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Background CONKO-006 was designed for patients with pancreatic adenocarcinoma with postsurgical R1 residual status to evaluate the efficacy and safety of the combination of gemcitabine and sorafenib (GemSorafenib) compared with those of gemcitabine + placebo (GemP) for 12 cycles. Patients and methods This randomised, double-blind, placebo-controlled, multicenter study was planned to detect an improvement in recurrence-free survival (RFS) from 42% to 60% after 18 months. Secondary objectives were overall survival (OS), safety and duration of treatment. Results 122 patients were included between 02/2008 and 09/2013; 57 were randomised to GemSorafenib and 65 to GemP. Patient characteristics were wellbalanced (GemSorafenib/GemP) in terms of median age (63/63 years), tumour size (T3/T4: 97/97%), and nodal positivity (86/85%). Grade 3/4 toxicities comprised diarrhoea (GemSorafenib: 12%; GemP: 2%), elevated gamma-glutamyl transferase (GGT) (19%; 9%), fatigue (5%; 2%) and hypertension (5%; 2%), as well as neutropenia (18%; 25%) and thrombocytopenia (9%; 2%). By August 2017, 118 (97%) RFS event had occurred. There were no difference in RFS (median GemSorafenib: 8.5 versus GemP: 9.4 months; p = 0.730) nor OS (median GemSorafenib: 17.6 versus GemP: 17.5 months; p = 0.481). Landmark analyses suggest that patients who received more than six cycles of postoperative chemotherapy had significantly longer OS (p = 0.021). Conclusion CONKO-006 is the first randomised clinical trial to include exclusively patients with PDAC with postsurgical R1 status thus far. Sorafenib added to gemcitabine did neither improve RFS nor OS. However, postoperative treatment exceeding six months seemed to prolong survival and should be further investigated in these high-risk patients. Clinical trial information German Tumor Study Registry (Deutsches Krebsstudienregister), DRKS00000242.

Background We studied the prognostic effect of CD3-, CD8- and CD103-positive T lymphocytes in a cohort of 165 patients with resected pancreatic ductal adenocarcinomas (PDACs) of the treatment group (adjuvant gemcitabine) and the untreated control group of the CONKO-001 study. Methods Immunohistochemical stainings on tissue microarrays (TMAs) against CD3, CD8 and CD103 were performed according to standard procedures. Results A high number of CD8-positive lymphocytes were significantly and independently associated with longer disease-free survival (DFS) and overall survival (OS) in the overall study population. Median DFS/OS were 7.4/18.1 months for patients with a low number of CD8-positive intratumoural lymphocytes ( ≤ 42 per 1 mm tissue core) and 12.7/25.2 months for patients with high numbers (>42 per 1-mm tissue core; p = 0.008/0.020; HR 0.62/0.65). The ratio of intraepithelial to total CD103-positive lymphocytes, but not total numbers of CD103-positive lymphocytes or CD103-positive intraepithelial lymphocytes, was associated with significantly improved DFS and OS in the overall study population (p = 0.022/0.009). Median DFS/OS was 5.9/15.7 for patients with a ratio of intraepithelial to total CD103-positive intratumoural lymphocytes higher than 0.3 and 11.6/24.7 for patients with a lower ratio. Conclusion T-lymphocyte subpopulations might be prognostic in resectable PDAC but need standardization and verification by further studies.

In pancreatic cancer there is a need for prognostic risk stratification and subsequent therapy strategies. Molecular analysis has shown in different cancers that variation in clinical behavior can be associated with specific alterations. The cell cycle regulators p16 and p53 belong to the most often alterated genes in pancreatic ductal adenocarcinoma (PDAC). We analyzed protein expression of p16, p53 and Ki67 by immunohistochemistry in 162 tumours of the CONKO-001 trial that investigated the role of adjuvant gemcitabine in pancreatic cancer patients. We could show that high proliferation of tumours and strong and consistent nuclear p53 expression by tumour cells is associated with a worse disease-free survival and overall survival in the overall study population. However, stratified analysis according to treatment arm revealed that the effect of deregulated p53 expression and high Ki67 expression was restricted to the disease free survival of patients treated with adjuvant gemcitabine. In multivariable survival analysis, p53 did not retain its prognostic status. Our study supports the important role of p53 and Ki67 expression in PDAC. They provide prognostic information in patients with adjuvant gemcitabine treatment and may contribute to treatment decision. However, these results should be validated in further studies.

Background High expression of human equilibrative nucleoside transporter 1 (hENT1) is considered to predict survival in patients treated with adjuvant gemcitabine for pancreatic cancer. A standard evaluation system for immunohistochemical analysis (antibody, scoring system) has not yet been established. Methods CONKO-001, a prospective randomised phase III study investigated the role of adjuvant gemcitabine (gem) as compared to observation (obs). Tumour samples of 156 patients were analysed by immunohistochemistry with the rabbit monoclonal antibody SP120 (Ventana Medical Systems) for expression of hENT1. Kaplan–Meier analyses for median disease-free survival (DFS) and overall survival (OS) were performed in dependence of hENT1 expression measured analogously to Farrell et al. 2009 and Poplin et al. 2013. Results For the 88 gem and 68 obs patients, median DFS/OS was 12.9/22.7months and 6.2/19.1months. High hENT1 expression was not associated with improved median DFS (Farrell: no hENT1 22.2months, low hENT1 13.7months, high hENT1 12.1months, p =0.248; Poplin: low hENT1 13.2months versus high hENT1 11.5months, p =0.5) or median OS (Farrell: no hENT1 21.7months, low hENT1 24.7months, high hENT1 19.5, p =0.571; Poplin: low hENT1 24.4months versus high hENT1 19.7months, p =0.92;) in the gem group or in the obs group (median DFS Farrell: no hENT1 5.1months, low hENT1 6.2months, high hENT1 7.5months, p =0.375; Poplin: low hENT1 6.2months versus high hENT1 5.9months, p =0.83; median OS Farrell: no hENT1 20.2months, low hENT1 17.7months, high HENT1 19.1months, p =0.738; Poplin: low hENT1 17.7months versus high hENT1 20.4months, p =0.65) measured by the Farrell or Poplin Score. Conclusions We cannot confirm a predictive role of hENT1 measured by the clone SP120 rabbit antibody in our study population. Reproducible standard procedures are urgently needed prior to the implementation or exclusion of hENT1 as a predictive biomarker in the treatment of pancreatic cancer. Trial registration ISRCTN34802808.

Ever since a pivotal study in 1997 demonstrated superiority of gemcitabine over 5-FU, gemcitabine monotherapy has, until recently, comprised the standard of care in patients with advanced pancreatic cancer. However, the emerging recognition of the pancreatic cancer microenvironment, including the particularly abundant stroma, as playing a key role in disease progression and resistance to chemotherapy has marked somewhat of a paradigm shift in the way treatment of advanced pancreatic cancer is viewed, with these very same biological defenses conversely offering an Achilles heel with which to combat this aggressive disease. Recently, this approach was validated for the first time in a pivotal phase III trial in which patients received nab-paclitaxel, a stroma-targeted drug, with gemcitabine. Overall survival was significantly (p

Mutations in K-ras are frequent in acute myeloid leukemia (AML). The association of these mutations to clinical features and their prognostic value are unclear. We used quantitative PCR with peptide nucleic acid mediated PCR clamping to specifically analyze 257 blood samples of 31 AML patients for K-ras codon 12 alterations. A total of 20 samples of nine patients harbored a K-ras mutation. The most frequent mutation was the GTT variant which causes an amino acid exchange from glycine to valine. Correlation with clinical data suggests K-ras mutations to be associated with higher age and a better response to anti-leukemic chemotherapy.

The purpose of this phase II trial was to investigate the efficacy and toxicity of oxaliplatin combined with folinic acid (FA) and 5-FU in patients with recurrent squamous cell carcinoma of the head and neck (scchn) in advanced stage of disease. Thirty-six patients with recurrent/metastatic disease with median age of 59 years were enrolled. Patients received oxaliplatin (85mg/m(2)) and FA (200mg/m(2)) followed by 5-FU (2000mg/m(2)) as 24h continuous infusion on day 1 and 15 in a 4-week cycle. On day 8 and 22 FA (200mg/m(2)) and 5-FU (2000mg/m(2)) were administered without oxaliplatin followed by two weeks without cytotoxic treatment. Toxic effects, length of survival and tumour response were assessable in 33/36 patients. The overall response was 60.6% with 7 (21.2%) complete responders (CR) and 13 (39.4%) partial responders (PR). Eight patients (24.2%) showed stable disease (SD) and 5 (15.2%) progressed. The median time to progression (TTP) was 8.1 month (range 2-14) and median overall survival was 10.8 months (range 5-16). The 1-year survival rate was 43.2%. The incidence of haematological toxicity was low but mild paraesthesias occurred in all patients received more then 3 cycles of cytotoxic therapy and dose reduction was necessary in two patients due to diarrhoea grade 3. In this small phase II study the combination of oxaliplatin, FA and 5-FU (OFF) demonstrated relative to the standard regimen of cisplatin and 5-FU a high antitumoural activity in previously treated scchn with favourable toxicity profile.

Aims Several new chemotherapy agents show varying degrees of activity in head and neck cancer. One of them is gemcitabine, which is a new nucleoside analogue with an innovative cytostatic mode of action. Gemcitabine has demonstrated a broad spectrum anti-tumoural effect and a favourable toxicity profile. These attributes prompted us to introduce gemcitabine into the treatment of head-and-neck tumours. Materials and methods Ten heavily pre-treated patients with recurrent and incurable squamous-cell carcinoma of the head and neck (SCCHN) were treated with Gem. The initial cycle consisted of six administrations of the drug (1250mg/m 2 once weekly intravenously over 30min) followed by a week without cytotoxic treatment. All following cycles were composed of two infusions once weekly (d1, 8), followed by a week of rest. Results Toxic effects, length of survival and tumour response was assessable in eight patients owing to one suicide and loss of one patient for follow-up. One complete remission, two partial remissions and three ‘no change' situations (stable disease) were observed, yielding a response rate of 37.5%. Median survival was 8 months (range 3–12). The incidence of haematological toxicity was low, with grade 3–4 neutropenia in less than 10%. Flu-like symptoms were reported by one-third of patients. Conclusions In this small phase-II study, gemcitabine demonstrated a high anti-tumoural activity in SCCHN, with a favourable toxicity profile. Gemcitabine seems to be a promising new drug without severe burden even for patients who are refractory to other cytostatic drugs. Within recent years, the activity and tolerability of gemcitabine was documented in several phase I and phase II trials, especially in combination with cisplatin, and paclitaxel resp, carboplatin/paclitaxel, cisplatin/ifosfamide, and 5-fluorouracil/paclitaxel. The results of these trials will be outlined in the discussion.

To determine the value of fluorine-18-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) for the detection of recurrent pancreatic cancer in comparison to computed tomography (CT) and magnetic resonance imaging (MRI).Thirty-one patients with suspected recurrence after surgery were included. Inclusion criteria were sudden weight loss, pain or increased CA 19-9 levels. FDG-PET was performed in all patients. After visual analysis, maximal standardized uptake values (SUVmax) were determined by placing regions of interest on the pancreas bed. Additionally, all patients underwent contrast-enhanced multidetector CT (n = 14) or MR (n = 17) imaging. Positive findings at FDG-PET or CT/MRI were compared to follow-up.All patients relapsed. Of 25 patients with local recurrences upon follow-up, initial imaging suggested relapse in 23 patients. Of these, FDG-PET detected 96% (22/23) and CT/MRI 39% (9/23). Local SUVmax ranged from 2.26 to 16.9 (mean, 6.06). Among 12 liver metastases, FDG-PET detected 42% (5/12). CT/MRI detected 92% (11/12) correctly. Moreover, 7/9 abdominal lesions were malignant upon follow-up of which FDG-PET detected 7/7 and CT/MR detected none. Additionally, FDG-PET detected extra-abdominal metastases in 2 patients.In patients suspected of pancreatic cancer relapse; FDG-PET reliably detected local recurrences, whereas CT/MRI was more sensitive for the detection of hepatic metastases. Furthermore, FDG-PET proved to be advantageous for the detection of nonlocoregional and extra-abdominal recurrences.

Abstract. At the time of first diagnosis, patients with squamous cell carcinoma in the head and neck are often in the advanced stage of their disease, therefore surgery is not a viable option for treatment. These patients also present frequently a high grade of anaemia as a result of either the malignant process itself or of the following therapy. The incidence of anaemia and the need for transfusion depends on several factors, such as the type and intensity of radiotherapy and radio-chemotherapy. Multimode therapeutic concepts such as radio-chemotherapy are being applied with increasing frequency, resulting in an ever increasing need for transfusion with great effects on the patient's quality of life. Even more important to tumour patients is the role of the haemaglobin (Hb) value as a prognostic factor for survival and/or local tumour control. A large number of studies show that recombinant human erythropoietin (r-HuEPO) is effective in the treatment of tumour-induced anaemia and prevention and correction of chemotherapy and radiotherapy-induced anaemia. The simultaneous application of r-HuEPO with chemotherapy can prevent patients with head and neck tumours from developing anaemia or can reduce the extent of the anaemia and the need for transfusion. Comparable effects were observed both in patients undergoing platinum-based and non-platinum-based chemotherapy. The direct correlation between anaemia, tumour hypoxia and poor response to radio and/or chemotherapy has been clinically proven. Recombinant human erythropoietin administration improves the therapeutic outcome and the patients' prognosis.

Herpes viruses have been implicated in the etiology of Hodgkin's disease (HD). We studied the prevalence of human cytomegalovirus (CMV), human herpes viruses type-6 (HHV-6), type-7 (HHV-7) and type 8 (HHV-8) DNA in up to 88 Hodgkin's disease biopsies in comparison to Epstein-Barr virus (EBV) DNA by polymerase chain reaction (PCR). Non-Hodgkin lymphomas (NHL) and reactive lesions served as controls. CMV and HHV-6 were found in 8/86 (9%) and 11/88 (13%) HD cases, respectively, by nested primer PCR. Except for three cases harbouring HHV-6 type-B, only HHV-6 type-A was detected in HD. HHV-7 was observed by nested PCR in 33/88 (38%) HD cases and was already detectable in 15/88 (17%) HD cases by a single-round PCR indicating elevated virus copy numbers. Seven of these cases showed co-infection with HHV-6, and 11 cases were found to contain EBV DNA. 7/8 CMV-positive HD cases also harboured EBV DNA. HHV-8 DNA was not detected by single round or nested PCR in any HD case investigated. Thus, CMV, HHV-6, and HHV-7 were present in small proportions of HD cases, with frequent co-infection of HHV-6 and HHV-7, and frequent association with EBV. In contrast to EBV, beta-herpes viruses are therefore unlikely to have a role in the aetiology of HD. Rather, the presence of these viruses seems to reflect impaired immunological surveillance.

Single strand conformation polymorphism analysis (SSCP) of PCR-amplified DNA and subsequent DNA sequencing of human cytomegalovirus (HCMV) glycoprotein B (gB) gene were applied to identify known HCMV strains and to detect new virus variants. 61 HCMV PCR positive patients were studied out of a cohort of 410 patients after liver transplantation (LTX). SSCP was able to distinguish between strains Davis, AD169, and Towne, and in addition could identify five new virus variants (Berlin B, C, E, F, and H). Their frequency, gB and gH types were determined. Simultaneous infections with two or three strains or variants, as well as a switch from one virus to another virus were observed during long-term follow-up. No correlation between the occurrence of certain virus strains or gB types and defined clinical manifestations of HCMV infection after LTX was drawn.

The suppression and eradication of malignant tumours by targeting the endothelial cells of the tumour is one of the rapidly evolving new approaches to cancer therapy. Head and neck tumours, because of their high levels of vascularization, present themselves as ideal candidates for such antiangiogenic strategies. We report a heavily pretreated patient with a tumour 15 cm in diameter representing fourth relapse of squamous cell carcinoma, which had its origin in the upper left jaw. The patient was treated with the antiangiogenetic, cyclic peptide, EMD 121974 [cilengitide] (600 mg/m 2 over 60 minutes iv) on day 1 and 4 in combination with gemcitabine (1000 mg/m 2 over 30 minutes) administered days 1 and 8 every 3 weeks for five months, and a partial remission was achieved. This resulted in a clinical improvement in the ability of the patient to eat and smell. The patient remained stable for 12 months on cilengitide mainenance therapy, with no tendancy towards spontaneous bleeding. This clinical case demonstrates the clinical efficacy of the antiangiogenetic agent cilengitide, in combination with gemcitabine, in inhibiting rapid growth of highly vascularized tumour and highlights the potential of this new therapeutic agent

Background and Objectives The continuous progress in treatment options for pancreatic adenocarcinoma has lead to a re-evaluation of prognostic markers. In this study the prognostic relevance of DNA Index and classical histopathological parameters with regard to disease-free (DFS) and overall survival (OS) was analyzed within the CONKO-001 patient population. Methods One hundred forty three fresh-frozen paraffin-embedded tissue samples of the resected tumor specimen of the CONKO-001 patient population were available for DNA index analysis to evaluate its impact on patient outcome. Results Median DFS (7.3 vs. 14.3 months; P = 0.004) and median OS (16.6 vs. 29.2 months; P = 0.011) were significantly decreased in patients with a high DNA index (>1.4). Multivariate analysis revealed both DNA index (DFS: P = 0.002; OS: P = 0.019) and tumor grading (DFS: P = 0.004; OS: P = 0.004) as individual prognostic markers for DFS and OS. The following prognostic subgroups were identified: good (low DNA Index + G1/2 tumor grading), intermediate (low DNA Index + G3 tumor grading or high DNA Index + G1/2 tumor grading), poor (high DNA Index + G3 tumor grading). Conclusion The DNA index/tumor grading constellation may serve as a helpful guide for personalized treatment recommendations for adjuvant therapy of patients with pancreatic adenocarcinoma. J. Surg. Oncol. 2015 111:66–71. © 2015 Wiley Periodicals, Inc.

Aim: Even after successful curatively intended surgery, up to 90% of patients (pts) with pancreatic cancer suffer a relapse. Adjuvant chemotherapy with gemcitabine (gem) or 5-FU/folinic acid for 6 months (mo) significantly delays recurrence of disease, improves survival and increases the rate of cure in R0 and R1 patients. Based on these results, CONKO-006 was designed for pts after R1 resection to analyse the benefit of a prolonged postoperative therapy with 12 instead of 6 months and to evaluate the safety and efficacy of the combination of gem (1000mg/m2 i.v. day 1,8,15, q29) and sorafenib (200 mg p.o. bid, day 1-28, q29) or placebo planned for 12 cycles. Methods: In a randomized, double-blinded placebo-controlled multi-center design, the study was planned based on the relapse rate to detect an improvement of disease-free-survival (DFS) from 42% to 60% after 18 mo. Secondary objectives were DFS at 12 and 24 mo, overall survival (OS) and treatment safety. Results: Between 02/2008 and 09/2013, 127 patients were included. Excluding 5 ineligible pts, 57 pts were randomised to SorGem and 65 to Gem. Pts characteristics are well balanced (SorGem/Gem) with median age (63/63y), tumor status (T3 + T4 97/97%), nodal status (N pos: 86/85%). Up to July 15th 111 events (91%) had occurred. Analysis shows no difference in median DFS [SorGem: 9.6 months (m), Gem: 10.7 m, p= 0.89] or OS [SorGem: 17.6 m, Gem: 15.6 m, p= 0.90]. Grade 3/4 toxicities per pt were: diarrhea (SorGem: 6%; Gem: 1%), fatigue (SorGem: 2%; Gem: 0%), neutropenia (SorGem: 7%; Gem: 16%), thrombocytopenia (SorGem: 4%; Gem: 1%), elevated GGT (SorGem: 8%; Gem: 5%), hypertension (SorGem: 2%; Gem: 0%), hand-foot-syndrome (SorGem: 3%; Gem: 0%). There was no relevant difference in median treatment duration: SorGem 27 weeks (range 1-51); Gem 27 weeks (2-62). Conclusions: CONKO-006 is the largest randomized clinical trial exclusively for R1 resected pancreatic cancer patients so far. The combination therapy of Gemcitabine with the multityrosinkinase-inhibitor Sorafenib for 12 months can not improve DFS or OS in this high-risk cancer cohort. Disclosure: M. Sinn, H. Riess, U. Pelzer, J. Stieler, J.K. Striefler, M. Bahra, B. Dorken and H. Oettle: CONKO-006 was supported in part by a grant from Bayer Vital AG.All other authors have declared no conflicts of interest.