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Trotz vieler medizinischer Fortschritte ist das Pankreaskarzinom weiterhin eine Erkrankung mit einer infausten Prognose. Die 5-Jahres-Überlebensrate beträgt lediglich 5-7%. Grund dafür ist vor allem die Resistenz gegenüber Chemotherapie-vermittelter Apoptose. Diese Resistenz wird unter anderem durch die Überexpression anti-apoptotischer Proteine wie Bcl-2, Bcl-xl und Mcl-1 bedingt. TRAIL ist in der Lage, selektiv in Tumorzellen Apoptose zu induzieren. Jedoch sind viele primäre Krebszellarten resistent gegenüber TRAIL. In jüngerer Zeit wurden BH3-Mimetics entwickelt. Diese Substanzen können selektiv anti-apoptotische Proteine inhibieren und eignen sich somit potenziell als TRAIL-sensitivierende Substanzen. Im Rahmen dieser Dissertation wurde erstens analysiert, ob die Expressionsprofile der drei anti-apoptotischen Proteine Bcl-2, Bcl-xl und Mcl-1 im Tumorgewebe von Patienten eine prognostische Relevanz haben. Zweitens wurde getestet, ob eine Kombinationsbehandlung von TRAIL und BH3-Mimetics die Apoptoseresistenz von Pankreaskarzinomzellen überwinden kann. Drittens wurde untersucht, welche funktionelle Rolle die einzelnen anti-apoptotischen Proteine für die Apoptoseresistenz spielen. Es wurden die BH3-Mimetics Navitoclax, Venetoclax und S63845 verwendet. Zuerst wurden diese als Monotherapie in verschiedenen Pankreaskarzinomzelllinien getestet. Danach erfolgten Kombinationsversuche mit TRAIL. Anschließend wurden Überexpressionsversuche sowie Knock-down-Versuche mittels siRNA durchgeführt. Zusammenfassend zeigte sich, dass die Expressionsprofile keine prognostische Relevanz hatten. Die Kombinationsbehandlung von TRAIL und BH3-Mimetics zeigte jedoch einen stärkeren Effekt als die jeweilige Monotherapie und insbesondere Mcl-1 scheint eine entscheidende Rolle für die Apoptoseresistenz zu spielen.

Chronic myeloid leukemia - update 2020

In modern oncology, molecular tumor boards are the interface between the public healthcare system and clinical research institutions. An interdisciplinary team of medical and scientific experts assesses if extensive molecular testing for tumor profiling is appropriate and discusses therapeutic options for patients with newly diagnosed treatable alterations. In the field of metastatic prostate cancer, patients especially with a strong family history, young age of diagnosis and those who have exhausted standard treatments may benefit from molecular profiling. Expression of the androgen receptor splice variant 7 (AR-V7) predicts nonresponse to next-generation AR-directed therapy like abiraterone or enzalutamide. Different blood tests for AR-V7 detection are now commercially available. Mutations in the DNA repair pathway are another frequent event in metastatic prostate cancer. Homologous recombination defects sensitize cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors. In the TOPARP-A trial, the PARP inhibitor olaparib led to high response rates (88%) in patients with mutated DNA repair genes. Furthermore, patients with DNA mismatch repair deficiency and/or microsatellite instability seem to benefit from PD-1 inhibitors, particularly pembrolizumab. At this time neither PARP inhibitors nor PD-1 inhibitors are approved for metastatic prostate cancer treatment in Germany. Therefore, a recommendation of a molecular tumor board for biomarker-matched off-label use of approved drugs across entity barriers will support coverage by health insurance.

Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) are widely used in non-small cell lung cancer patients harboring activating EGFR mutations. However, resistance mechanisms, particularly the T790 M mutation, hamper longer-term therapeutic success of first and second generation EGFR-TKIs. To address this unmet medical need, EGFR-TKIs of the third generation are under clinical development. Relevant clinical efficacy with mainly mild to moderate class-specific side effects has been shown for third-generation EGFR-TKIs. Molecular testing is of major importance in deciding for treatment with third generation EGFR-TKIs. This article elucidates the developmental state of third generation EGFR-TKIs with its focus on Osimertinib, the first and currently the only compound in this class which is approved in Germany. Additionally, the medical importance of molecular diagnosis using tumor tissue and circulating tumor DNA is discussed.Die Resistenzbildung gegenüber der 1. und 2. Generation von Tyrosinkinase-Inhibitoren (TKIs) des epidermalen Wachstumsfaktors (EGFR) stellt bei der Behandlung von Patienten mit nicht kleinzelligem Lungenkarzinom, die eine aktivierende Mutation im EGFR aufweisen, ein großes Problem dar. Drittgenerations-EGFR-TKIs richten sich sowohl gegen aktivierende als auch gegen die Resistenz-vermittelnde T790M-Mutation. EGFR-TKIs der 3. Generation zeigen in klinischen Studien bei T790M-positiven Patienten relevante Wirksamkeit bei meist milden bis moderaten klassenspezifischen Nebenwirkungen. Molekularpathologischen Analysen kommt bei der Entscheidung zur Therapie mit Drittgenerations-EGFR-TKIs eine bedeutsame Rolle zu. In dieser Übersichtsarbeit wird der aktuelle Entwicklungsstand von Drittgenerations-EGFR-TKIs dargestellt mit einem Schwerpunkt auf Osimertinib, dem ersten und bislang einzigen in Deutschland zugelassenen Wirkstoff dieser Klasse. Zudem wird die Relevanz einer molekularen Diagnostik an Tumorgewebe bzw. an zirkulierender Tumor-DNA diskutiert.

Cancer is characterized by proliferation of cells that have managed to evade central endogenous control mechanisms. Cancers are grouped according to their organ or tissue of origin, but increasingly also based on molecular characteristics of the respective cancer cells. Due to the rapid technological advances of the last years, it is now possible to analyze the molecular makeup of different cancer types in detail within short time periods. The accumulating knowledge about development and progression of cancer can be used to develop more precise diagnostics and more effective and/or less toxic cancer therapies. In the long run, the goal is to offer to every cancer patient a therapeutic regimen that is tailored to his individual disease and situation in an optimal way.

Acquired resistances to tyrosine kinase inhibitors in non-small cell lung cancer develop after 9 - 12 month. In 60 % of the cases these resistances arise because of a secondary EGFR-T790 M resistance mutation. This report is describing the case of a patient who developed parallel two different mechanisms of resistance: A T790 M resistance mutation and a transformation into a small cell neuroendocrine cancer. Under therapy with Osimertinib and chemotherapy with carboplatin and etoposide the tumor responsed partially.Erworbene Resistenzen gegenüber Tyrosinkinaseinhibitoren beim nicht kleinzelligen Lungenkarzinom entwickeln sich nach etwa 9 – 12 Monaten. In etwa 60 % der Fälle entstehen diese durch eine sekundäre EGFR-T790 M Resistenzmutation. In dieser Kasuistik wird der Fall einer Patientin mit einer Mutation im EGFR Exon 19 beschrieben. Es entwickeln sich unter TKI-Therapie 2 parallele Resistenzmechanismen. Zum einen eine T790M-Resistenzmutation, zum anderen die Transformation in ein kleinzelliges neuroendokrines Karzinom. Unter der Therapie mit Osimertinib sowie paralleler Chemotherapie mit Carboplatin und Etoposid konnte nach 2 Zyklen eine partielle Remission erzielt werden.

Although prostate cancer responds well to primary endocrine therapies, tumor progression with castration resistant tumor cells almost invariably occurs within a few years. Unfortunately, some CRPC patients do not respond to second-line therapies with abiraterone or enzalutamide. Moreover, patients who initially responded well to second-line hormone therapy develop resistance to abiraterone and/or enzalutamide within a short period of time. Besides an increase of intracellular androgen receptor (AR) levels, the predominant resistance mechanisms include AR aberrations (point mutations, AR splice variants) occurring predominantly at the androgen or ligand binding domain of the AR. The following review delineates recent progress in the development of AR inhibitors that do not depend on androgen binding and represent a putative third generation of AR inhibitors.

Androgen deprivation is still standard therapy for prostate cancer, either as primary androgen deprivation therapy or with the use of secondary hormonal drugs including abiraterone and enzalutamide. However, especially the clinically occult side effects like metabolic changes or cardiovascular complications and effects on the psyche of the patient are often not recognized in daily practice. Active monitoring of such side effects is essential for prevention and early intervention. In addition, the efficacy of androgen deprivation therapies is limited by primary and secondary resistance. The underlying molecular mechanism including splice variants of the androgen receptor in contrast to mutations are usually reversible and should be regarded as a sign of efficacy of the current treatment. Therefore, the clever, timely use of androgen deprivation or even the use of a bipolar androgen therapy should enable reversal of resistance to again render tumor cells sensitive to androgen-deprivation therapy.

During recent years, microRNAs (Greek: micros = small; miRNA) have become more important. miRNAs are highly conserved, noncoding, single-stranded RNA molecules 17–28 nucleotide in length. Secreted by tumor cells, miRNAs regulate many biological processes and are also involved in chemoresistance. Classical forms of cancer treatment lead to miRNA release. Which miRNAs are correlated to head and neck squamous cell carcinomas (HNSCC) and their chemoresistance to paclitaxel remains unknown.Identification of miRNAs expressed in HNSCC and elucidation of those involved in conferring chemoresistance to paclitaxel.To identify changes in gene expression, HNSCC cell lines were treated with 10 μM paclitaxel for 48 h and analyzed by microarray analysis. Thereafter, changed in expression of single miRNAs (miR221*, miR222 and miR222*) following paclitaxel treatment were analyzed using a quantitative real-time polymerase chain reaction (qRT-PCR).Under treatment with paclitaxel, miRNAs were released. The dominant change is upregulation of MIR222 gene expression. Regulation of miR222* expression under paclitaxel treatment seems to be different in human papillomavirus (HPV)-negative and HPV-positive HNSCC cell lines.Expression of mirR221/222 is correlated to cell cycle regulation, carcinogenesis, and chemoresistance. Detailed knowledge of the molecular mechanisms and effects ofmiRNAs is important for identifying miRNAs as cancermarkers, as well as for increasing the efficiency of cancer therapeutics.

Despite complex surgical and systemic therapies epithelial ovarian cancer has a poor prognosis. A small quantity of tumorigenic cells termed cancer stem cells (CSC) are responsible for the development of chemoresistance and high rates of recurrence.This review presents the CSC hypothesis and describes methods of identification and enrichment of CSCs as well as approaches for the therapeutic use of these findings.A systematic literature review based on PubMed and Web of Science was carried out.The CSC model is based on a hierarchical structure of tumors with few CSCs and variably differentiated tumor cells constituting the tumor bulk. Only the CSCs possess tumorigenic potential. Other essential functional characteristics of CSCs are their potential for self-renewal and their ability to differentiate into further cell types. The CSCs are structurally characterized by different surface markers and changes in certain signaling pathways. Currently there are phase I and II studies in progress investigating specific influences on CSCs.Various clinical characteristics of the course of disease in ovarian cancer are aptly represented by the tumor stem cell model. In spite of precisely defined functional characteristics of CSCs, surface markers and signaling pathways show individual differences and vary between tumor entities. This complicates identification and enrichment. Current experimental findings in various approaches and even first clinical studies raise hopes for a personalized cancer therapy targeting CSCs.

Drug development in oncology has seen major innovations in recent years. Based on the molecular changes found in malignant tumors, new drugs are being developed which specifically target these altered signaling pathways.In addition to the already broadly used inhibitors of growth factor and angiogenic signaling pathways, new and innovative target structures have been identified. Cancer stem cells which are thought to be the reason for drug resistance and tumor recurrence are now being targeted. c-MET signaling has emerged as an important new signaling module which can be influenced pharmacologically. Inhibitors of immune checkpoints like antibodies which target the CTLA4 molecule are leading to impressive results in clinical trials. Drugs which influence the epigenetic changes found in tumor cells are tested specifically for their ability to overcome drug resistance. Finally, treatment with oncolytic viruses has made a comeback in certain tumor entities.Oncological treatments will see a significant addition of new drugs and treatment options in the next few years which will hopefully improve the survival of patients with tumors.

In the past multiple mechanisms could be identified that are involved in anticancer drug resistance; however, diagnostic assays for prediction of therapy response to classical cytostatic drugs did not enter routine clinical diagnostics. Only when new targeted drugs, e.g. tyrosine kinase inhibitors or therapeutic antibodies, were introduced in oncology were diagnostics for prediction of therapy response routinely preformed. First and foremost this was the result of the development of highly standardized techniques, i.e. exact mutation analysis in functional relevant codons of genes encoding signal proteins of cancer-related signal transduction pathways targeted by the new drugs. Due to increasing costs of health systems, in the future predictive diagnostics will probably become more and more important. Therefore, it will be necessary to develop improved diagnostic assays for prediction of individual therapy response.

In patients with chronic myeloid leukemia, high-quality diagnostics is of paramount importance for the surveillance of treatment efficacy. The availability of new tyrosine kinase inhibitors providing more rapid and deeper responses requires the employment of standardized and highly sensitive diagnostic methods to ensure optimal monitoring of the patients. This review presents the current international diagnostic standards and the certified laboratories in Austria.

Advanced prostate cancer that progresses under androgen deprivation therapy has long been thought to be refractory to further hormonal treatment. The identification of the mechanism of cancer cells has revolutionized this understanding. Today it is known that castration-resistant prostate cancer (CRPC) still receives signals through the androgen receptor transduction pathways and furthermore is sensitive to hormone therapy. New substances, such as abiraterone, enzalutamide (MDV3100) and TAK 700 target these mechanisms of resistance of cancer cells, stop testosterone production and show not only better tolerance but also effective antitumor activity. Due to the heterogeneity of tumors with cells in varying states of differentiation, the treatment of CRPC with androgen deprivation therapy remains a cornerstone of disease management. To what extent the experimental findings and the recommendations in the guidelines are put into practice was the subject of a survey among urologists analyzing their treatment strategies with CRPC patients.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors in the digestive tract. In up to 90% of cases, they are characterized by activating mutations in the KIT or the PDGFRA gene. GIST represent a paradigm for successful targeted treatment with tyrosine kinase inhibitors (TKI). Since the approval of the TKI imatinib in 2002 the survival of patients with metastatic GIST has tripled. The next logical step was the concept of using imatinib in an adjuvant approach, which was recently shown to increase overall survival significantly. In both settings, the mutational status has high predictive implications. In detail, GIST with KIT exon 11 mutations show the best response rates with partial remission rates of up to 80%. In KIT exon 9 mutations, a doubled daily dose of 800 mg imatinib is now standard. The PDGFRA exon 18 mutation D842V has been shown to lead to primary resistance. The treatment strategy in GIST is driven by their molecular characterisation. Further research has increased our knowledge on resistance mechanisms in solid tumors against TKI. The number of patients with secondary resistance due to acquired KIT mutations is increasing with treatment duration. Strategies to address this situation are the introduction of novel pathway inhibitors targeting different levels of signal transduction pathways, such as the mTOR/Akt pathway, the RAS/RAF pathway, histone deacetylation, among others. Among the GIST without mutations in the common hot spot regions of KIT and PDGFRA, the so-called wildtype GIST, further genomic subgroups have been identified. One such subgroup carries inactivating germline mutations in the genes encoding succinate dehydrogenase B, C, or D. They are associated with the occurrence of paragangliomas, so-called Carney-Stratakis syndrome. Most frequently, these GIST are located in the stomach, showing an epithelioid phenotype and a multinodular growth pattern. They preferentially occur in young females and often show lymph node metastases, the latter being very unusual in sporadic GIST. In sporadic Carney's triad additional pulmonary chondromas are observed and there are no SDH mutations. Another small subgroup of sporadic GIST present with BRAF mutations as an alternative genomic event. Finally, very rare kindreds with germline mutations in either KIT or PDGFRA have been described who develop multiple GIST and depending on the mutational subtype mastocytosis, hyperpigmentation and/or dysphagia. In summary, the molecular characterisation of GIST has revolutionized their treatment due to increasing knowledge about the high relevance of predictive molecular typing in solid tumors.

First clinical experiences with abiraterone and cabazitaxel for the treatment of metastatic castration-resistant prostate cancer patients following docetaxel chemotherapy are reported.We describe PSA response rates and disease control rates determined by imaging studies at 3 months as well as side effects in the daily routine. All patients were treated within the"compassionate use" programs of cabazitaxel and abiraterone or treated according to their inclusion and exclusion criteria at the "Technische Universität München".Of 54 patients, 15 were treated with cabazitaxel and 39 with abiraterone. In patients treated with cabazitaxel, after 3 months of therapy the PSA reduction rate50% was 46.2%, the PSA progression rate was 15.4%, and the disease control rate was 83.3%. Main grade 3/4 hematotoxicities were neutropenia (40%) and anemia (20%). Febrile neutropenia was observed in 2 of 15 (13.3%) patients. Main non-hematological grade 3/4 toxicities were diarrhea (13.3%) and polyneuropathy (13.3%). In patients treated with abiraterone, after 3 months of therapy the PSA reduction rate50% was 35.1%, the PSA progression rate was 46.0%, and the disease control rate was 47.1%. Main grade 3/4 hematotoxicities were anemia (5.1%) and thrombocytopenia (5.1%). Main non-hematological toxicities were fatigue (20.5%), sweating (17.9%), and constipation (10.3%).Utilization of cabazitaxel and abiraterone in the daily routine show response rates comparable to their approval studies with acceptable side effects.

Since its first market authorisation 40 years ago, cisplatin is an important constituent of cytostatic chemotherapy regimens. Some tumour entities even lost their fright after introduction of cisplatin into the therapeutic armamentarium. For instance, cure rates of up to 95 % are reported for testicular cancer depending on the tumour-stage at the time of diagnosis. In the first-line breast cancer therapy cisplatin is regarded only a cytostatic reserve at present. However, platinum-based therapy regimes are widely used in anthracyclin- and/or taxan-refractory situations. In addition, platinum-based therapy is well-established in the palliative treatment of breast cancer.Breast cancer is the most common female cancer type and triple negative breast cancer (TNBC) has the poorest prognosis. Therapy options are limited to surgery, radiotherapy, and polychemotherapy since targeted therapies, which are based on a molecular interaction with a target protein, are not amenable at present. However, triple negative breast cancer specimens show good initial response to platinum-based chemotherapy. Therefore, clinical research of cisplatin therapy in BRCA-mutated triple negative breast cancer is currently intensified. However, despite successful first treatment, the tumour often reappears quickly, a phenomenon designated as the triple negative paradox. Throughout this article, current indications and possible future development to a potentially new indication is outlined.

Implementation of chemotherapy with the drug temozolomide increased the overall survival of patients with glioblastoma multiforme (GBM; WHO grade IV), in particular when the O(6)-methylguanine DNA methyltransferase (MGMT) promoter is epigenetically silenced. Nevertheless, the prognosis remains poor, and relapse in GBM occurs regularly. This clinical behavior seems to be due to the existence of a therapy-resistant subpopulation of cells that induce tumor regrowth. The objective of this work was to analyze the role of aldehyde dehydrogenase (ALDH) 1A1 in mediating temozolomide resistance and its value as a predictor of clinical outcome in GBM patients. Nine GBM cell lines were treated with temozolomide alone or in combination with 4-diethylaminobenzaldehyde (DEAB), an inhibitor of ALDH1A1, or with ALDH1A1 short hairpin (sh)RNA. ALDH1A1 expression and MGMT status of 70 primary GBM patients were correlated with median survival. ALDH1A1 overexpression predicted temozolomide resistance in vitro. Sensitivity of ALDH1A1 positive/MGMT-positive cells to temozolomide could be restored by inhibition of ALDH1A1 by DEAB or by knockdown with shRNA, as indicated by increased cytotoxicity, reduced clonogenicity, and accumulation in the G2/M cell-cycle phase. The prognosis of patients with a high level of ALDH1A1 expression was poor compared with that of patients with low levels (P < .0001). ALDH1A1 is a new mediator for resistance of GBM to temozolomide and a reliable predictor of clinical outcome and may serve as a potential target to improve treatment of human GBM.

Precise knowledge about the chance of success of a given pharmacologic therapy of head and neck squamous cell carcinoma (HNSCC) before starting therapy would be very desirable to guide the selection of the most suitable or the most efficient combination out of the ever-growing spectrum of available pharmaceuticals. This selection has hitherto been made at best on the basis of the availability of guideline-conformant and approved combinations according to results of published clinical studies and approved general effectiveness in HNSCC. However, the inhomogeneous biology of HNSCC depending on localization, varying metastatic behavior, TNM and UICC stage in the context of the patient's general condition and risk status according to lifestyle and occupational exposure make it impossible to accurately predict the success of pharmacological therapy regimens for the individual HNSCC based on today's clinical and pathohistological diagnostics. A solution may lie in the testing of biopsy specimens ex vivo before starting therapy. The present review describes recent advances in ex-vivo tests and discusses the requirements for their inclusion in the decision-making process.

Reliable prediction of the chance of a successful treatment of head and neck squamous cell carcinoma by cytostatics and targeting therapies would be very valuable, since HNSCC due to their heterogenic biology mostly respond non-uniformly and moreover with low response rates. To raise the prospect of chemotherapy by using multimodal therapies usually goes hand in hand with a higher incidence of severe adverse events and acute toxicity but also chemo-associated increased cancer risk following successful treatment. In addition, the increasing numbers of treatment options without availability of reliable prognostic biomarkers for a probably successful outcome make the decision for one or the other medication to something rather like gambling. Therefore, quite early a pre-therapeutic predictive exvivo chemoresponse testing of bioptic specimens was intended. However, the results gained mostly were disillusioning and allowed not for reliable prediction of chance of successful outcome of treatment with tolerable doses of the pharmaceuticals and in particular their combinations. Predictive testing, hence, was belittled as improper for the clinical context. Based on advanced methods, some working groups reassume this subject. This review describes recent advances in ex-vivo chemoresponse testing, discusses pre-requisites which have to be fulfilled before their inclusion into decision-making, and outlines why ex-vivo chemoresponse testing probably is not an old hat.

Our understanding of - as well as our approach to - castration resistant prostate cancer is currently undergoing major changes. New drugs like the CYP-17 inhibitor abiraterone have shown that even in the "hormone refractory" stage the progression of prostate cancer is still driven by signaling of the androgen receptor. Changing the term to castration resistant prostate cancer is one consequence of these new insights. Here we give an overview on the current situation of drug development, therapeutic consequences and future trends.

While the activity of tyrosine kinase inhibitors as the first line treatment for primary tumors in patients with stage IV non-small cell lung cancer and a positive EGF receptor mutation is well known, little data on the efficacy in controlling cerebral metastases are available.A 43-year-old woman was diagnosed with non-small cell lung cancer with cerebral and hepatic metastases. Emergency radiation therapy was initiated at the time of diagnosis due to superior vena cava syndrome. However, after she failed to respond to this therapy and in light of a positive EGF receptor mutation, gefitinib was added at a dose of 250 mg/day while continuing radiation to the primary lesion and cervical lymph nodes. She showed a rapid clinical and radiologic response with complete remission of the cerebral metastases 6 weeks after starting gefitinib. No severe toxicity was observed.This case demonstrates that gefitinib can be given during radiation treatment without significant toxicity. Furthermore, complete remission of cerebral metastases can be achieved with tyrosine kinase inhibitor monotherapy.

Survival of patients with chronic myeloid leukemia (CML) has dramatically improved with the introduction of the BCR-ABL-specific tyrosine kinase inhibitor imatinib. As a rule patients on therapy with imatinib achieve permanent complete cytogenetic and molecular remission. Patients who are primarily refractive to imatinib or lose remission achieved using imatinib are in the minority. This group has a poor prognosis. This article gives a transparent review of the diagnostics necessary when CML is primarily diagnosed and for assessment of the response during the course of the therapy. The guidelines developed for this procedure by the European leukemia network on the type and frequency of surveillance controls as well as the diagnostic criteria for imatinib resistance or suboptimal response will be presented. The indications for allogenic stem cell transplantation and the administration of second generation BCR-ABL inhibitors will be discussed as therapeutic alternatives in cases of imatinib failure in a stage-specific manner. Finally a view on therapy targets and forms of future first-line therapy of CML will be given.

peerReviewed

Unlike conventional systemic chemotherapies, the aim of targeted therapeutic approaches is not to address general mechanisms involved in cellular replication. In contrast, they aim at such regulatory pathways that have been identified to be involved in the progression of human malignant disease. Whereas the application of targeted therapeutic modalities is well established for the treatment of metastatic renal cell cancer, only very few data on their clinical efficacy during the treatment of other urological tumours such as prostate and bladder cancer are currently available. The aim of this paper is to reflect on the current status regarding the relevance of targeted therapeutic approaches during the treatment of urological cancers of different origin.

The application of angiogenesis inhibitors in neurooncology is increasing. Initially, these drugs seemed to be very promising because of the surprisingly high neuroradiological response rates that were observed in first clinical trials. Meanwhile, this enthusiasm is waning, as the high response rates did not translate into substantial improvements in progression-free and overall survival. Tumor progression during or after antiangiogenic therapy is often associated with rapid clinical neurological deterioration and sometimes even with diffuse infiltrative gliomatosis-like neuroradiological phenotypes. Thus, the characterization and understanding of escape mechanisms are needed. The identification of criteria for defining the personalized use of angiogenesis inhibitors remains a challenge.

In spite of intensive research and a huge amount of chemotherapy trials, the prognosis of metastastic non-small cell lung cancer (NSCLC) is still poor. Erlotinib and Gefitinb are tyrosine kinase inhibitors (TKIs) which act against the EGF receptor (EGF-R). Activation of mutations in the tyrosine kinase domain leads to an increase in effectiveness. What is the clinical impact of EGF-R mutation screening? What value do TKIs in 1st, 2nd and 3rd line have in therapy for metastatic NSCLC? Which treatment options exist after failure of TKI in the 1st line? These and other clinically relevant questions in the context of TKIs are discussed in the present comprehensive review.

Biological features of tumor cells relevant to progression, metastasis, and prognosis in cancer patients have been investigated for many years. During the past few years, the concept of tumor stem cells has gained widespread acceptance. The cancer stem cell (CSC) model is based on the observation that continuous growth of tumors depends on a small population of immature neoplastic cells with unlimited proliferative potential. In contrast to these CSC, more mature clonal cells in the same neoplasm undergo apoptosis and die after a variable number of cell divisions. The self-renewal capacity of CSC plays a central role in this scenario and enables permanent tumor cell repopulation in vivo in patients as well as in experimental animals, e.g., immunodeficient mice. Based on the stem cell concept, it is clear that the success of an anti-neoplastic approach depends on efficient targeting and elimination of CSC. An important aspect of CSC is their intrinsic resistance against conventional drugs. Therefore, a major focus in current research is molecular targets and their expression in CSC, with the goal to use targeted drugs for CSC elimination. It is the hope for the future that therapeutic approaches involving CSC-targeting concepts will lead to sustained remission and thus improvement of prognosis in leukemia and cancer patients.

Lung cancer is the most common tumor-related cause of death in western industrialized countries, despite continuous improvement in both diagnostic and therapeutic approaches. Since epidermal growth factor receptor (EGFR) is overexpressed in 80% of cases of non-small cell lung carcinoma, mediating important carcinogenic properties such as cell-cycle progression, apoptosis, angiogenesis and metastasis, it is considered a relevant target in novel specific therapies. This has lead to the development of the low-molecular EGFR tyrosine kinase inhibitors (EGFR-TKI) Gefitinib and Erlotinib. Predicting which patients will respond to an EGFR-targeted therapy is of particular clinical interest. Recent studies show a significantly better response and prolonged progression-free survival in patients with EGFR-mutated tumors, even when used as first-line therapy. Moreover, genetic mutations which correlate to primary EGFR-TKI resistance (e.g. KRAS) or produce secondary resistance to known TKI (e.g. EGFR mutation T790 M or MET amplification) have meanwhile been explained. Predictive diagnosis of these mutations using histological material is becoming increasingly important for patient stratification and will soon be indispensable not only for lung cancer.

Pathological diagnosis is essential today for the individualized therapy of colorectal cancer. In the routine analysis of colorectal carcinomas the molecular-pathological detection of a KRAS mutation predicts unresponsiveness to EGFR-targeted antibody therapies. Moreover, the detection of mismatch-repair deficiency or high-degree microsatellite instability indicates unresponsiveness to 5-FU monotherapy. Colorectal carcinomas with high-grade microsatellite instability and their associated morphologic subtypes, such as the medullary carcinoma, exhibit a low risk of distant metastasis and might be considered as carcinomas with low need for adjuvant chemotherapy.

Androgen withdrawal or surgical castration remains the standard therapy for advanced prostate cancer disease. Even for castration-resistant prostate cancer the therapeutic option of docetaxel-based chemotherapy is well studied and defined. Facing disease progression after docetaxel-based therapy there are multiple options to continue therapy but the evidence level is rather poor. In the last few years targeted therapy and immunomodulation have been the focus of clinical trials. The presented manuscript intends to provide an overview of classical cytostatic agents, endothelin inhibitors, immunotherapy, modified hormone therapy, multikinase inhibitors and radionuclide approaches which are currently under investigation for implementation in the clinical setting.

Formation of cancer stem cells which are both rare and variably therapy-resistant marks the beginning of a new disease without precursors. Based on molecular changes, these cells are derived from normal cells and exhibit pre-programmed malignant behaviour. In vitro studies have shown that hybrid cancers which behave in a similar way to Dukes A, B or C cancers in vivo can be produce by horizontal gene transfer. The level of aggressiveness follows a Galton curve in the probability distribution. In the current paper we analyzed colorectal cancers by PET-CT in follow-up studies which extended over several years. We conclude that the primary tumors behave differently from distant metastases. Radical exstirpation of the primary tumor is able to cure the malignant process if the homing area is resected. The primary tumor acts as the supplier of cancer stem cells for metastases which appear in different organs. When chemotherapy is administered the distribution of metastases in different organs appears dependent of the response or non-response of cancer stem cells to this therapy. Large numbers of colorectal carcinomas existed for the same time duration before death (15 years) independent of the malignancy grade. The tumor metastasizes immediately after formation. The primary tumor and the metastases appear variably quickly depending on the malignancy grade and are autonomic processes.

Interdisciplinary management is required in the therapy of gastrointestinal stromal tumors, in consideration of complex strategies in the treatment of patients with GIST. Endoscopy, histopathology - mutation analysis included - but also radio diagnostic, surgery and oncology are topics in treating patients suffering from GIST. Especially in cases of advanced gastrointestinal stromal tumor or metastatic disease our multidisciplinary knowledge is required, because information about these entities are rather rare.

In locally advanced inoperable patients and metastatic patients imatinib is a standard treatment. Standard dose of imatinib is 400 mg daily. Treatment should be continued indefinitely, since treatment interruption is generally followed by relatively rapid tumor progression in virtually all patients. Dose intensity should be maintained by adequate management of side effects and a correct policy of dose reductions and interruptions in the case of excessive toxicity. The standard approach in the case of tumor progression is to increase the imatinib dose to 800 mg daily with special attention to the occurrence of side effects. Patient non-compliance should be ruled out as a possible cause of tumor progression as well as drug interactions with concomitant medications. In case of progression or intolerance to imatinib standard second-line treatment is sunitinib. The drug was approved effective in terms of progression-free survival according to a 4 weeks on and 2 weeks off regimen. Preliminary data show that a continuous regimen with lower daily dose may be equally effective but possibly better tolerated. After failing on sunitinib, the patient should be considered for participation in a clinical trial of new therapeutic agents or combinations such as tyrosine-kinase inhibitors (e.g., nilotinib), sorafenib, or inhibitors of the mTOR (mammalian target of rapamycin)-pathway.

This article offers a review about the current facts of chemotherapy in testicular cancer. Besides a short presentation of the guideline-standard therapy the authors deal with the question as to why testicular cancer shows an extraordinarily high chemosensibility compared to other tumours. Furthermore, the current data on alternative chemotherapies as well as of molecular, molecular-genetic and pharmacogenetic therapeutic concepts are explored. Data were obtained from researches in Medline of the Pubmed database.