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 this study. We conducted a multi-phase study analysing 7,745 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 non-coding 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. This article is protected by copyright. All rights reserved

Neuroendokrin daganatok gyógyszeres kezelése = Drugs for the treatment of neuroendocrine tumours

A neuroendokrin tumorok a ritka daganatok igen heterogén csoportját alkotják, amelyek a test különböző területein elhelyezkedő neuroendokrin rendszerből indulnak ki. A neuroendokrin daganatok lehetnek funkcionálók, sokféle mediátort termelhetnek, nagyobb részük azonban a nem funkcionáló csoportba tartozik. Szövettani jellegük és biológiai viselkedésük alapján lehetnek jól differenciált formájú alacsonyabb malignitású, valamint rosszul differenciált nagy malignitású tumorok. Az előrehaladt alacsony malignitású daganatok esetében a szomatosztatinanalógok nemcsak csökkentik a tumor okozta tüneteket, hanem közvetlen tumorgátló hatásuk is van. Azoknál a betegeknél, akiknél a standard szomatosztatinanalóg-terápia ellenére progresszió észlelhető, az új szelektív agonistáktól, illetve kimerikus készítményektől és panszomatosztatinagonista alkalmazásától további terápiás előnyt remélünk. Vizsgálatok utalnak arra is, hogy a szomatosztatinanalógok interferonnal együtt adva szinergista hatást mutatnak. A jelenleg elfogadott kemoterápiás kombinációkat a progresszív folyamatok esetében főleg a rosszul differenciált formáknál alkalmazzuk, de a jól differenciált carcinomák esetében is javasoltak, ha azok más kezelésre nem alkalmasak, illetve ha a terápia ellenére előre haladnak. Az újonnan kifejlesztett daganatellenes szerek, a közeljövőben felválthatják a régi protokollokat. Klinikai vizsgálatok azt mutatják, hogy a telozolomiddal és capecitabinnal kedvezőbb mellékhatásprofil mellett magasabb és tartósabb terápiás választ lehet elérni jól differenciált tumorokban. A célzott terápia neuroendokrin daganatok esetén is a figyelem központjába került. A vascularis endothelialis növekedési faktor receptorra ható monoklonális antitest, a bevacizumab mind monoterápiában, mind szomatosztatinanalóggal vagy oxaliplatinnal/capecitabinnal kombinált kezelés során terápiás előnyt hozott. A kis molekulasúlyú multikinázgátló sunitinib hatékonyságát a pancreas neuroendokrin daganataiban fázis III-as vizsgálat igazolta. Az mTOR-gátló everolimus is szignifikánsan növeli a túlélést ugyanebben a daganataltípusban. További vizsgálatok szükségesek annak meghatározásához, hogy más lokalizációjú, illetve rosszul differenciált daganatok esetén melyik célzott terápia nyújthat előnyt. A 131I-MIBG, 90Y-DOTA-TOC és 177Lu-DOTA-TOC radionuklidkezelések előrehaladt, illetve metasztatikus daganatokban hatékony és jól tolerálható kezelések. Jelen összefoglaló célja, hogy áttekintse és elemezze a rendelkezésre álló kemoterápiás kezelések eredményeit annak érdekében, hogy meghatározható legyen a legmegfelelőbb terápia a neuroendokrin daganatok esetében. Orv. Hetil., 2011, 152, 379–391. | 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, 90Y-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. Orv. Hetil., 2011, 152, 379–391

Efficacy and safety of FOLFIRINOX in locally advanced pancreatic cancer: a single center experience

The management of locally advanced pancreatic cancer (LAPC) is a major challenge. Although new drugs are available for the treatment of metastatic disease, the optimal treatment of non-metastatic cases remains controversial. The role of neoadjuvant therapy is still a question of debate in this setting. The aim of the study was to prospectively collect and analyse data on efficacy and safety of a modified FOLFIRINOX regimen in LAPC patients treated in a single institution. Another major objective was to assess the capability of FOLFIRINOX to render primary non-resectable cancer to resectable. No bolus fluorouracil was given and a 20% dose reduction of oxaliplatin and irinotecan was applied. Primary G-CSF prophylaxis was applied to prevent febrile neutropenia. Thirty-two patients (mean age 60.2 years, range: 40-77 years) have been enrolled into the study. All patients had ECOG performance status of 0 or 1. Best response to therapy was stable disease (SD) or partial regression (PR) in 18 (56.2%) and 6 (18.8%) cases. Two patients (6.3%) underwent surgical resection (100% R0). The most frequent grade 3/4 adverse events were nausea (18.8%), fatigue (12.5%) and diarrhea (12.5%). The incidence of severe neutropenia was 28.1%, with only one documented case of febrile neutropenia. The probability of disease progression was 25% and 50% after 75 and 160 days with 88.4% of possibility of disease progression after 500 days. OS probability was 92.1, 71.5% and 49.5% at 180-, 365 and 540 days. Our data does not support the capability of FOLFIRINOX to render primary non-resectable cancer to resectable. However, due to the high disease control rate observed, FOLFRINOX might be recommended as first line option for the palliative treatment of LAPC. Despite reduced chemotherapy doses significant toxicity has been seen

Hazai tapasztalatok kasztraciorezisztens metasztatikus prosztatadaganatos betegek kabazitaxelterapiajaval

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

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