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Alena Novakova-Jiresova,1 Katerina Kopeckova,2 Ludmila Boublikova,1 Renata Chloupkova,3 Bohuslav Melichar,4 Lubos Petruzelka,5 Jindrich Finek,6 Ondrej Fiala,6,7 Peter Grell,8 Stanislav Batko,2 Zdenek Linke,2 Igor Kiss,8 Jana Prausova,2 Tomas Buchler1 1Department of Oncology, First Faculty of Medicine and Thomayer Hospital, Charles University, Prague, Czech Republic; 2Department of Oncology, University Hospital in Motol, Charles University, Prague, Czech Republic; 3Institute of Biostatistics and Analysis, Faculty of Medicine, Masaryk University, Brno, Czech Republic; 4Department of Oncology, Palacky University Medical and Teaching Hospital, Olomouc, Czech Republic; 5Department of Oncology, General Faculty Hospital, Charles University, Prague, Czech Republic; 6Department of Oncology and Radiotherapy, Medical School and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic; 7Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic; 8Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech RepublicCorrespondence: Tomas BuchlerDepartment of Oncology, First Faculty of Medicine and Thomayer Hospital, Charles University, Videnska 800, Prague 140 59, Czech RepublicTel +420-261-082-637Fax +420-261-082-522Email tomas.buchler@ftn.czPurpose: Regorafenib is an oral multikinase inhibitor approved for the therapy of previously treated metastatic colorectal carcinoma (mCRC). The aim of the present study was to analyze the outcomes of treatment with regorafenib in real-world clinical practice based on data from a national registry.Methods: The CORECT registry, the Czech non-interventional database of patients with mCRC treated with targeted agents, searched for patients with metastatic CRC treated with regorafenib. In total, 555 evaluable patients were identified.Results: The median age at diagnosis was 61.7 years. All patients had disease progression on or after previous systemic treatment. Most patients were treated with an initial dose of 160 mg daily (n = 463; 83.6%). The median duration of treatment was 2.7 months (range 0.0– 23.4 months). By the data cut-off date, 472 patients (85%) had completed treatment with regorafenib and were evaluable for treatment response evaluation. Partial response was reported in 13 patients (2.8%) and disease stabilization in 130 patients (27.5%). Median progression-free survival (PFS) and overall survival (OS) were 3.5 months (95% confidence interval [CI] 3.2– 3.7 months) and 9.3 months (95% CI 8.3– 10.3 months), respectively. The 6-month OS rate was 67.7% (95% CI 63.4– 72.1%). Multivariable analysis showed that female gender, longer interval from diagnosis of metastatic disease, M0 stage at diagnosis, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0 were associated with longer PFS, while higher body-mass index (BMI), longer interval from diagnosis of metastatic disease, and ECOG PS of 0 were associated with longer OS.Conclusion: OS of patients treated with regorafenib in the real-world clinical practice in this cohort exceeded that reported in randomized trials. Regorafenib is a safe and active treatment option for a subgroup of patients with mCRC who are progressing after other systemic therapies and maintain good performance status.Keywords: colorectal cancer, regorafenib, registry, survival, outcome analysis

Martin Lovecek,1,* Marketa Janatova,2,* Pavel Skalicky,1 Tomas Zemanek,3 Roman Havlik,1 Jiri Ehrmann,4 Ondrej Strouhal,3 Petra Zemankova,2 Klara Lhotova,2 Marianna Borecka,2 Jana Soukupova,2 Hana Svebisova,3 Pavel Soucek,5 Viktor Hlavac,5 Zdenek Kleibl,2 Cestmir Neoral,1 Bohuslav Melichar,3 Beatrice Mohelnikova-Duchonova3 1Department of Surgery I, Faculty of Medicine and Dentistry, Palacky University Olomouc, University Hospital Olomouc, Olomouc, Czech Republic; 2Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic; 3Department of Oncology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic; 4Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University Olomouc, University Hospital Olomouc, Olomouc, Czech Republic; 5Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen Czech Republic *These authors contributed equally to this work Background: The principal aim of this report was to study second primary malignant neoplasms (SMNs) in long-term survivors of pancreatic ductal adenocarcinoma (PDAC) with regard to the germline genetic background.Patients and methods: A total of 118 PDAC patients after a curative-intent surgery who were treated between 2006 and 2011 were analyzed. Of the 22 patients surviving for >5 years, six went on to develop SMNs. A genetic analysis of 219 hereditary cancer-predisposition and candidate genes was performed by targeted next-generation sequencing in germline DNA from 20 of these patients.Results: Of all the radically resected PDAC patients, six patients went on to subsequently develop SMNs, which accounted for 27% of the long-term survivors. The median time to diagnosis of SMNs, which included two cases of rectal cancer, and one case each of prostate cancer, malignant melanoma, breast cancer, and urinary bladder cancer, was 52.5 months. At the time of analysis, none of these patients had died as a result of PDAC progression. We identified four carriers of germline pathogenic mutations in 20 analyzed long-term survivors. One carrier of the CHEK2 mutation was found among four analyzed patients who developed SMNs. Of the remaining 16 long-term PDAC survivors, 3 patients (19%) carried germline mutation(s) in the MLH1+ ATM, CHEK2, and RAD51D gene, respectively.Conclusion: This retrospective analysis indicates that SMNs in PDAC survivors are an important clinical problem and may be more common than has been acknowledged to be the case. In patients with good performance status, surgical therapy should be considered, as the SMNs often have a favorable prognosis. Keywords: pancreatic ductal adenocarcinoma, second primary neoplasms, subsequent malignant neoplasm, hereditary cancer genes, long-term survivors, surgical treatment

Tomas Buchler,1 Renata Chloupkova,2 Alexandr Poprach,3 Ondrej Fiala,4,5 Igor Kiss,3 Katerina Kopeckova,6 Ladislav Dusek,2 Veronika Veskrnova,1 Lubomir Slavicek,7 Milan Kohoutek,8 Jindrich Finek,4 Marek Svoboda,3 Lubos Petruzelka,9 Bohuslav Melichar10 1Department of Oncology, First Faculty of Medicine, Charles University and Thomayer University Hospital, 140 59 Prague, Czech Republic; 2Institute of Biostatistics and Analyses, Faculty of Medicine, Masaryk University, 625 00 Brno, Czech Republic; 3Department of Comprehensive Cancer Care and Faculty of Medicine, Masaryk Memorial Cancer Institute and Masaryk University, Brno 656 53, Czech Republic; 4Department of Oncology, University Hospital, 304 60 Pilsen, Czech Republic; 5Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic; 6Department of Oncology, Motol University Hospital and Second Faculty of Medicine, Charles University, 150 00 Prague, Czech Republic; 7Department of Oncology, Jihlava Hospital Comprehensive Cancer Centre, Jihlava, Czech Republic; 8Department of Oncology, T Bata Hospital and Comprehensive Cancer Centre, Zlin, Czech Republic; 9Department of Oncology, General University Hospital and Charles University First Faculty of Medicine, 128 08 Prague, Czech Republic; 10Department of Oncology, Palacky University Medical School and Teaching Hospital, 775 20 Olomouc, Czech Republic Purpose: Although inhibitors of vascular endothelial growth factor and inhibitors of epidermal growth factor receptor (EGFRi) are commonly used for the treatment of metastatic colorectal cancer (mCRC), the optimal sequencing of these agents is currently unclear. Methods: A national registry of targeted therapies was used to analyze baseline ­characteristics and outcomes of patients with mCRC and wild-type KRAS exon 2 status who received ­bevacizumab and EGFRi (cetuximab or panitumumab) as a part of first- and second-line ­treatment in either sequence. Results: The cohort included 490 patients (181 patients treated with first-line EGFRi and second-line bevacizumab and 309 patients treated with first-line bevacizumab and second-line EGFRi). Median overall survival (OS) from the initiation on first-line therapy was similar for patients treated with either sequence, reaching 31.8 (95% CI 27.5–36.1) vs 31.4 months (95% CI 27.8–35.0) for EGFRi → bevacizumab vs bevacizumab → EGFRi cohort, respectively. Time from first-line initiation to progression on the second-line therapy [progression-free survival (PFS)] was 21.1 (95% CI 19.3–23.0) vs 19.3 months (95% CI 17.3–21.3) for bevacizumab → EGFRi vs EGFRi → bevacizumab cohort, respectively (P=0.016). Conclusion: This retrospective analysis of real-world data of patients with wild-type KRAS exon 2 mCRC showed no differences in OS between cohorts treated with bevacizumab → EGFRi vs the reverse sequence while combined PFS favored the bevacizumab → EGFRi sequence. Keywords: colorectal carcinoma, bevacizumab, panitumumab, cetuximab, sequence

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The activation of the immune system is associated with profound alteration of zinc metabolism. In human immunodeficiency type 1 (HIV-l) infection serum zinc is frequently decreased. To investigate a potential role of immune system activation on urinary zinc wasting, we compared urinary zinc and l1eopterin levels in 52 patients with HIV-J infection. In addition, serum zinc was studied in 25 of the patients. We confinned earlier reports of decreased serum zinc levels in the patients. As expected, urinary neopterin was significantly increased in HIV-l infection, the highest values being reached in AIDS patients. Urinary zinc concentrations were not statistically different between patients and controls. However, a positive correlation existed between urinary zinc and neopterin levels and between neopterin and zinc clearance coefficient in patients with more advanced stages of HIV infection. No correlation between serum zinc and urinary neopterin or urinary zinc was found. The data indicate that, in addition to malabsorption, chronic immune activation may contribute to the development of zinc deficiency by urinary zinc wasting.