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Supplementary Table 1 from Association of γ-Glutamyltransferase and Risk of Cancer Incidence in Men: A Prospective Study

Although several epidemiologic studies have shown that γ-glutamyltransferase (GGT) is independently associated with cardiovascular disease and all-cause mortality, its relationship with cancer incidence remains widely unexplored. In several experimental models, the ability of cellular GGT to modulate crucial redox-sensitive functions has been established, and it thus may play a role in tumor progression, as has been repeatedly suggested. We prospectively investigated the association between GGT and risk of overall and site-specific cancer incidence in a large population-based cohort of 79,279 healthy Austrian men with serial GGT measurements. Median follow-up was 12.5 years. Adjusted Cox proportional hazards models were calculated to evaluate GGT as an independent predictor for cancer incidence, and nonparametric regression splines were fitted to flexibly capture the dose-response relationship. Elevated GGT significantly increased overall cancer risk, showing a clear dose-response relationship (P for GGT log-unit increase < 0.0001; P for trend < 0.0001). In comparison with the reference GGT concentration (25 units/L), we found adjusted relative risks (95% confidence intervals) equalling 1.19 (1.15-1.22) for GGT concentrations of 60 units/L, 1.32 (1.28-1.36) for 100 units/L, 1.67 (1.60-1.75) for 200 units/L, and 2.30 (2.14-2.47) for 400 units/L. In cancer site-specific models, GGT was significantly associated with malignant neoplasms of digestive organs, the respiratory system/intrathoracic organs, and urinary organs (all P < 0.0001). Age of participants significantly modified the association of GGT and cancer risk (P < 0.001), revealing markedly stronger associations in participants ages ≤65 years. Our findings, for the first time, show that elevated GGT is significantly associated with increased cancer risk in men. [Cancer Res 2008;68(10):3970–7]

We report on a 42-year-old woman with colorectal cancer of the sigmoid colon with synchronous pulmonary metastases being treated since June of 2016. With a poorly differentiated, KRAS, NRAS and BRAF wildtype cancer and an advanced stage of the disease we look back to almost four years of treatment and a sequence consisting of four lines of polychemotherapy. Dynamic treatment without achieving relevant treatment-free periods resulted in a satisfying quality of life and prolonged overall survival. Exceptional cases in young and very fit patients support the benefit of a more aggressive treatment strategy.

Background: Tumor-stroma ratio (TSR) is an independent prognosticator in colon cancer.Objective: We set out to investigate the predictive power, as well as to validate the prognostic power of TSR in stage II colon cancer patients. Better identification of patients who could benefit from adjuvant chemotherapy remains an important issue in stage II disease.Methods: TSR was microscopically determined on haematoxylin and eosin-stained primary tumor tissue slides of 212 patients who received either adjuvant chemotherapy or surveillance after curative resection in a prospective randomized clinical trial (ABCSG-91).Results: Stroma-high tumors were associated with significantly more cancer-related death ((CaDeath) HR 2.30, 95% CI 1.05−5.03; p=0.037) and significantly shorter distant recurrence-free survival ((DRFS) HR 2.32, 95% CI 1.10−4.87; p=0.027) compared to stroma-low tumors. Backward multivariate Cox-regression analysis demonstrated TSR as an independent prognosticator for DRFS (p=0.027) and CaDeath (p=0.031). TSR did not validate as a predictive biomarker; CaDeath (HR 0.87, 95% CI 0.18−4.17; p=0.87), DRFS (HR 0.76, 95% CI 0.17−3.36; p=0.71) and OS (HR 0.96, 95% CI 0.29−3.21; p=0.95) for the type of chemotherapy given in ABCSG-91.Conclusions: TSR, an easily applicable and inexpensive observer-based method, is an independent predictor of poor prognosis in stage II colon cancer. Predictive value for adjuvant 5-FU/leucovorin could not be demonstrated.

The knowledge on molecular alterations in lung cancer have increased during the last decade considerably. Almost every year new genes were detected being targetable, and drugs have been developed and provided for those patients being diagnosed with such a lung cancer. Therefore, it was necessary to update previous recommendations to facilitate a uniform handling for the diagnosis and molecular tests of lung cancer specimen all over Austria. Originally mutation of the epidermal growth factor receptor (EGFR) was the only actionable molecular alteration, now there are more than 10 driver mutations known, and more are detected, and clinical studies are performed. In addition, the technique to test for these mutations have improved, next generation sequencing has opened the option to test several genes in one test. Immuno-oncology has entered the field, and besides the checkpoint death receptor and ligand molecules PD-1/PD-L1 more molecules have been detected and are also tested in clinical studies. To provide equal opportunities to our patients the tests have to be implemented in all pathological institutes involved in lung cancer management. Because pathologists as part of the tumor board have to explain the diagnosis and the molecular alterations and suggest possible treatment options, the tests should be performed in-house, which will provide the optimal quality control.

Summary The purpose of this observational study was to determine the prevalence of comorbid conditions in cancer patients with solid tumours selected for specific treatment at 12 divisions of medical oncology in Austria. Data from 1137 patients were collected using a standardized questionnaire; of these, 1036 datasets were evaluable for further analysis. Data were prospectively collected from patients during an in- or outpatient hospital visit over a 4-month period in 2011. Of these patients 42% had gastrointestinal cancer, 31% had breast cancer, 9% lung cancer and the remaining had urogenital cancer, sarcoma or other types of rare cancers. Around two-thirds of patients had metastatic disease (59%), confined to a single organ site in 55% of patients. A high proportion of patients had a good performance status (Eastern Cooperative Oncology Group [ECOG] 0, 1: 82%). Comorbid conditions were classified according to the Charlson scheme score and were present in 86% of patients with a median age of 64 years. The predominant conditions were cardiovascular diseases (57%), metabolic diseases (44%), endocrinological diseases (30%), gastrointestinal diseases (26%), neurological (23%) and respiratory diseases (23%). As has been reported by others we found a clear association between number of comorbid conditions and age. While 60% of the whole population had at least 2 comorbidities, most patients of the elderly population (89%) had more than three comorbidities. The high proportion of patients with comorbidities and accompanying medication represents a substantial challenge for medical oncologists in selecting the optimal cancer-specific treatment especially in the era of novel targeted and immunotherapies. Comorbid conditions and accompanying comedications require special precautions concerning potential interactions and unexpected adverse reactions from prescribed tumour-specific treatment.

This article intends to summarize personal highlights of the ESMO (European Society for Medical Oncology) 2018 meeting and does not aim to give a comprehensive overview. We will summarize the most recent presented data on the treatment of non-small cell lung establishing first-line combinational therapies (chemotherapy backbone with immunotherapy) as standard of care. Furthermore highly practice relevant data on the treatment of recurrent or metastatic head and neck squamous cell carcinoma were presented. Next the treatment landscape of metastatic prostate cancer is changing rapidly and some new aspects in metastatic disease are reported.

We aimed to investigate the effectiveness of oncological treatments in metastatic CRC related to comorbidities and age. This retrospective study included 1105 patients from three oncological centers. aaCCI and CCI was available from 577 patients. An aaCCI &gt, 3 was of the highest predictive value compared to other aaCCI-levels, CCI or age (p &lt, 0.001 for all). Treatment (best supportive care (BSC), systemic treatment only (STO) and resection of metastases (ROM)) significantly prolonged survival in patients with aaCCI &gt, 3 (STO: HR 0.39, CI 0.29–0.51, ROM: HR 0.16, CI 0.10–0.24) and patients older than 70 years (STO: HR 0.56, CI 0.47–0.66, ROM: HR 0.23, 0.18–0.30). Median overall survival was shorter in patients with aaCCI or age &gt, 70 years and interaction for treatment type not significant for aaCCI, but significant for age older or younger than 70 years (STO: p = 0.01, ROM p = 0.02). BSC is more often considered as optimal care for patients with an aaCCI &gt, 3 (37.6% vs. 12.4%, p &lt, 0.001) or age &gt, 70 years (35.7% vs. 11.2%, 0.001). Older patients or patients with comorbidities benefit from cancer-specific therapy independently of their age and comorbidities.

Background: 5-Fluorouracil (FU) is one of the most commonly used cytostatic drugs in the systemic treatment of cancer. Treatment with FU may cause severe or life-threatening side effects and the treatment-related mortality rate is 0.2–1.0%. Summary: Among other risk factors associated with increased toxicity, a genetic deficiency in dihydropyrimidine dehydrogenase (DPD), an enzyme responsible for the metabolism of FU, is well known. This is due to variants in the DPD gene (DPYD). Up to 9% of European patients carry a DPD gene variant that decreases enzyme activity, and DPD is completely lacking in approximately 0.5% of patients. Here we describe the clinical and genetic background and summarize recommendations for the genetic testing and tailoring of treatment with 5-FU derivatives. The statement was developed as a consensus statement organized by the German Society for Hematology and Medical Oncology in cooperation with 13 medical associations from Austria, Germany, and Switzerland. Key Messages: (i) Patients should be tested for the 4 most common genetic DPYD variants before treatment with drugs containing FU. (ii) Testing forms the basis for a differentiated, risk-adapted algorithm with recommendations for treatment with FU-containing drugs. (iii) Testing may optionally be supplemented by therapeutic drug monitoring.

Background Acquired epidermal growth factor receptor (EGFR) T790M mutation is the primary resistance mechanism to first-generation EGFR tyrosine kinase inhibitors (TKIs) used in advanced, EGFR mutation-positive non-small-cell lung cancer (NSCLC). Available data, predominantly in Asian patients, suggest that this mutation is also the major cause of resistance to the irreversible ErbB family blocker, afatinib. For EGFR T790M-positive patients who progress on EGFR TKI therapy, osimertinib is an effective treatment option. However, data on osimertinib use after afatinib are, to date, scarce. Objective To identify the prevalence of EGFR T790M mutations in predominantly Caucasian patients with stage IV EGFR mutation-positive NSCLC who progressed on afatinib, and to investigate the subsequent response to osimertinib. Patients and Methods In this single-center, retrospective analysis, EGFR T790M mutation status after afatinib failure was assessed using liquid biopsy and tissue rebiopsy. EGFR T790M-positive patients subsequently received osimertinib. Results Sixty-seven patients received afatinib in the first-, second-, or third-line (80.6%, 14.9%, and 4.5%, respectively). After afatinib failure, the T790M mutation was identified in 49 patients (73.1%). Liquid biopsy and tissue rebiopsy were concordant in 79.4% of cases. All patients with T790M-positive tumors received osimertinib (73.5% after first-line afatinib); 37 (75.5%) of these had an objective response (complete response: 22.4%; partial response: 53.1%). Response rate was independent of T790M copy number. Conclusion EGFR T790M mutation is a major mechanism of acquired resistance to afatinib. Osimertinib confers high response rates after afatinib failure in EGFR T790M-positive patients and its use in sequence potentially allows extended chemotherapy-free treatment.

We hereby report the course and management of a patient with human epidermal growth factor receptor 2 negative esophageal cancer who received neoadjuvant chemoradiation, surgical resection and subsequently palliative therapy for recurrent disease. The critical role of the staging procedure is discussed. Additionally the options of systemic palliative therapies are presented and the rationale for immuno-oncologic treatment is highlighted. The patient received pembrolizumab as second-line therapy, which unfortunately did not result in a response and caused minor autoimmune side effects.

We report a patient with pretreated recurrent diffuse large B-cell lymphoma who was admitted to our ward due to emesis, headache and fatigue. Radiologic workup inlcuding brain magnetic resonance imaging showed no abnormalities but consecutively carried out lumbar puncture due to persistent headache reveiled cryptococcus neoformans meningitis. Treatment consisted of intravenous liposomal amphotericin B followed by maintenance therapy with fluconazole. Disease characteristics and therapy of cryptococcal meningitis are reviewed in this article.

The patient described here presented with relapsed multiple myeloma progressing after therapy with immunomodulatory agents (thalidomide and lenalidomide) and proteasome inhibitors (bortezomib and carfilzomib). Eventually, the patient achieved an excellent response to the combination of panobinostat, bortezomib and dexamethasone, overcoming resistance to proteasome inhibitors and achieving a sustained VGPR (very good partial remission), which was consolidated with high-dose melphalan and autologous stem-cell transplantation.

The tumour microenvironment and tumour angiogenesis play a critical role in the development and therapy of many cancers, but in vitro models reflecting these circumstances are rare. In this study, we describe the development of a novel tri-culture model, using non-small cell lung cancer (NSCLC) cell lines (A549 and Colo699) in combination with a fibroblast cell line (SV 80) and two different endothelial cell lines in a hanging drop technology. Endothelial cells aggregated either in small colonies in Colo699 containing microtissues or in tube like structures mainly in the stromal compartment of microtissues containing A549. An up-regulation of hypoxia and vimentin, ASMA and a downregulation of E-cadherin were observed in co- and tri-cultures compared to monocultures. Furthermore, a morphological alteration of A549 tumour cells resembling “signet ring cells” was observed in tri-cultures. The secretion of proangiogenic growth factors like vascular endothelial growth factor (VEGF) was measured in supernatants. Inhibition of these proangiogenic factors by using antiangiogenic drugs (bevacizumab and nindetanib) led to a significant decrease in migration of endothelial cells into microtissues. We demonstrate that our method is a promising tool for the generation of multicellular tumour microtissues and reflects in vivo conditions closer than 2D cell culture.

Recently, the combination of antiangiogenic agents, chemotherapy and immunotherapy has shown synergistic anticancer effects in non-small cell lung cancer (NSCLC). The future for this approach appears bright in lung cancer treatment; however, many challenges remain to be overcome regarding its true potential, optimal sequence and timing of therapy, and safety profile. In this review, we will discuss the current status and future direction of antiangiogenic therapy for the treatment of NSCLC, and highlight emerging strategies, such as tumor vessel normalization (TVN).Bevacizumab was the first antiangiogenic agent approved for the treatment of advanced NSCLC. Recently, the combination of chemotherapy/antiangiogenic therapy with immunotherapy showed high efficacy in first-line settings. A subgroup of patients with liver metastasis and driver mutation-addicted tumors benefited most, suggesting that the metastatic location, as well as the genetic background of the tumor, are key determinants for therapy responses.The efficacy of antiangiogenic therapies in unselected patients is rather limited. The tumor microenvironment has appeared to be more complex and heterogeneous than previously assumed. Only a contextual rather than a cell-specific approach might provide valuable insights towards the clinical validation of combinational therapies.

Background Preclinical studies demonstrate synergism between cancer immunotherapy and local radiation, enhancing anti-tumor effects and promoting immune responses. BI1361849 (CV9202) is an active cancer immunotherapeutic comprising protamine-formulated, sequence-optimized mRNA encoding six non-small cell lung cancer (NSCLC)-associated antigens (NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC-1), intended to induce targeted immune responses. Methods We describe a phase Ib clinical trial evaluating treatment with BI1361849 combined with local radiation in 26 stage IV NSCLC patients with partial response (PR)/stable disease (SD) after standard first-line therapy. Patients were stratified into three strata (1: non-squamous NSCLC, no epidermal growth factor receptor (EGFR) mutation, PR/SD after ≥4 cycles of platinum- and pemetrexed-based treatment [n = 16]; 2: squamous NSCLC, PR/SD after ≥4 cycles of platinum-based and non-platinum compound treatment [n = 8]; 3: non-squamous NSCLC, EGFR mutation, PR/SD after ≥3 and ≤ 6 months EGFR-tyrosine kinase inhibitor (TKI) treatment [n = 2]). Patients received intradermal BI1361849, local radiation (4 × 5 Gy), then BI1361849 until disease progression. Strata 1 and 3 also had maintenance pemetrexed or continued EGFR-TKI therapy, respectively. The primary endpoint was evaluation of safety; secondary objectives included assessment of clinical efficacy (every 6 weeks during treatment) and of immune response (on Days 1 [baseline], 19 and 61). Results Study treatment was well tolerated; injection site reactions and flu-like symptoms were the most common BI1361849-related adverse events. Three patients had grade 3 BI1361849-related adverse events (fatigue, pyrexia); there was one grade 3 radiation-related event (dysphagia). In comparison to baseline, immunomonitoring revealed increased BI1361849 antigen-specific immune responses in the majority of patients (84%), whereby antigen-specific antibody levels were increased in 80% and functional T cells in 40% of patients, and involvement of multiple antigen specificities was evident in 52% of patients. One patient had a partial response in combination with pemetrexed maintenance, and 46.2% achieved stable disease as best overall response. Best overall response was SD in 57.7% for target lesions. Conclusion The results support further investigation of mRNA-based immunotherapy in NSCLC including combinations with immune checkpoint inhibitors. Trial registration ClinicalTrials.gov identifier: NCT01915524. Electronic supplementary material The online version of this article (10.1186/s40425-019-0520-5) contains supplementary material, which is available to authorized users.

Immune suppression is a hallmark of multiple myeloma (MM), but data on soluble factors involved in the fate of immune effector cells are limited. The CXCR3-binding chemokine monokine induced by interferon-gamma (MIG/CXCL9) has been associated with tumor progression, immune escape, and angiogenesis in several malignancies. We here aimed to evaluate the prognostic relevance of MIG in MM. MIG serum levels were significantly elevated in newly diagnosed MM patients (n = 105) compared to patients with monoclonal gammopathy of undetermined significance (MGUS; n = 17) and healthy controls (n = 37). MIG expression in stromal compartments but not purified MM cells correlated with serum levels. High MIG serum levels were significantly associated with established prognostic markers (international staging system: R = 0.25, p = 0.001; age: R = 0.47, p 0.0001; lactate-dehydrogenase: R = 0.34, p = 0.0005) and poor overall survival (OS) (median OS 17.0 months vs. not reached, p 0.001). A similar association was found for CXCL10 and CXCL11. Multivariate regression analysis indicated MIG as an independent prognostic factor of OS.

Numerous antiangiogenic agents are approved for the treatment of oncological diseases. However, almost all patients develop evasive resistance mechanisms against antiangiogenic therapies. Currently no predictive biomarker for therapy resistance or response has been established. Therefore, the aim of our study was to identify biomarkers predicting the development of therapy resistance in patients with hepatocellular cancer (n = 11), renal cell cancer (n = 7) and non-small cell lung cancer (n = 2). Thereby we measured levels of angiogenic growth factors, tumor perfusion, circulating endothelial cells (CEC), circulating endothelial progenitor cells (CEP) and tumor endothelial markers (TEM) in patients during the course of therapy with antiangiogenic agents, and correlated them with the time to antiangiogenic progression (aTTP). Importantly, at disease progression, we observed an increase of proangiogenic factors, upregulation of CEC/CEP levels and downregulation of TEMs, such as Robo4 and endothelial cell-specific chemotaxis regulator (ECSCR), reflecting the formation of torturous tumor vessels. Increased TEM expression levels tended to correlate with prolonged aTTP (ECSCR high = 275 days vs. ECSCR low = 92.5 days; p = 0.07 and for Robo4 high = 387 days vs. Robo4 low = 90.0 days; p = 0.08). This indicates that loss of vascular stabilization factors aggravates the development of antiangiogenic resistance. Thus, our observations confirm that CEP/CEC populations, proangiogenic cytokines and TEMs contribute to evasive resistance in antiangiogenic treated patients. Higher TEM expression during disease progression may have clinical and pathophysiological implications, however, validation of our results is warranted for further biomarker development.

Aim: A global afatinib named patient use program in non-small-cell lung carcinoma (NSCLC) commenced in 2010. Materials & methods: Eligible NSCLC patients had progressed after clinical benefit on prior erlotinib/gefitinib and/or had activating EGFR/HER2 mutations, exhausted all other treatments, and were ineligible for afatinib trials. Results: Data, as of January 2016, were reported on 3966 heavily pretreated NSCLC patients (41 countries; six continents). Among 2595/3966 (65.4%) patients with tumor EGFR status, 2407 (92.8%) were EGFR mutation positive. Median time to treatment failure (2862/3966 [72.2%] patients with available data) was 4.4 months. Among 1141/2862 (39.9%) patients with response reported, objective response rate was 23.4% (267/1141). Safety findings were as expected. Conclusion: Time to treatment failure durations and objective response rates were encouraging.

Background The incidence of lung cancer (LC) is increased in patients with a history of liver transplantation (LT). The purpose of our study was to compare the clinical characteristics and outcomes of patients with postliver transplantation LC (PLTLC) with cohorts of patients with "transplant-naive" LC, and LT patients without LC. Patients and Methods All the patients who had undergone LT or had been diagnosed with LC from 1987 to 2012 were included in the present analysis. The PLTLC cohort was compared with a LT cohort (n = 725) and the local LC registry (n = 2803). The standardized incidence ratios (SIRs) were computed in the classic manner after adjustment for sex, age, and year of follow-up. Results Within the LT cohort, 22 patients (5 women) developed PLTLC (2.3%). The SIR for LC in LT recipients was 4.4 in the women and 2.6 in the men. The PLTLC cohort was older at LT (58.4 vs. 53.3 years; P = .028). Also, 90.5% of the PLTLC group had a history of smoking; 8 patients (42.1%) had had LC detected by annual routine lung cancer screening. The median post-LT survival was significantly inferior in the PLTLC cohort (117.1 vs. 182.6 months; P = .041). The median overall survival (OS), starting from the diagnosis of LC, was similar in the PLTLC and LC cohort (14.7 vs. 15.1 months; P = .519). Conclusion The incidence of LC is significantly increased in the LT population. Therefore, LC screening might be an option for LT patients with a history of smoking. The prognosis of LC does not seem to be impaired by LT, suggesting a minor effect of LT on OS in patients with lung cancer.

Introduction Patients with non–small-cell lung cancer (NSCLC) and cardiovascular (CV) disease often share a comparable demographic profile. The aim of this analysis was to assess the significance and prevalence of preexisting CV comorbidity and events in NSCLC. Patients and Methods A total of 715 consecutive NSCLC patients diagnosed between 2004 and 2009 at the Medical University of Innsbruck were retrospectively assessed regarding CV comorbidities, risk factors, cancer treatment, CV events occurring after the start of treatment, and outcome. Results At least one CV comorbidity was present in 462 (67.2%) of 687 evaluable patients. CV events were documented in 68 patients (9.5%), with conduction disorders being the most prevalent (n = 19), followed by cardiomyopathy (n = 13), myocardial infarction (n = 13), sudden CV death (n = 12), need of revascularization (n = 6), and pericardial effusion (n = 5). Median time between diagnosis of NSCLC and CV event was 13.9 months. CV comorbidities and events both showed a direct correlation with increasing age, affecting up to 87.3% and 35.2% of all octogenarians in the study, respectively. The following CV comorbidities were significantly associated with CV events: atrial fibrillation, myocardial infarction, and cardiomyopathy. Overall survival was not reduced in patients experiencing a CV event compared to patients without an event. Conclusion CV disease and events are frequently observed in NSCLC patients. To provide definitive recommendations on impact, prevention, and screening of CV disease in NSCLC, prospective trials are desirable.

Because of recent failures of novel drugs in phase II and III trials innovative in vitro models are needed that may predict drug efficacy in patients. Although, numerous modifications of traditional cell culture and animal models were undertaken significant improvements in cell culture- based drug development have not been achieved. Three-dimensional (3D) cell culture may represents an modern alternative to bridge the gap between 2D cell cultures and animal models.

Introduction The aim of this study was to describe a large consecutive cohort of non-small cell lung cancer (NSCLC) patients treated in daily routine within the last 25 years. An extensive list of general baseline characteristics (comorbidities, laboratory values, symptoms, performance state), NSCLC related factors (stage, histology), treatment related parameters (approach, applied therapies) and outcome (PFS, RFS, OS, perspective of decades) were analyzed in detail. Patients and methods Medical files of 2293 consecutive NSCLC patients diagnosed between 1989 and 2009 at the Medical University of Innsbruck and affiliated hospitals were retrospectively analyzed. Patients were documented within our institution's comprehensive lung cancer project "Twenty-Year Retrospective of Lung Cancer (TYROL study)". Results Mean age at diagnosis was 64.1 years and 1611 patients (70.3%) were male. Most patients were diagnosed in stage IV (37.9%). The most frequent comorbidities present at diagnosis were cardiovascular disease (62.1%) and COPD (62.0%). The most common symptoms at diagnosis were coughing (54.7%) and dyspnea (45.3%). Of all 2293 patients 1981 (86.4%) received adequate antineoplastic treatment. In total 874 patients were radically operated, 119 received radiotherapy/radio-chemotherapy and the majority of patients ( n =1278) were treated in palliative intent. A 2nd, 3rd, 4th and 5th-line palliative therapy was administered to 612, 278, 102, and 36 patients. Median OS, RFS and PFS were 16.4 months, 86.4 months and 5.1 months, respectively. A multitude of factors was associated with all three outcome variables. Of note, outcome has improved stepwise in the recent decade based on increased response rates leading to prolonged OS. Conclusion This work incorporates most clinical aspects relevant in the treatment of NSCLC and beyond. Therefore, this comprehensive analysis provides a definite benchmark for prognostication and epidemiology of NSCLC in a Western European society.

This minireview covers novel drugs and treatment concepts being evaluated in early studies for therapy of patients with multiple myeloma (MM). Panobinostat, a histone deacetylase inhibitor, showed limited improvement in progression-free survival, thus raising doubt whether these substances will provide clinical meaningful benefits in MM. Some of the new proteasome inhibitors beyond carfilzomib offer the benefit of oral administration and reduced neurotoxicity. Monoclonal antibodies with antimyeloma or antistroma cell activity raise expectations for improved treatment outcome when combined with conventional chemotherapy. A series of new inhibitors of signal pathways important for proliferation and progression in MM presently are scrutinized for their clinical usefulness. Among these, inhibitors of the mitogen activated protein kinase (MAPK), epidermal growth factor receptor (EGFR), protein kinase B (AKT), and B-cell receptor pathway as well as drugs inhibiting the spindle protein, Bcl-2, and cyclin-dependent kinases show promise for becoming important antimyeloma dugs. Checkpoint inhibitors have shown significant activity in some solid tumors and are now tested in MM as well. Measles viruses bind via CD46 to myeloma cells, self-amplify at sites of tumor growth, and induce cell death in myeloma but not in normal cells, thus offering a completely new treatment strategy. However, before introduction of these interesting approaches into the clinic, confirmation of their clinical efficacy is needed.

In recent years, considerable advances concerning therapeutic strategies in patients with metastatic cancer have been achieved. Particularly in renal cell cancer (RCC) and advanced stage non-small cell lung cancer (NSCLC), immune-activating and antiangiogenic (AA) drugs (i.e., checkpoint antibodies and vascular endothelial growth factor (VEGF)/VEGF receptors (VEGFR) targeting compounds, respectively) have been successfully developed. As immune-effector cells have to enter the tumor, it is tempting to speculate that the combination of immunotherapy with AA treatment may induce synergistic effects. In this short review, we explore the theoretical background and the therapeutic potential of this novel treatment option for patients with advanced RCC or NSCLC. We discuss the growing body of evidence that pro-angiogenic factors negatively modulate the T-cell-mediated immune response and examine the preclinical evidence for testing combined immune-activating and AA therapy concepts in clinical practice. Particular attention will also be paid to potential novel treatment-related adverse events induced by combination treatment.

Aviscumine, a recombinant lectin I, has been identified as an immunomodulatory agent within a new class of ribotoxic stress-inducing anticancer substances that have demonstrated efficacy in phase I/II trials. The aim of the present study was to elucidate the presumed effect of aviscumine on enhancing human natural killer (NK) cell antitumor cytotoxicity. To measure the effect of aviscumine on human NK cell cytotoxicity, chromium-51-release assays against K-562 cells were performed with isolated NK cells from the whole blood of 34 healthy volunteers. Two effector-to-target cell ratios (12.5:1 and 25:1) were used by two independent investigators with a focus on the concentration-dependent effect (0.5 vs. 1 ng/ml aviscumine), reproducibility (first vs. second investigator) and the specificity of the effect by comparison to a heat-inactivated aliquot and interleukin 2 (IL-2) stimulation (10 ng/ml). The mediation of the effect via degranulation was demonstrated by flow cytometric analyses of CD107α expression. Statistics were performed with SPSS using Student's t-tests for normally distributed data. Aviscumine induced a significant and reproducible, concentration-dependent increase in NK cell cytotoxicity (n=22; P

Background Maintenance therapy (MT) with pemetrexed has been shown to improve overall and progression-free survival of patients with non-squamous non-small cell lung cancer (NSCLC), without impairing patients’ health-related quality of life (HRQOL) substantially. Comprehensive data on HRQOL under real-life conditions are necessary to enable informed decision-making. This study aims to (1) assess HRQOL during first-line chemotherapy and subsequent MT and (2) record patients’ and physicians’ reasons leading to clinical decisions on MT. Methods Patients treated for NSCLC at three Austrian medical centres were included. HRQOL was assessed at every chemotherapy cycle using the EORTC QLQ-C30/+LC13 questionnaire. Semi-structured interviews were conducted before MT initiation and at the time of discontinuation to evaluate patients’ and physicians’ reasons for treatment decisions. Longitudinal QOL analysis was based on linear mixed models. Results Sixty-one (73%) out of 84 patients were considered for MT. Thirty-six patients (43%) received MT and 29 (35%) discontinued therapy. Decisions on MT initiation (in 20 cases by the physician vs 4 by the patient) and discontinuation (19 vs 10) were mainly voiced by the physician. Treatment toxicity of first-line chemotherapy was the main reason for rejection of MT in patients with stable disease and was more often indicated by patients than clinicians. HRQOL data were collected from 83 patients at 422 assessment time points and indicated significantly lower symptom severity during MT compared with first-line therapy for nausea and vomiting (p = 0.006), sleep disturbances (p

Background Regulatory T cells (Treg) are critical for cancer immune evasion; whereas natural killer (NK) cells are central for effective anti-tumor immunity including antibody-induced cellular cytotoxicity (ADCC). The predictive role of Treg levels for clinical response to chemo-immunotherapy in non-small cell lung cancer (NSCLC) as well as therapy-induced Treg changes remain to be defined. Patients and methods The impact of Treg on NK-mediated cetuximab-dependent cellular cytoxicity was tested in vitro . Frequency and functional activity of Treg was analyzed in 31 NSCLC stage IB-IIIA patients treated by neoadjuvant Cetuximab/Docetaxel/Cisplatin prior to surgery. Data were correlated with clinical outcome variables and Treg tumor infiltration. Results Treg potently inhibit NK-mediated and cetuximab-induced ADCC in vitro . In addition, a significant correlation between Treg reduction and clinical response was seen. However, the grade of tumor infiltrating Treg in resected tumors did not correlate with peripheral Treg levels. Moreover, Treg levels at diagnosis did not predict clinical response to chemo-immunotherapy. Conclusions The drop of Treg levels during neoadjuvant chemo-immunotherapy in NSCLC patients significantly correlates with clinical response. However, Treg at diagnosis are not linked to inferior clinical response to chemo-immunotherapy in NSCLC in vivo even though Treg efficiently inhibit ADCC in vitro .

We report on a patient with multiple myeloma and light-chain induced renal failure, diagnosed with hepatitis C and high viral load in the pre-transplant period. We show that the new hepatitis C virus directed drugs daclatasvir and sofosbuvir can be safely applied concomitantly to high-dose therapy with autologous hematopoietic stem cell transplantation. Liver enzymes remained in the normal range during the transplant and in the post-transplant period.

At American Society of Clinical Oncology meeting 2013, some new data were presented, which might have a practice-changing potential. Epidermal growth factor receptor mutational testing was successfully performed in plasma samples, giving hope that tumor biopsies might be replaced by a more comfortable blood analysis. Some studies focused on new second-generation anaplastic lymphoma kinase inhibitors, which showed an impressive efficacy even in crizotinib refractory patients in phase I/II studies and support a sequence of tyrosine kinase inhibitors (TKIs) in this sub-entity of non-small-cell lung cancer (NSCLC). Immunological strategies are worth being tested also in lung cancer, as different strategies have proven first signs of efficacy (MUC1 antigen-specific cancer immunotherapy, programmed cell death ligand 1). Finally, a large phase III trial found that a new oral vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor TKI (nintedanib) combined with docetaxel improved outcome in second-line NSCLC patients when compared with docetaxel monotherapy.

Skeletal-related events represent a substantial burden for patients with advanced cancer. Randomized, controlled studies suggested superiority of denosumab over zoledronic acid in the prevention of skeletal-related events in metastatic cancer patients, with a favorable safety profile. Experts gathered at the 2012 Skeletal Care Academy in Istanbul to bring forward practical recommendations, based on current evidence, for the use of denosumab in patients with bone metastases of lung cancer. Based on current evidence, use of denosumab in lung cancer patients with confirmed bone metastases is recommended. It is important to note that clinical judgment should take into consideration the patient’s general performance status, overall prognosis, and live expectancy. Currently, the adverse event profile reported for denosumab includes hypocalcemia and infrequent occurrence of osteonecrosis of the jaw. Therefore, routine calcium and vitamin D supplementation, along with dental examination prior to denosumab initiation are recommended. There is no evidence for renal function impairment due to denosumab administration. At present, there is no rationale to discourage concomitant use of denosumab and surgery or radiotherapy.

The introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) for non-small cell lung cancer (NSCLC) with activating mutations of the EGFR has opened a new area of lung cancer treatment strategies and led to an enthusiastic search for additional mutations. Since then, numerous driver mutations such as EML4-ALK and ROS1 have been detected and specific treatment options have already been developed. However, molecular tests have to follow specific rules if applied in daily practice. The Austrian Working Group on Pulmonary Pathology and Oncology (AWGPPO) is presenting an updated version of their previous recommendation published in 2011. Several practical questions raised during the last 2 years will be addressed, such as reflex testing, selection of tissues, order of molecular tests, and the issue of resistance mechanisms.

O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1

In recent times, the treatment of advanced disease stages of thyroid cancer (TC) followed the strategy of targeted therapy with encouraging results. Thus, eight patients with metastasized thyroid carcinomas, who had multiple lines of prior interventions, were treated with sorafenib and have now been retrospectively evaluated. This retrospective evaluation included four patients with classified medullar carcinoma, two follicular, one papillary and one anaplastic, respectively. Within this population a clinical benefit rate of more than 70 % in daily routine, including a 29 % partial response rate could be determined, which correlates with the findings of recently published clinical trials with multi-kinase inhibitors. Furthermore, in all patients the observed toxicities were manageable after dose reductions. In conclusion, these data support a potential value of sorafenib in treatment of this rare disease.

The worldwide population shift towards older ages will inevitably lead to more elderly patients being diagnosed with cancer. Lung cancer is the number one cause for cancer mortality and surgical resection is the treatment of choice whenever possible. This study investigates whether elderly patients with non-small cell lung cancer (NSCLC) are characterized by distinct clinical and pathologic features and different clinical course after resection. Special emphasis is placed on disease recurrence, which is an important, but rarely described parameter for biological tumor behavior. Sex, stage, histology, differentiation grade, smoking status, performance status, hemoglobin, C-reactive protein, lactate dehydrogenase, Ki-67 index, recurrent disease and overall survival were analyzed in 383 surgically resected NSCLC patients. Calculations were performed comparing patients70 to ≥70 years. A postoperative follow-up period of 15 years enabled detailed correlations. Rate of disease recurrence and disease-free survival did not differ between any age groups and was not influenced by clinico-pathologic parameters. Elderly patients with a Ki-67 index of3% were associated with significantly decreased overall survival time when compared to younger patients (36.3 and 47.3 months respectively, p=0.029). The biological behavior of NSCLC as reflected by characteristics of disease recurrence is similar for surgically resected patients among different age groups and does not warrant specific recommendations for the elderly surgical patient. The Ki-67 index offers prognostic information for overall survival in the elderly.