive diverticular disease and healthy control subjects. UC was also subgrouped according to the severity of inflammation. Immunostaining was determined semiquantitatively. Independent colonic biopsies from healthy and severe UC cases were used for gene expression analyses. For further comparison MMP-9 serum antigen levels were also determined in patients with UC and control patients without macroscopic or microscopic changes during colonoscopy. MMP-9 mucosal expression was significantly higher in UC (26.7 ± 19.5%) compared to LC (6.6 ± 9.3%), CC (6.4 ± 7.6%), active diverticulitis (5.33 ± 2.4%), inactive diverticular disease (5.0 ± 2.2%) and controls (6.3 ± 2.6%) (P < 0.001). The immunohistochemical expression of MMP-9 in LC and CC was similar as compared to controls. MMP-9 expression was significantly higher in each inflammatory group of UC compared to controls (mild: 11.0 ± 2.8%, moderate: 23.9 ± 3.7%, severe UC: 52.6 ± 3.9% and 6.3 ± 2.6%, respectively, P < 0.005). The gene expression microarray data and RT-PCR results demonstrated a significantly higher expression of MMP-9 in severely active UC compared to healthy controls (P < 0.001). Significantly higher MMP-9 serum antigen concentrations were observed in UC patients compared with the control group (P < 0.05). MMP-9 seems to play no role in the inflammatory process of LC and CC. In contrast, the mucosal up-regulation of MMP-9 correlated with the severity of inflammation in UC. The increased MMP-9 expression could contribute to the severity of mucosal damage in active UC.

Low bone mass in microscopic colitis.

BACKGROUND: Microscopic colitis presents with similar symptoms to classic inflammatory bowel diseases. Osteoporosis is a common complication of Crohn's disease but there are no data concerning bone metabolism in microscopic colitis. AIMS: The aim of the present study was to evaluate bone density and metabolism in patients with microscopic colitis. METHODS: Fourteen patients microscopic colitis were included in the study, and 28 healthy persons and 28 age and gender matched Crohn's disease patients were enrolled as controls. Bone mineral density was measured using dual x-ray absorptiometry at the lumbar spine, femoral neck and the radius. Serum bone formation and bone resorption markers (osteocalcin and beta-crosslaps, respectively) were measured using immunoassays. RESULTS: Low bone mass was measured in 57.14% patients with microscopic colitis. Bone mineral density at the femoral neck in patients suffering from microscopic colitis and Crohn's disease was lower than in healthy controls (0.852 ± 0.165 and 0.807 ± 0.136 vs. 1.056 ± 0.126 g/cm²; p < 0.01). Bone mineral density at the non-dominant radius was decreased in microscopic colitis patients (0.565 ± 0.093 vs. 0.667 ± 0.072 g/cm²; p < 0.05) but unaffected in Crohn's disease patients (0.672 ± 0.056 g/cm²). Mean beta-crosslaps concentration was higher in microscopic colitis and Crohn's disease patients than controls (417.714 ± 250.37 and 466.071 ± 249.96 vs. 264.75 ± 138.65 pg/ml; p < 0.05). A negative correlation between beta-crosslaps concentration and the femoral and radius t-scores was evident in microscopic colitis patients. CONCLUSIONS: Low bone mass is frequent in microscopic colitis, and alterations to bone metabolism are similar to those present in Crohn's disease. Therefore, microscopic colitis-associated osteopenia could be a significant problem in such patients.

[The epidemiology of pancreatic cancer]. / A hasnyálmirigyrák epidemiológiája.

Pancreatic cancer is a relatively uncommon tumor, but even with early diagnosis, mortality rates are high, explaining why this form of cancer has now become a common cause of cancer mortality. There are no screening tests for early detection of pancreatic cancer. It is more common in men than women and is predominantly a disease of elderly people. There is wide variation in the incidence of pancreatic cancer around the world, suggesting that environmental factors are important in the pathogenesis. Smoking is the major known risk factor for pancreatic cancer, while dietary factors seem to be less important. Other possible risk factors include chronic pancreatitis, obesity and type 2 diabetes. Numerous inherited germ line mutations are associated with pancreatic cancer. Of these, hereditary pancreatitis confers the greatest risk, while BRCA2 mutations are the commonest inherited disorder. Polymorphisms in genes that control detoxification of environmental carcinogens and metabolic pathways may alter the risk of pancreatic cancer.

[Quality colonoscopy: assumptions and expectations]. / Minoségi kolonoszkópia: feltételek és elvárások.

Colonoscopy has become accepted as the most effective method of screening of the colon for neoplasia. Evidences prove that utilization of colonoscopy has increased dramatically in the past few years, largely because of increased rates of CRC screening. Effectiveness and safety of colonoscopy depend on the quality of examination, and growing body of evidence suggests that the quality of colonoscopy varies in clinical practice. Quality assurance of colonoscopy could be expected to contribute significantly to improved patient care. There is a clear need for evidence-based quality measures to ensure the quality of colonoscopy. In this review we present an overview of literature concerning criteria for best practice and important quality indicators for colonoscopy.

[Probiotics in gastrointestinal disorders]. / Probiotikumok emésztoszervi betegségekben.

Probiotics are preparations containing viable microorganisms that confer potential health benefits for the host. Alteration of bacterial flora both in terms of specific content and concentration may be beneficial in many gastrointestinal disorders. Probiotics are widely used for the management of these conditions in many countries. However, mechanisms of probiotics are incompletely understood. Benefits observed clinically with one species or combinations of species can not be generalized. The optimal dose of treatment has to be determined. Although probiotics are generally regarded safe, caution is needed when using these supplements routinely. It has been proved, that severe adverse events can occur as a complication of probiotic treatment. This review summarizes the recent knowledge concerning the use of probiotics in gastrointestinal disorders.

Comparison of the effects of 1,25 dihydroxyvitamin D and 25 hydroxyvitamin D on bone pathology and disease activity in Crohn's disease patients.

BACKGROUND: Vitamin D is essential for osteopenia therapy in Crohn's disease (CD). The active form of vitamin-D (aVD) is the 1,25(OH)2D. There are no data available whether aVD or plain vitamin-D (pVD) has any advantage in managing osteoporosis in CD or has any effect on the activity of the disease itself. Our work is a prospective study to compare the effects of aVD and pVD on bone metabolism and the clinical course of CD. METHODS: In all, 37 inactive CD patients were involved in the study and divided into 2 age-, gender-, and t-score-matched groups. Group A was treated with aVD while group B received pVD. Osteocalcin, beta-CrossLaps, osteoprotegerin, and receptor activator nuclear factor kappa-B ligand concentrations were estimated at the start of the study and at 6 weeks and 3 and 12 months. The activity of CD was also measured clinically and by laboratory parameters. RESULTS: At week 6 the Crohn's Disease Activity Index (CDAI) scores and concentration of C-reactive protein decreased (69.44 +/- 58.6 versus 57.0 +/- 54.89 and 15.8 +/- 23.57 mmol/L versus 7.81 +/- 3.91 mmol/L, respectively, P < 0.05) parallel with markers of bone turnover (beta-CrossLaps: 0.46 +/- 0.21 ng/mL versus 0.40 +/- 0.25 ng/mL, and osteocalcin: 32.29 +/- 15.3 ng/mL versus 29.98 +/- 14.14 ng/mL, P < 0.05); however, osteoprotegerin concentration (marker of osteoblast activity) increased (3.96 +/- 2.1 pg/mL versus 4.58 +/- 2.19 pg/mL) in group A, but did not change in group B. Osteocalcin and beta-CrossLaps concentrations changed more significantly by the 3rd month; however, these changes disappeared by the 12th month. CONCLUSIONS: According to our study, aVD has a more prominent short-term beneficial effect on bone metabolism and disease activity in CD compared with pVD.

Increased p53 expression in the malignant transformation of Barrett's esophagus is accompanied by an upward shift of the proliferative compartment.

Neoplastic progression in Barrett's esophagus (BE) occurs by a multistep process associated with early molecular and morphological changes. This study evaluated cell proliferation and p53 expression and their correlation in the development and progression of esophageal adenocarcinoma. PCNA and p53 expressions were analyzed in biopsy samples by immunohistochemistry including patients with reflux esophagitis, BE, BE with concomitant esophagitis, Barrett's dysplasia, esophageal adenocarcinoma and a control group without any histological changes. Progressive increase in cell proliferation and p53 expression was found in the sequence of malignant transformation of the esophageal mucosa. While cell proliferation was significantly lower in the control group compared with all other groups, there was no increase in p53 expression of esophageal tissues that were negative for dysplasia. Dysplastic BE tissues revealed significantly higher cell proliferation and p53 expression levels compared to BE, reflux esophagitis or BE with concomitant esophagitis. Both, cell proliferation and p53 expression were significantly higher in adenocarcinoma compared to BE or Barrett's dysplasia. Interestingly, while just BE with concomitant esophagitis showed significantly higher p53 expression levels than BE, both, BE with concomitant esophagitis and reflux esophagitis revealed significantly higher cell proliferation levels compared to BE. Alterations of cell proliferation and p53 expression showed a strong correlation. Simultaneous activation of cell proliferation and p53 expression strongly suggest their association with esophageal epithelial tumor genesis and particularly, their specific role in the biology of esophageal adenocarcinoma. Quantification of these parameters in BE is thought to be useful to identify patients at higher risk for progression to adenocarcinoma.

[Antiangiogenic therapy for gastrointestinal tumors]. / Erképzodést gátló kezelés emésztoszervi daganatokban.

Angiogenesis plays a major role in the pathogenesis of many disorders. Vascular endothelial growth factor has been shown to be the key regulator of normal and pathological angiogenesis. Increased expression of VEGF has been associated with tumor neovascularization, metastasis and proliferation of cancer cells. Bevacizumab, a monoclonal antibody against VEGF, has shown promising preclinical and clinical activity against different types of cancer, particularly in combination with chemotherapy. There is an increasing evidence that bevacizumab has a disease-modifying effect in metastatic colorectal carcinoma (CRC), and also in advanced hepatocellular carcinoma. Further investigation is needed to evaluate the role of antiangiogenic therapeutic strategies in other gastrointestinal malignancies. This review summarizes recent knowledge about antiangiogenic therapy for gastrointestinal cancers.

[The safety of COX-2 inhibitors]. / A COX-2-gátlók biztonságossága.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed drugs worldwide, but they can cause serious gastrointestinal (GI) side effects. NSAIDs are capable of damaging the whole gastrointestinal tract. Cyclooxygenase-2 (COX-2) inhibitors (coxibs) have been developed with the aim of maintaining the anti-inflammatory benefits but reducing gastrotoxicity. There is a good evidence that these drugs effectively prevent gastroduodenal ulcers and ulcer complications. Little is known about the side effects of these agents in the small and large intestine. There is an increasing evidence that COX-2 is constitutively expressed in the gastrointestinal tract and is important for the maintenance of bowel integrity. There have also been growing concerns about the potential for coxibs to increase the frequency of adverse cardiovascular events. The purpose of this review is to summarize recent knowledge about the safety profile of selective COX-2 inhibitors.