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The entity of NENs represent a highly heterogenous group of malignancies that require a multidisciplinary approach during the treatment of patients. The following article aims to provide a concise overview of the current state of the art in diagnostics and therapy. One specific feature of G1/G2 NENs is that the indication for surgery is given even in metastatic settings. Specific details regarding the treatment of its various different subgroups need to be gathered from available guidelines or current clinical studies. The field of nuclear medicine offers promising options for diagnostics and therapy which needs further investigation.NENs stellen aufgrund ihrer Heterogenität und ihres Anspruches auf multidisziplinäre Behandlung eine Herausforderung für die Betreuung betroffener Patienten dar. Der vorliegende Artikel zielt darauf ab, einen konzisen Überblick über den aktuellen Stand in Diagnostik und Therapie zu bieten. Eine Spezifität von NENs stellt die breite Empfehlung der chirurgische Resektion von G1/G2 NENs, selbst bis in metastasierte Stadien, dar. Details zu konkreten Therapieoptionen bzw. zu den Therapien der diversen Subgruppen sind den entsprechenden Leitlinien bzw. Studien zu entnehmen. Nuklearmedizinische Möglichkeiten im Bereich der Diagnostik und Therapie bieten neue vielversprechenden Optionen, die noch weiter in Studien ergründet werden müssen.

This article provides a short overview of current issues in psychooncological care. Psychooncology, a relatively new interdisciplinary field, is meanwhile well estabilished as cancer diseases can lead to numerous psychological challenges and changes throughout the different stages of the disease. A significant proportion of cancer patients suffer during diagnosis and treatment from emotional distress. Main focus of psychological interventions is coping with fear, grief, pain, fatigue and how to improve quality of life under these circumstances. Psychological support has proven efficacious for helping patients as well as their families.Krebs ist eine lebensverändernde Krankheit. Wer lebensbedrohlich erkrankt, fällt zumindest eine Zeit lang aus dem normalen Leben. Die Psychoonkologie unterstützt, mit dieser neuen veränderten Realität leben zu lernen. Psychoonkologie als multidisziplinäre Fachrichtung innerhalb der Onkologie ist eine noch junge wissenschaftliche Disziplin, die sich Mitte der 1970er-Jahre entwickelt hat. Sie beschäftigt sich mit der Bedeutung von psychosozialen Faktoren in der Entwicklung, im Verlauf und in der Verarbeitung von Krebserkrankungen.

Being one of the most common tumor entities worldwide, the colorectal carcinoma accounts for approximately 10% of all tumor-related deaths. With screening programs such as preventive colonoscopy, a decreasing incidence and mortality rate can be seen in the last decades. Many risk factors, which favor or prevent the development of colorectal carcinoma, can be traced back to lifestyle choices. Many patients with localized disease can be cured through tumor resection and adjuvant chemotherapy, in systemic disease, targeted therapy and immunotherapy have improved survival in the last years. This article aims to provide an overview on the basic epidemiologic, diagnostic and therapeutic principles of colorectal carcinoma, as well as a short excerpt of the newest therapeutic developments.Als eine der häufigsten Tumorentitäten weltweit ist das kolorektale Karzinom für etwa 10 % aller malignom-assoziierten Todesfälle verantwortlich. Durch Screening Programme wie die Vorsorgekoloskopie sehen wir in den letzten Jahrzehnten eine fallende Inzidenz sowie Mortalität. Viele Risikofaktoren, welche die Entwicklung eines kolorektalen Karzinoms begünstigen, aber auch verhindern, lassen sich auf Faktoren des Lebensstils zurückführen.Durch Tumorresektion und adjuvante Chemotherapie kann ein Teil der Betroffenen im lokalisierten Stadium der Erkrankung geheilt werden, im fortgeschrittenen Stadium gab es durch neue gezielte Therapie und Immuntherapie in den letzten Jahren eine Verbesserung des Überlebens.Das Ziel des vorliegenden Artikels ist es, einen kurzen Überblick über die Grundlagen der Epidemiologie, Diagnostik und Therapie des kolorektalen Karzinoms zu verschaffen, und auch einen kurzen Auszug aus den aktuellen Therapieentwicklungen wiederzugeben.

Introduction: A total of 60–80% of patients undergoing rectal resection (mostly as a treatment for rectal cancer) suffer from a variety of partly severe functional problems despite preservation of the anal sphincter. These patients are summarized under the term low anterior resection syndrome (LARS). Preoperative radiotherapy, vascular dissection and surgical excision of the low rectum and mesorectum lead, alone or all together, to a significant impairment of colonic and (neo-) rectal motility. This results in a variety of symptoms (multiple defecation episodes, recurrent episodes of urge, clustering, incontinence, etc.) which are associated with severe impairment of quality of life (QOL). Methods: This narrative review summarizes the present state of knowledge regarding the pathophysiology of LARS as well as the evidence for the available treatment options to control the symptoms resulting from this condition. Results: A review of the literature (Medline, Pubmed) reveals a variety of treatment options available to control symptoms of LARS. Medical therapy, with or without dietary modification, shows only a modest effect. Pelvic floor rehabilitation consisting of muscle exercise techniques as well as biofeedback training has been associated with improvement in LARS scores and incontinence, albeit with limited scientific evidence. Transanal irrigation (TAI) has gained interest as a treatment modality for patients with LARS due to an increasing number of promising data from recently published studies. Despite this promising observation, open questions about still-unclear issues of TAI remain under debate. Neuromodulation has been applied in LARS only in a few studies with small numbers of patients and partly conflicting results. Conclusion: LARS is a frequent problem after sphincter-preserving rectal surgery and leads to a marked impairment of QOL. Due to the large number of patients suffering from this condition, mandatory identification, as well as treatment of affected patients, must be considered during surgical as well as oncological follow-up. The use of a standardized treatment algorithm will lead to sufficient control of symptoms and a high probability of a marked improvement in QOL.

Simple Summary The treatment of patients with relapsed/refractory multiple myeloma has advanced considerably in recent years, irrespective of whether they are younger or older patients. Treating patients with relapsed/refractory multiple myeloma and renal impairment is far more complicated than treating patients with normal renal function due to the frequent dose adjustments that are necessary and the resulting loss in effectiveness. Abstract Background: Renal insufficiency is one of the most frequent complications in multiple myeloma. The incidence of renal insufficiency in patients with multiple myeloma ranges from 20% to 50%. Renal impairment in patients with multiple myeloma results primarily from the toxic effects of monoclonal light chains on the kidneys. Dehydration, hypercalcemia, hyperuricemia, the application of nephrotoxic NSARs, antibiotics, contrast agents, etc., all play a major role in the deterioration of renal function in patients with multiple myeloma. The diagnosis and treatment of these patients use an interdisciplinary approach in consultation with hematologist–oncologists, radiologists, nephrologists and intensive care specialists. Using new drugs in the treatment of patients with refractory/relapsed multiple myeloma and renal insufficiency markedly improves progression-free survival and overall survival in these patients. Conclusions: New drugs have helped to widen the treatment options available for patients with renal impairment and refractory/relapsed multiple myeloma, since dose adjustments are unnecessary with carfilzomib as well as with panobinostat, elotuzumab, pomalidomide or daratumumab in patients with renal impairment. Several new substances for the treatment of refractory/relapsed multiple myeloma have been approved in the meantime, including belantamab mafodotin, selinexor, melflufen, venetoclax, CAR T-cell therapy and checkpoint inhibitors. Ongoing studies are investigating their administration in patients with renal impairment.

The abundance of OATP4A1 in colorectal cancer (CRC) might be related to tumor progression. This was studied by immunohistochemistry on paraffin-embedded samples obtained from 178 patients (43 patients with a relapse within 5 y) with early-stage CRC. Positivity for OATP4A1 in tumor cells and noncancerous mucosal cells was proved by double-immunofluorescence staining with antibodies against OATP4A1 and keratin 8, whereas antibodies against appropriate CD markers were used to identify immune cells. Automated microscopic image analysis was used to measure the percentage of OATP4A1-positive cells and OATP4A1 staining intensity in tumor, immune, and adjacent normal-looking mucosal cells separately, as well as in the mucosal and immune cells of 14 nonmalignant tissue samples. In CRC the percentage of OATP4A1-positive cells, but not staining intensity, was significantly higher in tumor and mucosal cells adjacent to the tumor compared to the mucosa of nonmalignant samples (P

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) is currently finally determined in laboratory settings by real-time reverse-transcription polymerase-chain-reaction (rt-PCR). However, simple testing with immediately available results are crucial to gain control over COVID-19. The aim was to evaluate such a point-of-care antigen rapid test (AG-rt) device in its performance compared to laboratory-based rt-PCR testing in COVID-19 suspected, symptomatic patients.MethodsFor this prospective study, two specimens each of 541 symptomatic female (54.7%) and male (45.3%) patients aged between 18 and 95 years tested at five emergency departments (ED, n=296) and four primary healthcare centres (PHC, n=245), were compared, using AG-rt (positive/negative/invalid) and rt-PCR (positive/negative and cycle threshold, Ct) to diagnose SARS-CoV-2. Diagnostic accuracy, sensitivity, specificity, positive predictive values (PPV), negative predictive value (NPV), and likelihood ratios (LR+/-) of the AG-rt were assessed.ResultsDifferences between ED and PHC were detected regarding gender, age, symptoms, disease prevalence, and diagnostic performance. Overall, 174 (32.2%) were tested positive on AG-rt and 213 (39.4%) on rt-PCR. AG correctly classified 91.7% of all rt-PCR positive cases with a sensitivity of 80.3%, specificity of 99.1%, PPV of 98.3, NPV of 88.6%, LR(+) of 87.8, and LR(-) of 0.20. The highest sensitivities and specificities of AG-rt were detected in PHC (sensitivity: 84.4%, specificity: 100.0%), when using Ct of 30 as cut-off (sensitivity: 92.5%, specificity: 97.8%), and when symptom onset was within the first three days (sensitivity: 82.9%, specificity: 99.6%).ConclusionsThe highest sensitivity was detected with a high viral load. Our findings suggest that AG-rt are comparable to rt-PCR to diagnose SARS-CoV-2 in COVID-19 suspected symptomatic patients presenting both at emergency departments and primary health care centres.SUMMARYThe rapid SARS-Cov-2 antigen test (SARS-CoV-2 Rapid Antigen Test (Roche Diagnostics), was compared in symptomatic patients with PCR testing both in emergency departments and primary health care centres. It showed an overall sensitivity of 80.3% and specificity of 99.1%; these were higher with lower PCR cycle threshold numbers and with a shorter onset of symptoms.

Standard blood laboratory parameters may have diagnostic potential, if polymerase-chain-reaction (PCR) tests are not available on time. We evaluated standard blood laboratory parameters of 655 COVID-19 patients suspected to be infected with SARS-CoV-2, who underwent PCR testing in one of five hospitals in Vienna, Austria. We compared laboratory parameters, clinical characteristics, and outcomes between positive and negative PCR-tested patients and evaluated the ability of those parameters to distinguish between groups. Of the 590 patients (20–100 years, 276 females and 314 males), 208 were PCR-positive. Positive compared to negative PCR-tested patients had significantly lower levels of leukocytes, neutrophils, basophils, eosinophils, lymphocytes, neutrophil-to-lymphocyte ratio, monocytes, and thrombocytes; while significantly higher levels were detected with erythrocytes, hemoglobin, hematocrit, C-reactive-protein, ferritin, activated-partial-thromboplastin-time, alanine-aminotransferase, aspartate-aminotransferase, lipase, creatine-kinase, and lactate-dehydrogenase. From all blood parameters, eosinophils, ferritin, leukocytes, and erythrocytes showed the highest ability to distinguish between COVID-19 positive and negative patients (area-under-curve, AUC: 72.3–79.4%). The AUC of our model was 0.915 (95% confidence intervals, 0.876–0.955). Leukopenia, eosinopenia, elevated erythrocytes, and hemoglobin were among the strongest markers regarding accuracy, sensitivity, specificity, positive and negative predictive value, positive and negative likelihood ratio, and post-test probabilities. Our findings suggest that especially leukopenia, eosinopenia, and elevated hemoglobin are helpful to distinguish between COVID-19 positive and negative tested patients.

Background: MIF is a pleiotropic cytokine critically implicated in tumorigenesis. Tumor cell- and immune effector cell-derived MIF are localized to exosomal, extracellular, cytoplasmic and intranuclear compartments. MIF activates MAPK and PI3K signal transduction, inhibits apoptosis, promotes angiogenesis, elicits premetastatic niche formation and resolves DNA replication stress; contributing to unperturbed cancer cell growth and metastasis. MIF overexpression in several cancers is a negative prognostic indicator associated with poor overall patient survival. Methods & Results: Active novel INV-88 MIF inhibitors were discovered using structure-based drug design against critical MIF pharmacophoric binding sites guided by high-resolution X-ray crystallography (Brookhaven) of INV-88 compound:hu-MIF protein bound complexes. Following an iterative medicinal chemistry campaign; stringent biochemical, pharmacological and ADMET funnel screening identified promising INV-88 lead candidates with potent antitumor activities. Strong MIF binding by INV-88 compounds was demonstrated using thermal shift and fluorescence polarization assays. Profound in vitro antitumor pharmacological properties of INV-88 were established on several murine & human tumor cell lines (HCT116, MeWo, DU145, 4T1, B16-F10, CT26). INV-88 inhibitors demonstrated potent anti-proliferative effects down to nM IC50 potencies and impeded 3D spheroid growth & viability. Disruption of MIF:CD74/CD44-mediated MAPK and PI3K signal transduction pathways by INV-88 compounds blocked ERK and AKT phosphorylation leading to decreased pERK1/2 and pAKT levels. INV-88 inhibitors increased Caspase-3/7, p53 and Bax but decreased Bcl-2 levels. INV-88 lead compounds inhibited tumor MIF protein production in 2D & 3D cell culture systems with concomitant pan-inhibition of tumorigenic proinflammatory cytokine (TNF-α, IL-1β, IL-6, and IL-8) expression by stromal cells. Optimal ADMET properties of INV-88 compounds enabled oral dosing of select INV-88 clinical candidate compounds in mouse syngeneic B16-F10 melanoma and CT26 colon carcinoma models. Mice were dosed daily with INV-88 or vehicle per oral gavage starting in BALB/c and in C57/BL6 mice upon demonstrating palpable tumors after s.c. implantation of CT26 and B16-F10 tumor cells, respectively. Tumor growth inhibition was observed with rates of 71% on Day 24 (CT26) and 75% on Day 20 (B16-F10). INV-88 treatment significantly inhibited CT26 [p Conclusion: The data presented highlight the potential therapeutic utility of pharmacological MIF inhibition with oral INV-88 new chemical entities as a novel immunotherapeutic treatment modality for cancer. Citation Format: Anderson Gaweco, Vincent Chung, Jefferson Tilley, William Windsor, Terry Stouch, John Ellingboe, Gregg Crichlow, Philipp Sabanas, Christian Sebesta. Design and discovery of novel oral INV-88 macrophage migration inhibitory factor (MIF) inhibitors: Potent anti-tumor activity in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2643.

BackgroundCoronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is current pandemic disease. Acute polymerase-chain-reaction is the gold standard test for this disease, is not available everywhere. Standard blood laboratory parameters may have diagnostic potential.MethodsWe evaluated standard blood laboratory parameters of 655 COVID-19 patients suspected to be infected with SARS-CoV-2, who underwent PCR testing in one of five hospitals in Vienna, Austria. Additionally, clinical characteristics and 28-day outcome were obtained from medical records. We compared standard blood laboratory parameters, clinical characteristics, and outcomes between positive and negative PCR-tested patients and evaluated the ability of those parameters to distinguish between groups.ResultsOf the 590 study patients including 276 females and 314 males, aged between 20 and 100 years, 208 were tested positive by means of PCR. Patients with positive compared to negative PCR-tests had significantly lower levels of leukocytes, basophils, eosinophils, monocytes, and thrombocytes; while significantly higher levels were detected with hemoglobin, C-reactive-protein (CRP), neutrophil-to-lymphocyte ratio (NLR), activated-partial-thromboplastin-time (aPTT), creatine-kinase (CK), lactate-dehydrogenase (LDH), alanine-aminotransferase (ALT), aspartate-aminotransferase (AST), and lipase. Our multivariate model correctly classified 83.9% of cases with a sensitivity of 78.4%, specificity of 87.3%, positive predictive value of 79.5%, and negative predictive value of 86.6%. Decreasing leucocytes and eosinophils and increasing hemoglobin and CRP were significantly associated with an increased likelihood of being COVID-19 positive tested.ConclusionsOur findings suggest that especially leucocytes, eosinophils, hemoglobin, and CRP are helpful to distinguish between COVID-19 positive and negative tested patients and that a certain blood pattern is able to predict PCR-results.SummaryDecreasing leucocytes and eosinophils and increasing hemoglobin and CRP were significantly associated with an increased likelihood of being COVID-19 positive tested. Each single parameter showed either a high sensitivity (leucocytes, eosinophils, CRP, monocytes, thrombocytes) or specificity (NLR, CK, ALT, lipase), or a sensitivity and specificity around 60% (Hb, LDH, AST).

Renal insufficiency in patients with multiple myeloma represents a major challenge for the treating physician. In patients with etiologically unclear renal failure it is important to consider multiple myeloma as a possible cause of such renal failure. The diagnosis and treatment of these patients is interdisciplinary, in cooperation with hemato-oncologists, radiologists, nephrologists and intensive care specialists. The main goal of all treatment methods is the rapid reduction of pathological free light chains in the serum, resulting in an improvement of renal function. Equally important is the avoidance of nephrotoxic drugs and iodinated contrast agents in patients with renal insufficiency and multiple myeloma. A few new drugs have been used in the systemic treatment of patients with multiple myeloma (MM) and renal failure with much success, especially the beneficial use of pomalidomide is interesting and other drugs will follow soon.

Whatman FTA® cards provide the most reliable method for DNA storage and extraction, however, the literature lacks reports on the epigenetic analysis of FTA card-derived tumor DNA. Therefore, this study aimed at demonstrating that punches from colonic adenoma samples preserved on FTA filter cards are suitable for methylation analysis by real-time methylation-specific PCR (MSP). Genomic DNA was isolated from a total of 40 sporadic colorectal adenoma samples stored on FTA cards for a median of 59.60 (range 48–72) months. After bisulfite treatment, deaminated DNA was analyzed by SYBR Green real-time MSP using primers specific for methylated and unmethylated promotor sequences of the secreted frizzled-related protein 1 (SFRP1) gene. Amplifiable DNA could be isolated from all FTA card punches while SFRP1 promotor methylation was present in 34/40 (85.0%) colorectal adenomas. Our results indicate that genomic DNA isolated from colonic tumor samples preserved on FTA cards is suitable for downstream methylation detection methodologies such as MSP even after prolonged storage periods.

Myeloid and lymphoid neoplasms with fibroblast growth factor receptor 1 (FGFR1) abnormalities, also known as 8p11 myeloproliferative syndrome (EMS), represent rare and aggressive disorders, associated with chromosomal aberrations that lead to the fusion of FGFR1 to different partner genes. We report on a third patient with a fusion of the translocated promoter region (TPR) gene, a component of the nuclear pore complex, to FGFR1 due to a novel ins(1;8)(q25;p11p23). The fact that this fusion is a rare but recurrent event in EMS prompted us to examine the localization and transforming potential of the chimeric protein. TPR-FGFR1 localizes in the cytoplasm, although the nuclear pore localization signal of TPR is retained in the fusion protein. Furthermore, TPR-FGFR1 enables cytokine-independent survival, proliferation, and granulocytic differentiation of the interleukin-3 dependent myeloid progenitor cell line 32Dcl3, reflecting the chronic phase of EMS characterized by myeloid hyperplasia. 32Dcl3 cells transformed with the TPR-FGFR1 fusion and treated with increasing concentrations of the tyrosine kinase inhibitors ponatinib (AP24534) and infigratinib (NVP-BGJ398) displayed reduced survival and proliferation with IC50 values of 49.8 and 7.7 nM, respectively. Ponatinib, a multitargeted tyrosine kinase inhibitor, is already shown to be effective against several FGFR1-fusion kinases. Infigratinib, tested only against FGFR1OP2-FGFR1 to date, is also efficient against TPR-FGFR1. Taking its high specificity for FGFRs into account, infigratinib could be beneficial for EMS patients and should be further investigated for the treatment of myeloproliferative neoplasms with FGFR1 abnormalities.

No actual data are available on the epidemiology and morbidity of community acquired pneumonia (CAP) in youths and children in Vienna, Austria. The objective was to determine the epidemiology of CAP and morbidity of children hospitalized due to CAP in a tertiary care facility. During three winter seasons youths and children hospitalized due to CAP were enrolled. Testing for viral and bacterial pathogens of pneumonia was performed in a routine clinical setting. Blood cultures were performed; respiratory viruses, Mycoplasma pneumoniae and Chlamydia pneumoniae were searched for by an established Real Time polymerase chain reaction (PCR) panel. Clinical signs and indices of inflammation were documented. Out of 279 children and youths with CAP a causative agent could be detected in 190 (68 %). Viruses and bacteria were diagnosed in 107 (57 %) and 58 patients (30 %), respectively. Co-infection was found in 20 patients (10 %), Mycoplasma pneumoniae or Clamydia pneumoniae in 16 cases (8 %). In seven patients blood cultures were positive. C-reactive protein (CRP) was significantly higher in children with positive Streptococcus pneumoniae antigen (SPAG) than with viral infection and/or co-infection. Clinical parameters showed no statistically significant differences. C. pneumoniae and M. pneumoniae were only diagnosed in children and youths with 5 years and older. Testing for pathogens in CAP in clinical routine achieves a high recovery rate. Blood cultures are rarely helpful, but the molecular testing for viruses seemed to be helpful to establish the diagnosis.

The role of the CLSTN2 (rs6439886) and KIBRA (rs17070145) SNPs in cognitive impairment was analysed in a 75-76 years old group. Various memory assessment tests were carried out on individuals at baseline and during follow-up investigations, and biallelic genotyping was performed. No influence of the allele status of either SNPs was observed on any memory test. No increased risk of any type of late development, and cognitive impairment was associated with rs6439886 or rs17070145.

BACKGROUND: Retinol-binding protein (RBP) 4, a human adipokine that specifically binds to retinol, has been reported to provide a link between obesity and insulin resistance. Plasma RBP4 concentration may be under the influence of age and obesity, but only a few studies has investigated this link in elderly individuals. Consequently, we tested the correlation between RBP4 concentrations and type 2 diabetes/metabolic syndrome (MetS) components in a large population based cohort study (VITA) of elderly [1, 2]. Using a single birth cohort, this investigation could exclude the influence of age. METHODS: We evaluated the correlation of RBP4 with type 2 diabetes and MetS components including Body Mass Index (BMI), blood pressure, lipid parameters, fasting glucose insulin, homeostasis model assessment insulin resistance (HOMA-IR), and smoking in exclusively 75–76 year old participants (N = 232). RESULTS: In the present study, RBP4 concentrations were associated with type 2 diabetes and metabolic syndrome (MetS) components. Of all the individual components of metabolic syndrome that were associated with RBP4 concentrations, the correlations of RBP4 with serum triglycerides and a negative correlation with HDL were the strongest ones observed in our study cohort (p

Globally, cardiovascular diseases (CVDs) are the number one cause of all mortalities. Of these deaths, 7.6 million are due to heart attacks, and 5.7 millions are due to stroke. The Vienna Transdanube Aging Study (VITA), a population-based cohort study, enabled us to evaluate associations between the known major risk factors for cerebrovascular and CVDs and their appearance beyond age 75 years. Using a single birth cohort, age was excluded as confounding factor. In the baseline investigations in the Danube Hospital, 606 individuals took part and were examined completely at baseline. After 60 months, 508 patients were re-examined. Each participant underwent an indepth investigation with the duration of 7 h, including neuropsychological testing, as well as analyses of biochemical, clinical chemical and genetic parameters, and magnetic resonance imaging (MRI) of the brain. In the present study, only a history of cerebral and cardiovascular events at the baseline or smoking was associated significantly with the appearance of CVDs. In a multiple model both risk factors—history of cerebral and cardiovascular events at the baseline (p = 0.0003, OR 2.36, 95% CI 1.49–3.76) and smoking (p = 0.0005, OR 1.57, 95% CI 1.22–2.03)—remained significant. However, the predictive value of this assessment model was low. The rescaled r 2 of the model was 0.088. A significant correlation was found only between exposure to cigarette smoke or a history of previous CVDs, such as stroke or myocardial infarction. Smoking or earlier CVDs greatly increase the risk for further cerebral and cardiovascular events in persons after 75 years.

Myeloid and lymphoid neoplasms with fibroblast growth factor receptor 1 (FGFR1) abnormalities, also known as 8p11 myeloproliferative syndrome (EMS), represent rare and aggressive disorders, associated with chromosomal aberrations that lead to the fusion of FGFR1 to different partner genes. We report on a third patient with a fusion of the translocated promoter region (TPR) gene, a component of the nuclear pore complex, to FGFR1 due to a novel ins(1;8)(q25;p11p23). The fact that this fusion is a rare but recurrent event in EMS prompted us to examine the localization and transforming potential of the chimeric protein. TPR-FGFR1 localizes in the cytoplasm, although the nuclear pore localization signal of TPR is retained in the fusion protein. Furthermore, TPR-FGFR1 enables cytokine-independent survival, proliferation, and granulocytic differentiation of the interleukin-3 dependent myeloid progenitor cell line 32Dcl3, reflecting the chronic phase of EMS characterized by myeloid hyperplasia. 32Dcl3 cells transformed with the TPR-FGFR1 fusion and treated with increasing concentrations of the tyrosine kinase inhibitors ponatinib (AP24534) and infigratinib (NVP-BGJ398) displayed reduced survival and proliferation with IC50 values of 49.8 and 7.7 nM, respectively. Ponatinib, a multitargeted tyrosine kinase inhibitor, is already shown to be effective against several FGFR1-fusion kinases. Infigratinib, tested only against FGFR1OP2-FGFR1 to date, is also efficient against TPR-FGFR1. Taking its high specificity for FGFRs into account, infigratinib could be beneficial for EMS patients and should be further investigated for the treatment of myeloproliferative neoplasms with FGFR1 abnormalities.

A 57-yr-old woman with multiple myeloma received an autologous tandem transplant at a 4-month interval. She was conditioned twice with 225 mg/m 2 melphalan. After the second transplant, interstitial pneumonitis (IP) ensued. The clinical course was life threatening and mechanical ventilation was required for 32 d. All attempts to identify an infectious agent failed. A presumptive diagnosis of idiopathic IP, possibly related to melphalan toxicity, was made. High-dose methylprednisolone administration led to rapid and durable improvement. Melphalan was employed for conditioning in the tandem setting with an interval of only 3-4 months between two courses or a dose elevation to 225 instead of 200 mg/m 2 , may have induced IP which responded favorably to methylprednisolone.

Die auserordentlich hohe Pravalenz von peptischen Lasionen im oberen Gastrointestinaltrakt unter Langzeitanwendung von nichtsteroidalen Antirheumatika macht eine mukosaprotektive Begleitmedikation insbesondere in Patientenkollektiven mit erhohtem Risiko unverzichtbar. In prospektiven Studien wurden Misoprostol, Protonenpumpeninhibitoren und Histamin-2-Rezeptorantagonisten in dieser Indikation untersucht.

The aims of this study were to evaluate the effectiveness of magnetic resonance cholangiography (MRC) in diagnosing patients with cholestasis and to compare these results to those obtained with endoscopic retrograde cholangiopancreaticography(ERCP). From January 1996 to December 1998 a total of 85 consecutive patients who were candidates for ERCP because of a suspected diagnosis of mechanical cholestasis were included in this study. All patients underwent MRC and consecutive ERCP 24 to 48 hours later. The sensitivity for detecting common bile duct stones was 93%,specificity 74%, positive predictive value 89%, and negative predictive value 82%. For the determination of tumorous bile duct stenosis the sensitivity and specificity were both 100%. MRC might be an ideal method for evaluating patients with unclear laboratory or ultrasonography findings before laparoscopic cholecystectomy, thereby avoiding unnecessary invasive diagnostic tests with possible harmful complications.

We describe in detail a 67-yr-old woman who was treated with a cytostatic combination chemotherapy for newly diagnosed common-acute lymphoblastic leukaemia. At the end of induction therapy, the patient acquired invasive mould infection affecting lung and brain. The patient entered complete remission of her leukaemia. Treatment with liposomal amphotericin B was initiated along with surgical excision of the fungal brain abscess. Intrathecal instillation of amphotericin B deoxycholate was started using an Ommaya reservoir because of an anatomical connection between the postoperative cavity and the ventricle. Full dose cytostatic chemotherapy was continued with little delay. A computerised tomography scan of the chest performed 2 months later revealed no fungal abscesses. Magnetic resonance imaging of the brain did not reveal any fungal manifestation. During maintenance therapy/week 69, the patient relapsed from leukaemia. High doses of intravenous liposomal amphotericin B were administered prophylactically. The patient's leukaemia proved refractory to reinduction chemotherapy and the patient died from pneumonia 8 wk later. Post mortem microbiological investigation and histopathological examination of lung and brain tissue did not reveal any macroscopical or microscopical fungal manifestations. This case underlines the feasibility and successful application of combined antileukaemic, antifungal and surgical therapy in a patient with acute leukaemia.

The serum protein designated 90K/Mac-2BP has been found at elevated concentrations in the sera of patients with various types of cancer and viral infections. The importance of the 90K/Mac-2BP serum concentrations in predicting the response towards interferon-α treatment for hepatitis C virus (HCV) infection prompted us to utilize a new ELISA for soluble human 90K/Mac-2BP to monitor the serum concentrations of this protein in our HCV-positive patients. Seventy HCV-PCR and anti-HCV antibody positive patients were analyzed for their serum levels of aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, cholinesterase, HCV-viral load, viral subtypes, and 90K/Mac-2BP. On correlation of age and 90K/Mac-2BP levels, we found an apparent correlation that was proved rather to be a strong dependence of 90K/Mac-2BP concentrations on disease severity/duration, which increases with age. Multiple correlation analysis demonstrated the independent nature of 90K/Mac-2BP concentrations, underscoring the potential high utility of this new marker. Our data corroborate the potential of the scavenger receptor family protein 90K/Mac-2BP as an independent predictor of disease severity during HCV infection.

PURPOSE: This retrospective study was undertaken to evaluate immunohistochemically the expression of CD44 standard protein and CD44v5 and CD44v6 isoforms in colorectal adenomas and early invasive cancers developing within adenomas as possible markers characterizing colorectal polyps with a more aggressive biologic potential. METHODS: Archival tissues of 81 consecutive locally resected colorectal polyps, comprising 57 colorectal adenomas and 24 carcinomas-in-adenomas, were stained immunohistochemically with the use of commercially available mouse monoclonal antibodies: SFF-2 for CD44 standard protein, VFF-8 for CD44v5, and VFF-7 for CD44v6. RESULTS: Sixtythree percent of the colorectal polyps were positive for CD44 standard protein, 59 percent were positive for CD44v5, and 27 percent were positive for CD44v6. Ninetythree percent of the low-grade adenomas were CD44 standard protein-positive, in contrast to 50 percent of the high-grade adenomas and only 42 percent of the carcinomas-in-adenomas (Kendall's Tau =−0.42;P

Background: The potential for faster detection of human herpes viruses using PCR compared to other methods is undisputed. However, because of fear of contamination, the clinical implication of nucleic amplification methods in routine laboratories is not widespread. Herpes viruses cause a wide spectrum of diseases and can cause morbidity and mortality in immune-compromised patients. Using real-time PCR, most of the problems associated with PCR (contamination, cumbersome detection, and rather expensive tests) are solved, and a rapid, economical, and – most importantly – closed system is at hand. Methods: We evaluated work procedures in our laboratory that enable the routine diagnosis of viral infections with high accuracy and rapid turn-around time. In parallel, inherent problems usually associated with PCR testing, especially cross-contamination could be suppressed to a minimum. The start of the work flow process begins with an automated nucleic acid extraction procedure that yields high quality DNA. A common – internally and externally controlled – PCR program for all six viruses allows rapid sample turn around. Results: In all, 7500 analyses for human herpes virus infection were performed in the last 5 years. Results for various different specimens were produced within 24 h. Contamination occurred rarely and could be ameliorated easily. The use of internal controls identified rare PCR-inhibited samples. The detection limits for our assays are markedly below the clinically relevant range. Conclusions: Our workflow allowed rapid, cost-efficient, and labor saving routine diagnostic detection of viral infections. Clin Chem Lab Med 2009;47:1141–5.

The Kirsten-ras (onco)gene codes for a GTP-binding membrane protein that is involved in signal transduction. Activated ras triggers a cascade of protein-phosphorylations that ultimately lead to cell proliferation. Ras-mutations are the main cause for adenocarcinomas of the pancreas besides some mutations in the tumor suppressor gene p53 and the c-erbB-2 oncogene. The site of ras mutations in pancreatic cancer is restricted to codon 12 that normally encodes a glycine. For analysis of codon-12 mutations, DNA is extracted from cells in pancreatic fluid and amplified by PCR. Because most of these cells originate from normal tissue with only a few tumor cells in the fluid, “enrichment PCR” must be utilized: In a first round of the PCR, ras sequences from all cells are amplified. By utilizing an appropriate restriction enzyme, wild-type sequences can be digested and the remaining fragments containing mutated sequences be amplified again. An artificial restriction site must be introduced by the 5′ primer (…GGA C̱CT GGT…) for an enzyme (BstNI) (5′CC!WGG 3′) to differentiate between wild-type sequence (…GGA G̱CT GGT…) (during amplification, the G̱ is replaced by a C̱) and mutated sequences (̱…GGA GCT (GTT), (CGT), (CCT), etc.). The necessary manipulations pose a considerable risk for contamination for the second round of the PCR procedure. Therefore, we considered whether it would be feasible to perform the restriction digest simultaneously with the first PCR reaction, and avoiding the secound round altogether. The results of our experiments demonstrate that one tumor cell in 1000 normal cells can be determined readily, paralleling the results with the original two step-assay. The restriction enzyme used to enrich mutated sequences is stable long enough to be included into the PCR procedure. By this, wild-type sequence amplicons are digested while they are formed and mutated sequences can be enriched selectively.

A 57-yr-old woman with multiple myeloma received an autologous tandem transplant at a 4-month interval. She was conditioned twice with 225 mg/m2 melphalan. After the second transplant, interstitial pneumonitis (IP) ensued. The clinical course was life threatening and mechanical ventilation was required for 32 d. All attempts to identify an infectious agent failed. A presumptive diagnosis of idiopathic IP, possibly related to melphalan toxicity, was made. High-dose methylprednisolone administration led to rapid and durable improvement. Melphalan was employed for conditioning in the tandem setting with an interval of only 3-4 months between two courses or a dose elevation to 225 instead of 200 mg/m2, may have induced IP which responded favorably to methylprednisolone.

Due to the extraordinary high prevalence of peptic lesions in the upper gastrointestine in the long-term treatment with nonsteroidal anti-inflammatory drugs, a prophylaxis in patients belonging to high-risk groups is essential. Misoprostol, proton pump inhibitors and histamine 2-receptor antagonists have been evaluated in prospective studies. The efficacy of Misoprostol is well documented, though its use in prevention is frequently limited due to side effects. Proton pump inhibitors are also well established, especially in the therapy of nonsteroidal anti-inflammatory drugs associated peptic ulcers and in consecutive secondary prevention. The histamine 2-receptor antagonist Famotidine in a high oral dosage is able to reduce the frequency of peptic lesions too, but not to the same degree as Misoprostol and proton pump inhibitors. It is very likely that helicobacter pylori eradication without any further mucosaprotective therapy will only decrease the incidence of upper gastrointestinal bleeding in low dose Aspirin application. In spite of controversial studies this eradication seems to be a useful additional therapy for ulcer prophylaxis in high risk groups. Selective Cyclooxygenase-2 inhibitors may become a promising alternative, from a pathophysiological perspective. However, to date there has been a lack of clear comparative studies with common nonsteroidal anti-inflammatory drugs plus mucosaprotecting agents. Daily therapy costs are higher with a Cyclooxygenase-2 inhibitor than using the traditional nonsteroidal anti-inflammatory drugs together with either proton pump inhibitors, histamine 2-receptor antagonists or Misoprostol--a fact that should be considered in primary therapeutic decisions. In the following review we will present the most important results of the different prophylactic and therapeutic modalities. On the basis of placebo-controlled, prospective studies on the one hand and the recommendations of the scientific societies on the other, a guideline for daily clinical practice will be suggested.

Prolactin is a suspected promotor of breast cancer cell growth, and it shares pleiotropic immunoregulatory properties. We studied plasma prolactin and its drug-induced modulation in 20 women with breast cancer undergoing high-dose chemotherapy and autologous blood stem-cell transplantation. Plasma prolactin levels were serially assayed before and during conditioning and within and beyond 30 days after transplant. Before transplant, prolactin plasma levels were in the age-adjusted range of normal women. During conditioning and within 30 days after transplant, prolactin levels increased in all patients (p < 0.0001), but remained in the normal range. Antiemetic drugs such as metoclopramide and phenothiazines, known to enhance pituitary prolactin secretion, further elevated prolactin plasma levels (p < 0.00001). Patients remaining in continuous complete remission after transplant (median follow-up, 3 years) disclosed higher prolactin levels compared with those obtaining only partial remission or ensuing early relapse. Prolactin levels are regularly elevated during conditioning and within 30 days after autologous transplantation for breast cancer. Further elevations of prolactin plasma levels are induced by metoclopramide and other antiemetic drugs. Elevated plasma prolactin had no adverse effect on disease-free survival after transplant. We propose to investigate further the upregulation of prolactin after transplant aiming to induce a posttransplant consolidative immune reaction.

481 Background: OATP-transporter proteins, such as OATP4A1, present influence cancer progression by providing compounds (hormones, prostaglandins, cyclic nucleotides, second messenger proteins, drugs) which either inhibit or stimulate tumor cells growth. Therefore, OATP expression in cancer cells and in the stroma, i.e., the microenvironment surrounding the epithelial cells can become a critical parameter. Methods: OATP4A1 was investigated in paraffin-embedded specimens from 148 patients with colorectal cancer and 20 with diverticulitis by immunohistochemistry (IHC) on an automatic quantitative microscopic image analysis system (TissuesFaxs). With the Histoquest program, the immunoreactive score (IRS), was calculated from the degree of the staining intensity and the number of OATP4A1-positive cells. To identify OATP4A1+-cells, double-immunofluorescence staining (IF) was done with antibodies against appropriate cellular markers. Results: OATP4A1 was located in the membrane and cytosol of colon cancer cells and immune cells, while membranous OATP4A1staining was seen in normal mucosa. OATP4A1 levels were higher in cancer cells in patients without tumor recurrence for up to 5 years (NR) than in patients with an early relapse (R) having IRS of 4391±231 and 3026±373 (Mean±SEM), respectively. Highest OATP4A1 levels were observed in immune cells in the tumors of Rs (IRS, 5712 ±254, while in NRs they were lower (IRS: 3549±358; p=0.05). In both groups, OATP4A1 levels in stroma cells were low (288±54 vs. 611±82). OATP4A1 expressing immune cell subtypes in cancer and diverticulitis sections were identified as CD45+ leukocytes, CD3+ T- and CD20+ B-cells, CD68+ macrophages, CD34+precursor cells. OATP4A1 was not detectable in Conclusions: High levels of OATP4A1 in immune cells in malignant and non-malignant colon disease suggest a role of the transporter in the activation of the immune system in malignant and non-malignant colon disease. Whether OATP4A1 might be a therapeutical target has to be established.

430 Background: Organic anions transporters (OATPs) are important for tumor progression and therapeutic response by regulating cellular levels of hormones, second messenger proteins and drugs. OATP4A1 is a transporter of pro-inflammatory prostaglandin E2 and may contribute to cancer progression. Data on the expression of OATP4A1 and its clinical impact in primary colorectal cancer (CRC) is rare. Our study was designed to proof the overexpression of OATP4A1 in primary CRC. Methods: Frozen samples from 20 unselected CRC patients (pat) and five CRC cell lines were analyzed for OATP4A1 mRNA expression by real time PCR (mean level normalized to the calibrator, MNE). Immunohistochemistry was performed on paraffin- embedded tumor sections from 50 CRC pat., UICC 0-II (25/50 with subsequent relapse). An automatic quantitative image analysis program was applied to quantify OATP4A1 expression. Expression and intensity was correlated with clinical parameters and relapses. Results: Significant (p>0.05) higher levels of OATP4A1 mRNA were observed in 20 cancer samples as compared to adjacent non-cancerous tissue (2.44 vs. 0.46 MNE). The highest expression (9.85 MNE) was observed in a well-differentiated tumor sample. Similar high levels were observed in the COGA1A cell line, expression in the other cell lines ranged between 1.83 and 0.28 MNE. Immunoreactive staining for OATP4A1 was located in the membrane and occasionally in the cytosol of tumor cells, it was exclusively membrane located in the adjacent non-cancerous epithelial cells. The staining intensity was significantly higher in cancer cells compared to non-cancerous areas (1528±326 vs.376±218) while staining of stroma cells was only occasionally detectable. Surprisingly, the highest OATP4A1 levels were observed in immune cells (2839±381 vs.298±56). Data on the clinical impact of OATP4A1 in the early stage CRC pat. will be presented at the meeting. Conclusions: The profound expression of OATP4A1 in CRC cells and in the inflammatory infiltrates supports its implication on cancer progression. Suitability of OATP4A1 as a potential prognostic marker has to be established on a larger patient collective.

415 Background: 15-20% of sporadic colorectal cancers (CRC) are characterized by DNA mismatch repair (MMR) deficiency resulting in the phenomenon of microsatellite instability (MSI). There is evidence that CRC with MSI have a significant better prognosis compared to those with intact MMR. We investigated MMR gene expression in patients (pat.) with CRC and correlated it with early relapse rate. Methods: The study relates to 146 pat. with primary CRC UICC stage 0-II who underwent surgical resection at the Donauspital in Vienna and had a complete follow up of at least 60 months. Expression of the MMR genes MLH1, PMS2, MSH2, MSH6 was detected by immunohistochemical staining. Expression of MMR genes was correlated with pat. and disease characteristics as well as relapse frequency within the first 5 years after diagnosis. Chi-squared test was used to compare the distribution of the given variables between MMR gene proficient and deficient pat. Results: Mean age of the total group was 66.14 years, 45.2% were females and 54.8 males. Localization of the tumor was the colon in 69.2% and the rectum in 30.8% of pat., respectively. 33.6% of diseases were classified as UICC stage 0-I, and 66.4% as UICC stage II. 37/ 146 pat. experienced relapse, mean duration to relapse was 2.17 years. 13.7% of all pat. displayed a MMR deficient state. All MMR deficiencies occurred in the colon, none in rectum tumors. MLH1 was always associated with PMS2 deficiency and occurred in 9.6% of pat. There was a significant difference in sex distribution between the proficient and deficient group with 71.4% females with MLH1/PMS2 deficiency (p= 0.038). MSH2 deficiency was detected in 1 pat. only. MSH6 deficiency occurred in 5.5% of pat., none of the variables was significantly different distributed between the proficient and deficient group. None of the MMR deficiencies correlated with relapse rate. Conclusions: Our data suggest that the supposed better prognosis of MMR deficient compared to proficient pat. might not be explained by a different relapse rate within 5 years from diagnosis. Larger and prospective trials are warranted to elucidate plausible explanations for the proposed survival benefit of a MMR deficient state.

e14087 Background: Immunotherapy in real-life, unselected patients with metastatic colorectal cancer (mCRC) was analyzed retrospectively at a single center in Austria. Methods: We have treated 137 mCRC patients with at least one antibody containing therapy since 2004 at our center based at data available at that time and patient eligibility. Results: Most mCRC patients were between 55 and 75 years old. The KRAS mutation testing performed routinely from 2008 onwards shows a distribution of 55 % wildtype (wt) and 45% mutant (mut) KRAS. Median overall survival (OS) was 24 months (n=82) with a trend towards greater benefit for KRAS wt patients compared to KRAS mut (26.8 vs. 20.9 months, respectively). Most patients received between 3 and 5 treatment lines. 40% of patients were treated with 5 therapies and 8% reached treatment line 8. The median OS correlated with the number of therapy lines. Chemotherapy alone regimens are decreasing constantly due to the establishment of biomarker analysis based treatment decisions and the increase in available antibodies for immunotherapy in mCRC. Based on direct positive experience with various antibodies, we were successfully treating patients repeatedly with the same antibodies in non-consecutive treatment lines. 75.7% of all patients treated with Cetuximab received the antibody only once during 3.8 therapy lines. 13% of patients who obtained the agent in two lines received on average 5.7 treatment lines resulting in improved OS. This was even more prominent in 8.5% patients receiving Cetuximab in 3 lines with a trend towards further OS benefit. These data describe that multiple applications of the same antibody is not only feasible but also very effective. Conclusions: By taping the full potential of treatment options, optimizing their usage and expanding the number of treatment lines we could achieve a median OS in real-life patients similar to that previously described in large phase III studies. Our analysis describes the following key factors for reproducing clinical benefits reported in large trials: biomarker assessment, early and if possible multiple applications of available therapeutic antibodies, treatment until progression and use of supportive therapy to alleviate possible toxicities.

Background. To determine the maximum tolerated dose of epirubicin for use in combination with 5-fluorouracil (5-FU) and low-dose leucovorin (LV), a Phase I–II trial was conducted in 37 patients with advanced gastric carcinoma. Methods. The doses of 5-FU (425 mg/m2) and LV (20 mg/m2), both given intravenously on days 1–5, were held constant while the dose of epirubicin was escalated in cohorts of patients (beginning dose, 50 mg/m2 on day 1). Cycles were repeated every 4 weeks. Results. Significant gastrointestinal symptoms and myelosuppression were observed infrequently at the initial dose level. At a dose of 60 mg/m2 of epirubicin on day 1, however, five of eight patients had significant mucosal toxic effects during the first cycle of therapy. In addition, two patients treated at this dose level had Grade 4 granulocytopenia with insufficient recovery to permit a second course by day 28, and one patient each had severe diarrhea and nausea and vomiting. Among 37 patients with assessable disease, there were 3 complete and 11 partial responses (response rate, 38%). Conclusions. LV modulation of 5-FU can be incorporated safely into combination chemotherapy with epirubicin and provides a relatively active regimen for treatment of disseminated gastric cancer.