Association between a polymorphic variant in the CDKN2B-AS1/ANRIL gene and pancreatic cancer risk.

Genes carrying high-penetrance germline mutations may also be associated with cancer susceptibility through common low-penetrance genetic variants. To increase the knowledge on genetic pancreatic ductal adenocarcinoma (PDAC) aetiology, the common genetic variability of PDAC familial genes was analysed in our study. We conducted a multiphase study analysing 7745 single nucleotide polymorphisms (SNPs) from 29 genes reported to harbour a high-penetrance PDAC-associated mutation in at least one published study. To assess the effect of the SNPs on PDAC risk, a total of 14 666 PDAC cases and 221 897 controls across five different studies were analysed. The T allele of the rs1412832 polymorphism, that is situated in the CDKN2B-AS1/ANRIL, showed a genome-wide significant association with increased risk of developing PDAC (OR = 1.11, 95% CI = 1.07-1.15, P = 5.25 × 10-9 ). CDKN2B-AS1/ANRIL is a long noncoding RNA, situated in 9p21.3, and regulates many target genes, among which CDKN2A (p16) that frequently shows deleterious somatic and germline mutations and deregulation in PDAC. Our results strongly support the role of the genetic variability of the 9p21.3 region in PDAC aetiopathogenesis and highlight the importance of secondary analysis as a tool for discovering new risk loci in complex human diseases.

A European survey on the insights of patients living with metastatic colorectal cancer: the patient journey before, during and after diagnosis - an Eastern European perspective.

BACKGROUND: Despite being highly preventable and treatable if diagnosed early, colorectal cancer (CRC) remains the second leading cause of cancer-related death in Europe. Limited information is available from the patient perspective on the persisting unmet needs of the journey of the patient with CRC. OBJECTIVE: To capture European metastatic CRC (mCRC) patients' insights during the patient journey (prediagnosis; diagnosis; postdiagnosis) through a patient survey. METHODS: In total, 883 patients from 15 European countries participated. Participants were divided into four groups from Hungary, Poland, Serbia and 'other European countries' (n=103, 163, 170 and 447 patients, respectively). RESULTS: General awareness of CRC and its symptoms prediagnosis varied among groups, with patients from Poland recording the lowest levels. Screening practices and attitudes also varied; while more patients from Serbia had been invited to CRC screening (~15%) compared with the other groups, the ones not invited claimed mostly (~20%) that would not have attended if they had been invited. Whereas most patients were diagnosed within a month after the first consultation/positive screening, the percentages varied substantially being lowest among patients in Poland (~30%) and Serbia (~25%). Although CRC-related information provision varied, with most informed patients from Hungary (~90%) and least from Serbia (~50%), all groups requested an easier-to-understand language by the healthcare team. Approximately 50% of patients from Eastern Europe had to wait longer than a month to receive treatment, in contrast to ~30% from other European countries. All groups emphasised the unmet need for support from psychologists and other patients. CONCLUSIONS: Our survey reveals the key aspects of the journey of the patient with mCRC and highlights the areas of similarities and differences between patients with mCRC from Eastern Europe versus those from other European countries as well as among patients from different Eastern European countries, calling for improvement particularly around awareness, screening, treatment availability, communication and support networks.

[Experience with cabazitaxel therapy for patients with metastatic castrate resistant prostate cancer in Hungary]. / Hazai tapasztalatok kasztrációrezisztens metasztatikus prosztatadaganatos betegek kabazitaxelterápiájával.

Our aim was to assess the efficacy and adverse effects of cabazitaxel (CBZ), a chemotherapeutic agent that can be administered to patients with metastatic castrate resistant prostate cancer (mCRPC) after docetaxel (DOC) therapy. We retrospectively analyzed data of CBZ received by mCRPC patients in 12 Hungarian oncological centers between 01/2016 and 06/2017. CBZ (25 or 20 mg/m2 q3w) was administered after DOC. Physical and laboratory examinations were performed in every cycle, tumor response was evaluated in every third cycle based on PCWG2 criteria. Adverse effects were evaluated based on CTCAE 4.0. Data of 60 patients were analyzed. CBZ was administered in 2nd and 3rd lines in 31.6% and 46.6%, while in 4th and 5th lines in 15% and 6.6% patients, respectively. Its starting dose was 25 mg/m2 and 20 mg/m2 in 65% and 35% of cases, respectively. The median number of cycles was 5. Progression-free survival and overall survival were 5.52 and 15.77 months, respectively. Survival results were similar in case of DOC-CBZ-ART/alfaradin and DOC-ART/alfaradin-CBZ sequences. Adverse effects were detected in 63,3% of patients. The most common adverse effects were neutropenia, anemia, and diarrhea. Our observations suggest that CBZ, with the appropriate support and chemotherapeutic experience, is well-tolerated and effective therapy of mCRPC after DOC.

[First Hungarian experience with pazopanib therapy for patients with metastatic renal cancer]. / Áttétes vesedaganatos betegek pazopanibterápiájával szerzett elsõ hazai tapasztalatok.

Pazopanib, a tyrosine kinase inhibitor, is one of the new registered first-line therapeutic options in the treatment of metastatic clear cell renal carcinoma. Our aim was to evaluate the efficiency and toxicity of first-line pazopanib therapy administered for patients with metastatic clear cell renal carcinoma with good- and medium prognosis according to MSKCC criteria. Between January and May, 2011, 24 patients have been treated with pazopanib in 8 oncology centers in Hungary, out of them 21 patients' data were analyzed. The mean age was 65.3 (49-81) years, 10 males and 11 females. According to MSKCC the prognosis was good and medium in 3 and 18 cases, respectively. Daily dose of pazopanib was 800 mg administered continuously in 28 day cycles. Dose reduction was performed according to the instructions of the registration study. Tumor response was evaluated according to RECIST 1.0. Currently 6 (28.6%) patients are on treatment. Dose reduction was necessary in 6 (28.6%) cases with an average duration of 14.55 (7-150) days. Mean±SE daily dose was 692.97±13.67 (400-800) mg. Median PFS was 12.41 months (95% CI 11.52-12.94 months). Complete remission (CR), as the best tumor response occurred in 2 (9.5%) cases. Partial remission (PR), stable disease (SD) and progression was observed in 6 (28.6%), 10 (47.6%) and 3 (14.3%) cases, respectively. Objective tumor response was observed in 8 pts (38%). Median survival could not be statistically analyzed yet due to the insignificant number of fatal outcomes. Median follow-up was 25.22 months (95% CI 2.47-28.1 months). As common side-effect fatigue, weakness and diarrhea occurred in 11 (52.4%), 9 (42.9%) and 8 (38%) cases, respectively. Besides these, worsening of high blood pressure and ALT/AST elevation was observed in 5 (23.8%) and 6 (28.6%) cases, respectively. Based on the initial Hungarian experiences, pazopanib is a well tolerable product and can be administered safely. According to our results its efficiency in terms of tumor response and progression-free survival is comparable to the results of the registration study.

[The treatment of castration-resistant prostate cancer]. / A kasztrációrezisztens prosztatadaganatok onkológiai kezelése.

The last several years have seen extraordinary progress in the management of patients with castration resistant prostate cancer (CRPC). Although metastatic prostate cancer remains an incurable disease, substantial advances have been made in therapeutic options. Development of novel agents that modulate the androgen receptor pathway, growth factor signalling pathways, and immune function and bone targeting pathways has been the focus of therapeutic strategies because of its significance in the biology of prostate cancer progression. In 2004, docetaxel/prednisone was the first therapy shown to prolong survival. For the next 6 years, no substantial progress was made in prolonging survival, but the latest 2 years have marked the beginning of a new and exciting era for the treatment of mCRPC. Based on phase III clinical trials cabazitaxel, abiraterone acetate, sipuleucel-T and denosumab represent available therapeutic options in this setting, radium-223 chloride and MDV3100 demonstrated a survival advantage in phase III trials and the road for their introduction in clinical practice is rapidly ongoing. Results are also awaited for phase III studies currently underway or planned with new drugs given as monotherapy (TAK-700, cabozantinib, tasquinimod, PROSTVAC-VF, ipilimumab) or in combination with docetaxel (custirsen, aflibercept, dasatinib, zibotentan), while other emerging molecules have shown hopeful results. The aim of this review is to summarize the most important new findings for metastatic CRPC (mCRPC) according to the different molecular pathways and to discuss their potential influence on future management of this disease.

[Pharmacologic therapy for neuroendocrine tumours]. / Neuroendokrin daganatok gyógyszeres kezelése.

Neuroendocrine tumours are heterogeneous and rare malignancies arising from endocrine cells located in various anatomical locations. Neuroendocrine tumours can be functional and may produce a wide variety of mediators, however, the majority of neuroendocrine tumours do not produce biologically active hormones (non-functioning tumours). On the basis of their pathological and biological characteristics they can be well differentiated as low malignant and poorly differentiated highly malignant tumours. In the case of the advanced low malignant tumours the application of somatostatin analogues not only may control symptoms but they also have direct anti-tumour effect. The use of higher doses of somatostatin analogues or new subtype selective agonists, and chimeric or pan-somatostatin analogues will probably improve the clinical management of the patients who fail to respond to standard somatostatin analogue treatment. Data show that somatostatin analogues and interferon have a synergistic effect. The currently used chemotherapy in progressive neuroendocrine tumors is mainly devoted to poorly differentiated tumours, but also to well differentiated carcinomas which are either not eligible or resistant to other therapies. However, the new anti-tumoural agents, could eventually replace these old recipes in the near future. Clinical trials show that telozomide with capecitabine result in more favorable toxic profile and higher and longer response rate in the case of well-differentiated tumours. Targeted therapy became a new possibility in neuroendocrine tumours too. The monoclonal antibody bevacizumab, which affects the vascular endothelial growth factor receptors, has beneficial effects both in monotherapies and in combination with somatostatin analogues or with oxaliplatine and capecitabine. Recently, the low molecular multikinase inhibitor, sunitinib has demonstrated efficacy in pancreas neuroendocrine tumors, which was proven in a phase 3 trial. The mammalian target of the rapamycin inhibitor everolimus, currently investigated in phase 3 trials, was also efficient in the same subtype. Further trials are needed to determine that in the case of other types of neuroendocrine tumours which targeted therapy could be efficient. Radioisotope-labeled peptide receptor therapy with ¹³¹I-MIBG, 9°Y-DOTA-TOC or ¹77Lu-DOTA-TOC may offer a highly effective option for patients with progressive and advanced stage of neuroendocrine tumours. The purpose of this review is to review and analyze data available regarding contemporary chemotherapeutic management of neuroendocrine tumours in order to determine which therapy should be applied in the therapeutic arsenal.

[The possibility of the use of MRI images in the three-dimensional external radiotherapy treatment planning]. / MRI-képek használatának lehetôsége a háromdimenziós külsô besugárzástervezésben.

PURPOSE: To review the application of MRI images in the radiation treatment planning,to discuss the advantages and disadvantages of MR imaging with respect to treatment planning, and to investigate the geometric distortion. METHODS: Humanoid therapy phantom was used for MRI and CT scanning, and distances between markers inside and on the surface of the phantom were measured in order to quantify the geometric distortion. The procedure of MRI/CT image fusion, which makes it possible to use the data of both imaging modalities for treatment planning, was described. RESULTS: At small volumes (head phantom) the geometric distortion was negligible (<2 mm), but at large volumes (eg. pelvis) remarkable geometric inaccuracies were observed. For example, the width of the pelvis measured in the MRI images was 7 mm less than the real distance, which corresponds to 2% inaccuracy. Geometric distortion was observed not only in the axial, but also in the sagittal and coronal planes. We have found that the geometric error increases with the distance measured from the magnetic isocenter. When the geometric distortion is not significant, the MRI/CT image fusion can be carried out reliably with the use of surface markers. CONCLUSIONS: At small volumes the MRI images can be used for treatment planning after their fusion with CT images. At larger volumes the geometric distortion without any correction may preclude the MRI images from using them in the treatment planning. A detailed assessment of geometric distortion must be carried out before the introduction of MRI images into the radiation treatment planning.

[Radiotherapy of MALT-lymphoma of the stomach]. / A gyomor MALT-lymphomák sugárkezelése.

INTRODUCTION: The stomach is the most common extranodal site of the low-grade MALT lymphoma. This lymphoma usually appears in elderly patients, with typically indolent signs. At the time of the diagnosis, the lymphoma is usually localized in the stomach and/or the adjacent lymph nodes. The choice in these cases is local treatment, which in the past involved only a surgical approach (total/partial gastrectomy), whereas more recently radiotherapy is preferred. PURPOSE: The radiation fields cover the whole stomach and the paragastric lymph nodes. The radiation doses range from 30 to 40 Gy, given in 1.5 Gy fractions 5 days a week. An adequate dose distribution to the target volume can be achieved by 3D treatment planning and conformal irradiation. METHODS: At our institute, 5 patients were treated with this method, the intention was curative in 3 cases, and palliative in 2 cases. The median dose in the 4 cases completed as initially planned was 33.6 Gy, delivered at 1.5 Gy per fraction. The adjacent critical organs do not exceed the tolerance doses by this method. RESULTS: In these 4 cases, complete regression was achieved, as determined by endoscopy and biopsy. In the fifth, locally advanced case, irradiation had to be terminated because of gastric bleeding. During irradiation, no other severe acute side-effects were detected. CONCLUSION: The literature and our preliminary results confirm that radiation therapy for early, localized MALT lymphoma of the stomach, or in disseminated cases, can be not only effective and safe, but offers the significant advantages of low treatment-related morbidity and preservation of the gastric function.

[Diagnostic possibilities of positron emission tomography in oncologic pulmonology]. / A pozitronemissziós tomográfia alkalmazási lehetóségei a tüdógyógyászati onkológiában.

The authors present the possibilities of applying positron emission tomography (PET) in oncopulmonology. In addition to reviewing the literature, they share their own experience obtained during the diagnostic work-up and follow-up of twenty-three patients. The basic indications and the relevant properties of the most frequently used radiopharmaceuticals are discussed. Finally, the authors raise the question of cost-effectiveness of PET-investigations vs. conventional techniques, and suggest possible algorithms to include this non-invasive imaging method in the diagnostic work-up of patients with malignant or benign pulmonary diseases.

[Principles of radiotherapy of non-small cell lung cancer]. / A nem kissejtes tüdôrák sugárterápiájának irányelvei.

The long-term survival probability for Hungarian lung cancer patients is 10% worse than the best results published in the most highly developed countries (the mean 5-year survival probability in Hungary is 5%, in contrast with the 15% survival probability in the USA). On the basis of the international recommendations and personal experience, an attempt was made to formulate the guidelines for radiotherapy as one of the fundamental non-small cell lung cancer (NSCLC) treatment modalities for national use. An expert panel was set up comprising physicians from 6 radiotherapeutic centers (the National Institute of Oncology / Semmelweis University, Budapest; the Beth Israel Medical Center, New York; the University of Kaposvár; the University of Essen; the University of Debrecen; and the County Hospital of Gyula). Experts in two important medical fields closely related to radiotherapy (surgery and diagnostic imaging) were also engaged in the elaboration of the manuscript. Discussion of the most important principles of the radiotherapy and an overview of the prognostic factors was followed by a critical analysis of the protocols applied in the radiotherapy of Hungarian NSCLC patients during recent decades. The new guidelines suggested for the radiotherapy of NSCLC are presented separately for the postoperative period, marginally resectable tumors, and the aggressive or non-aggressive radiotherapy of inoperable tumors. Detailed accounts are given of the techniques of external irradiation and brachytherapy, and of the acute and late radiation-induced damage of normal tissues. The authors believe that this document may be instrumental in improving the survival index of Hungarian NSCLC patients in the near future.

Successful treatment of a T1 cancer of the pancreatic head with high dose rate brachytherapy and external radiotherapy.

In this report, a unique case of a localized (T1N0M0) adenocarcinoma of the head of the pancreas is presented, which was successfully treated with interstitial high dose rate brachytherapy combined with percutan irradiation after biopsy. A total dose of 18 Gy was delivered with brachytherapy (6 Gy per fraction on three consecutive days) to the tumor via after-loading catheter. Brachytherapy was followed by external radiotherapy, delivering an additional dose of 46 Gy (18 MV-x) with four-field technique using conventional fractionation (2 Gy/day). Thirty-six months after completion of the treatment the patient is alive with no evidence of disease. The combination of interstitial high dose rate brachytherapy and external beam radiation therapy may be an effective tool to deliver curative dose without any significant sequelae in the treatment of operable pancreatic carcinoma, when the patient's condition contraindicates surgery.