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The EML4-ALK pathway plays an important role in a significant subset of non-small cell lung cancer patients. Treatment options such as ALK tyrosine kinase inhibitors lead to improved progression free survival and overall survival. These therapeutic options are chosen on the basis of the identification of the underlying genetic signature of the EML-ALK translocation. Efficient and easily accessible testing tools are required to identify eligible patients in a timely fashion. While FISH techniques are commonly used to detect this translocation, the broad implementation of this type of ALK testing into routine diagnostics is not optimal due to technical, structural and financial reasons. Immunohistochemical techniques to screen for EML4-ALK translocations may therefore play an important role in the near future. This consensus paper provides recommendations for the test algorithm and quality of the respective test approaches, which are discussed in the light of the current literature.

Assessment of several clinical factors on progression-free (PFS) and overall survival (OS) in NSCLC patients (pts.) (stage IV) with mutated epidermal growth factor receptor (EGFRm+) treated with gefitinib (gef) or with chemotherapy (CT) under real-world conditions.285 EGFRm+ pts. of the non-interventional REASON study treated with gef (n = 206) or CT (n = 79) as first-line therapy or with gef (n = 213) or CT (n = 61) in any line throughout the course of therapy were analyzed according to age, gender, smoking history and histology.Compared with CT, patients treated with gef showed prolongation of PFS and OS in all subgroups. PFS was significantly increased in women and non-smokers. OS was significantly increased in women, non-smokers, (ex)-smokers, patients with adenocarcinoma and elderly patients when treated with gef compared to CT. Female gender turned out to be an independent positive predictive factor for OS in patients treated with gef (HRmale: 1.74, p = 0.0009).A clinical benefit of gef was shown for all analyzed clinical subgroups of EGFRm+ pts. This was confirmed for the female gender in a multivariate analysis.

To analyze the influence of the localization of mutations in the epidermal growth factor receptor (EGFR) gene on progression-free (PFS) and overall survival (OS) in patients (pts) with locally advanced or metastatic non-small cell lung cancer (NSCLC) treated with gefitinib (gef) or chemotherapy (CT) under real world conditions within the REASON study.Subgroups of pts with mutations in exon 19 (n = 141), 18/20 (n = 43), and 21 (n = 104) were analyzed for PFS and OS according to gef or CT treatment and compared using the log-rank test.Pts with mutations in exon 19 and 18/20 treated with gef as first line therapy showed increased PFS and OS compared to CT. This increase was statistically significant in pts with exon 19 mutation (11.3 vs. 6.5 months), but was not found in pts with exon 21 mutation (9.1 vs. 9.3 months). Also, OS was significantly increased in patients with mutation in exon 19 treated with gef ever over all treatment lines compared to CT (21.8 vs. 10.6 months), whereas this was not found in pts with mutation in exon 21 (14.1 vs. 13.9 months).Localization and nature of EGFR mutations influences gefitinib treatment outcomes under routine conditions and should therefore be analyzed in detail.

Valid HER2 testing is essential for the optimal care of patients with HER2-positive gastric cancer and the correct use of first-line treatment. Although all cases of breast cancer are routinely tested for the HER2 status, HER2 testing in gastric cancer has still not become part of the routine and is usually only done upon request by the therapist. An interdisciplinary group of German experts has taken on the challenges of HER2 testing in gastric cancer as an opportunity to address essential aspects and questions on the practical use of HER2 testing in this indication from the perspective of pathologists and therapists. The recommendations made in this article reflect the consensus of all participants and correspond to their opinions and long-term experience.

The EML4-ALK pathway plays an important role in a significant subset of non-small cell lung cancer patients. Treatment options such as tyrosine kinase inhibitors directed against the EML4-ALK signalling pathway lead to improved progression free and overall survival. These therapeutic options are chosen on the basis of the identification of the underlying genetic signature of the EML-ALK translocation. Efficient and easily accessible testing tools are required to identify the patients in time. While FISH techniques have been implemented to characterize this translocation for some time, the implementation of this testing is hampered by its broad use of resources. Immunohistochemical techniques to identify and screen for EML4-ALK translocations may play an important role in the near future. This consensus paper offers recommendations of the sequence and quality of the respective test approaches which are validated on the basis of the current literature.

Six seated tests were evaluated in the laboratory to determine whether they would be feasible for use on the water as sobriety tests to measure impairment from alcohol at blood alcohol concentrations (BACs) of >0.08%. The standardized field sobriety tests (SFSTs) currently used at roadside are not suitable for the marine environment; marine law enforcement officers are left with insufficient methods to assess impairment on the water. One hundred fifty-seven participants were randomly assigned to a BAC group: 0.00%, 0.04%, 0.08%, and 0.12%. Six tests were administered to the participants by experienced law enforcement officers. Neither the testers nor the participants were privy to the participants' BACs. A variable called BAC status (N = 138) was obtained by dividing the average BAC into two groups: BAC < 0.08% and BAC ≥ 0.08%. A combination of four tests—horizontal gaze nystagmus (HGN), finger to nose (FTN), palm pat (PP), and hand coordination (HC)—correctly classified 82% of the BACs ≥0.08% and 67% of the BACs

Deprotonation of Ap*pyH {Ap*pyH = (6-methylpyridin-2-yl)-[6-(2,4,6-triisopropylphenyl)-pyridin-2-yl]-amine} using KH leads to Ap*pyK which undergoes a clean salt metathesis reaction with [YbI 2 (thf) 4 ] and [EuI 2 (thf) 4 ] in THF forming [Yb 2 (Ap*py) 3 I(thf)] and [Eu 2 (Ap*py) 3 I(thf)], respectively. The two Yb II centers in [Yb 2 (Ap*py) 3 I(thf)] are in close proximity and chemically different. Thus, an f-block-element-f-block-element coupling pattern was observed. The low-field 171 Yb signal consists of a central singlet and two satellites with integral intensities of about 7 % each. This 14 % approximately corresponds to the natural abundance of the 171 Yb isotope and was assigned as a doublet arising from 1 J( 171 Yb, 171 Yb) spin-spin coupling with a magnitude of 76.1 Hz. The 151 Eu Mossbauer spectrum of [Eu 2 (Ap*py) 3 I(thf)] recorded at 77 K shows an isomer shift (δ) of -11.9(1) mm/s with an experimental line width (Γ) of 6.9(1) mm/s. This line width is extremely large and results from an overlap of the signals from both crystallographically independent europium sites. The reaction of [Yb2(Ap*py) 3 I(thf)] with Ap*pyK leads to [Yb 2 (Ap*py) 4 -(thf) 2 ]. In the reactions of [Yb 2 (Ap*py) 3 I(thf)] with azidotri-methylsilane and sulfur the rearrangement products [Yb 2 -(Ap*py) 3 I 2 ] and [Yb 2 (Ap*py) 3 I 3 ] were obtained, respectively. Treating [Yb 2 (Ap*py) 3 I(thf)] with NaN(SiMe 3 ) 2 afforded homoleptic "ate" complex Na 2 [Yb(Ap*py) 4 ]. A mixed silyl-amide dipyridylamide complex was obtained in the reaction of NaYb[N(SiMe 3 ) 2 ] 3 with Ap*pyH. All complexes - three of which are paramagnetic - were characterized by X-ray crystal structure analysis.

Since the introduction of target-oriented anticancer therapies, clinical pathology has begun to play an increasingly significant role in the selection of antineoplastic drugs. This holds especially true for the use of therapeutic antibodies in the treatment of solid and hematological tumors as well as the selection of specific kinase inhibitors, utilizing so-called small molecules, for the treatment of lung cancer or gastrointestinal stromal tumors. The introduction of various immunological methods, the use of molecular biology for diagnosis, and the adaptation of these methods to the specifics of tissue-based diagnostics has resulted in tumor tissue being increasingly investigated using systematic immunophenotyping or molecular analysis during pathological routine diagnostics. This multimodal approach is regarded as the new standard for various tumor entities and is likely to be expanded to include additional tumor types and special patient-oriented issues. This gives rise to the fascinating possibility of determining predictive biomarkers in addition to the existing diagnostic spectrum in clinical pathology, providing the clinical oncologist with additional therapeutically relevant data, such as a prediction of drug response and/or the probability of metastases, etc.

An in-vitro test was developed for predicting the efficacy of anti-tumour chemotherapy. Cell cultures were grown from freshly removed tumours and it was then demonstrated by DNA cytophotometry and immuno-cyto-chemistry whether the growing tumour cells corresponded to those of the original tumour cells. Several cytostatic agents were then tested for their efficacy of inhibiting growth at clinically customary dosage. Growing cell cultures were established in 306 of 413 submitted tumours (74%). They responded quite differently to the various drugs that were tried. The clinical course in 94 cases was observed for minimally four and a mean of eight months to obtain an in-vitro to in-vivo correlation of response, with 178 individual correlations. A discrepancy was recorded in 16% of cases, a false-positive in-vitro sensitivity result was 3.6 times more frequently associated with an in vivo resistance than the reverse. Concordance between test results and clinical tumour response occurred in 84%. The monolayer proliferation assay correctly indicated resistance in 93.8%, sensitivity in 72.8%.

This is a report on the synthesis and structure of novel dinuclear YbII complexes. In one of the described compounds, the two YbII centres are in close proximity and chemically different. Thus, an f-block-element–f-block-element coupling pattern was observed. The low-field 171Yb signal consists of a central singlet and two satellites with integral intensities of about 7 % each. This 14 % approximately corresponds to the natural abundance of the 171Yb isotope and was assigned as a doublet arising from 1J(171Yb, 171Yb) spin–spin coupling with a magnitude of 76.1 Hz. Furthermore, the relevance of such studies in understanding dimer equilibria and the rearrangement chemistry of rather bulky structural ensembles is discussed.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Gene expression arrays are currently used to guide therapy decisions in breast cancer. The indications for gene expression tests are especially important in the group of hormone receptor negative, HER2 positive tumors to decide whether endocrine therapy alone is sufficient or additional chemotherapy is necessary. In this group of luminal tumors conventional clinicopathological parameters are often not suitable to select patients who would benefit from an endocrine therapy alone. Gene expression tests can provide additional information and, therefore, support decision-making and avoid unnecessary chemotherapy. There are a variety of test systems available which poses the questions of which tests should be selected for which patients and how the test results should be evaluated in a direct comparison. This report provides information about three currently available gene expression tests (i.e. OncotypeDx®, Endopredict® and PAM50/Prosigna®), comments on similarities and differences and discusses the impact on therapy decisions. The focus of this article is on a discussion of clinical studies that have compared the different molecular tests in the same clinical study cohort. These investigations allow a first comparative evaluation of the various assays for breast cancer.

Hormone replacement therapy (HRT) has gained widespread and in some areas indiscriminate use. In reference to recent epidemiological studies which showed unexpected and controversial associations of HRT use with malignant tumours, here we review the current understanding of the dynamics of tumour growth. The pathomorphological characteristics and sex hormone sensitivity of cancers of the breast, endometrium, ovary and colon are discussed. The development of cancer from the first malignant tumour cell to clinical diagnosis takes many years. Hormones can influence tumour growth, but it is questionable whether hormones induce malignant tumours de novo. It is much more likely that hormones 'merely' promote the growth of already existing tumour cells. The long developmental process of tumours is in apparent contradiction to results of some epidemiological studies that describe an increased cancer risk, implying primary initiation, in HRT users within observation periods of 1-6 years. The mechanisms of initiation versus promotion of hormone-sensitive cancers, particularly breast cancer, are only partly understood. The conventional methods of epidemiological studies cannot detect potential risk factors without bias if they do not include a pathomorphological component on growth characteristics. The results of previous studies should be interpreted with great caution with regard to tumour biology.

Warthin tumors (cystadenolymphoma, cystadenoma lymphomatosum papilliferum) account for approximately 10-15 % of all benign salivary gland tumors and are bilateral in approximately 10-15 %, as well as extraparotideal in approximately 8 % of cases. Nasopharyngeal Warthin tumors are extremely rare; however they should be borne in mind as a consideration of differential diagnostics. Furthermore, parotid glands and cervical lymph nodes should be examined as associated synchronous or metachronous manifestations are possible. Palpation, sonography and other radiological imaging of the cervical region, if applicable, might be required.

Cancer medicine relies on the paradigm that cancer is an organ- and tissue-specific disease, which is the basis for classifying tumors. With the extensive genomic information now available on tumors it is possible to conduct analyses to reveal common genetic features across cancer types and to explore whether the established anatomy-based tumor classification is actually reflected on the genetic level, which might provide important guides to new therapeutic directions. Here, we have conducted an extensive analysis of the genetic similarity of tumors from 14 major cancer entities using somatic mutation data from 4,796 cases available through The Cancer Genome Atlas (TCGA) based on all available genes as well as different cancer-related gene sets. Our analysis provides a systematic account of the genetic similarity network for major cancer types and shows that in about 43% of the cases on average, tumors of a particular anatomic site are genetically more similar to tumors from different organs and tissues (trans-similarity) than to tumors of the same origin (self-similarity). The observed similarities exist not only for carcinomas from different sites but are also present among neoplasms from different tissue origin, such as melanoma, acute myeloid leukemia, and glioblastoma. The current WHO cancer classification is therefore reflected on the genetic level by only about 57% of the tumors. These results provide a rationale to reconsider organ- and tissue-specificity in cancer and contribute to the discussion about whether personalized therapies targeting specific genetic alterations may be transferred to cancers from other anatomic sites with similar genetic properties.

Die klinische Pathologie hat in den vergangenen Jahren zahlreiche Methoden der Molekularbiologie an die wissenschaftlichen und diagnostischen Fragestellungen des Fachgebietes adaptiert*. Nach der Einfuhrung der Immunhistologie vor etwa 20 Jahren, die zur Immunphanotypisierung der Gewebsveranderungen fuhrte und heute als Standard anzusehen ist, stellt die Molekularpathologie einen weiteren “Quantensprung” in der Entwicklung der pathologischen Diagnostik dar. So konnen in der Infektionsdiagnostik Bakterien, Viren oder andere Erreger spezifisch und mit hoher Empfindlichkeit in Gewebeproben nachgewiesen und genotypisch charakterisiert werden. Hieraus resultiert, insbesondere auch fur Fragen aus der Gynakopathologie, die Moglichkeit eines erheblich erweiterten Diagnosespektrums in der klinischen Pathologie.

A survey is presented on various reactions of Cp * V(CO) 4 , including CO ligand substitution and/or oxidative decarbonylation, to give complexes in which the formal oxidation state of vanadium may vary from 0 to V. Diamagnetic Cp * V complexes can be rapidly and conveniently characterized by 51 V NMR spectroscopy.

The basic structure of the new (1999) WHO classification of ovarian tumors differs only slightly from that of the previous (1973) system. The impact of new research findings is limited, particularly regarding epithelial borderline tumors (tumors of low malignant potential), so that this diagnostic gray zone persists. The new classification has added a large number of rare and sometimes imprecisely defined tumors. For example, the very extensive subclassifications of certain groups of tumors (for example, nine types of monodermal teratomas) is not conducive to clarity or reproducibility and of questionable clinical relevance. Immunohistochemical methods and molecular pathology could have contributed to a clearer and in some cases more precise classification. Nonetheless the new WHO classification should be used as the international standard.

BACKGROUND: While cigarette smoking and chronic alcohol consumption are the major risk factors for the development of head and neck cancer, it is assumed that genetic factors contribute to risk. MATERIAL AND METHODS: We examined genotype frequencies from leukocyte DNA of 269 laryngeal cancer patients, 123 pharyngeal cancer patients and 216 controls. Polymorphisms at different glutathione-S-transferase (GST) gene loci were investigated. Losses of heterozygosity (LOH) at 12 different chromosomal gene loci were determined in 37 of the study patients by comparing blood and tumor cell DNA. The relationship between high risk genotypes and the occurrence of LOH was investigated. RESULTS: Glutathione-S-transferase high risk genotypes were identified at the first and third genes of the M family (GSTM1, GSTM3) and the first gene of the P family (GSTP1). These high risk genotypes are seen to have a statistically significant influence on the occurrence of LOH in the tumor tissue. CONCLUSION: There is evidence that the polymorphisms studied play a role in the carcinogenic process by influencing the chromosomal fragility which may lead to the inactivation of tumor suppressor genes or the activation of oncogenes.

AIMS Adenocarcinomas account for about 60% of metastatic cancers of unknown primary (CUP) site. In such a clinical CUP situation, histopathologists are challenged to differentiate renal cell carcinomas (RCC) from other adenocarcinomas with similar immunophenotypes, especially chemotherapeutically treatable mammary and ovarian carcinomas. METHODS AND RESULTS Recently, we produced a monoclonal antibody (mAb), designated 138H11, against human gamma-glutamyl-transferase (gamma GT), which stained over 98% primary clear cell and chromophilic RCC on frozen sections. The 138H11 epitope could not be stained using conventional techniques in most paraffin-embedded sections of the same origin, due to destruction by formalin fixation below the detection level. Here, we demonstrate that mAb 138H11 can specifically stain gamma GT in paraffin-embedded primary and metastatic RCC after enhancement with an ultrasensitive immunohistochemical method. We analysed a selected subgroup of adenocarcinomas with immunophenotypes which would not allow a differentiation from RCC in a CUP situation. We found a predominantly membranous expression of the 138H11 target antigen in 26/51 primary RCC and 15/ 34 metastatic RCC. In contrast, all 43/43 primary ovarian and bronchial carcinomas as well as 54/54 metastases of ovarian, mammary, bronchial and gastric carcinomas were negative for mAb 138H11. CONCLUSIONS The data suggest that mAb 138H11 is useful for the immunohistochemical differentiation of RCC from other metastatic adenocarcinomas if the primary site of the tumour is not known.

Optimal management of breast cancer patients is based on efficient multidisciplinary cooperation. The role of pathologists is to survey those parameters that are crucial for the individually adopted therapy. Thereby, distinct quality criteria have to be considered concerning the handling of the tissue samples, including preparation and examination, as well as the analytical methods used. The interdisciplinary S3 guideline "Diagnosis, therapy and follow-up of breast cancer" includes recommendations concerning these aspects based on current evidence. Its third edition was published in July 2012. In this article an overview of the topics relevant for pathologists that have been modified in the latest edition is provided.

To test the possibility of immunohistochemical differentiation of cytostatically treatable metastatic breast carcinomas from other metastatic adenocarcinomas of unknown primary site, we studied a total of 328 metastatic adenocarcinomas including 35 bronchogenic, 26 pancreatic, 25 colonic, 39 gastric, 45 renal, 29 ovarian and 129 breast carcinomas with a panel of 13 commercially available monoclonal antibodies. The expression of gross cystic disease fluid protein 15 and/or oestrogen or progesterone receptors had a sensitivity of 0.83, a specificity of 0.93 and a predictive accuracy of 0.92 for carcinomas of the breast against all other carcinomas. Excluding ovarian carcinomas, this combination had a sensitivity, specificity and predictive accuracy for mammary carcinomas of 0.83, 0.98 and 0.98, respectively. Carcinoembryonic antigen and/or cytokeratin 20 identified bronchogenic, gastric, pancreatic and colorectal carcinomas versus breast carcinomas lacking gross cystic disease fluid protein 15 and oestrogen or progesterone receptors with a sensitivity, specificity and predictive accuracy of 0.82, 0.99 and 0.95, respectively. Vimentin differentiates renal cell carcinomas from gross cystic disease fluid protein 15 and oestrogene or progesterone receptor negative breast carcinomas with a sensitivity, specificity and predictive accuracy of 0.93, 0.82 and 0.84. Thus, it should be possible to differentiate most metastatic mammary carcinomas from metastatic adenocarcinomas of other common primary sites, even if the former lack expression of gross cystic disease fluid protein 15 and oestrogen or progesterone receptors.

Aims-To develop a protocol that is applicable to single strand conformation polymorphism (SSCP), direct sequencing and loss of heterozygosity analysis of DNA.Methods-The protocol is based on the detection of biotinylated DNA by a Streptavidin-alkaline phosphatase conjugate. Biotinylation of DNA was achieved by using 5'-end biotinylated primers for PCR. After polyacrylamide gel electrophoresis, the DNA fragments were transferred to a nylon membrane by contact blotting. Depending on the alkaline phosphatase substrate, DNA was visualised either colorimetrically or by chemiluminescence.Results-The method was verified by the identification and characterisation of p53 mutations by SSCP analysis and direct DNA sequencing, as well as the assessment of DNA loss in human lung carcinomas by microsatellite polymorphism allelotyping.Conclusions-The protocol is simple, does not require specialised equipment and would be particularly useful for laboratories with experience in Streptavidin-biotin methodology.

A major problem in cytostatic treatment of many tumours is the development of multidrug resistance (MDR4). This is most often accompanied by the overexpression of a membrane transport protein, P-glycoprotein, and its encoding mRNA. In order to reverse the resistant phenotype in cell cultures, we constructed a specific hammerhead ribozyme possessing catalytic activity that cleaves the 3'-end of the GUC sequence in codon 880 of the mdr1 mRNA. We demonstrated that the constructed ribozyme is able to cleave a reduced substrate mdr1 mRNA at the GUC position under physiological conditions in a cell-free system. A DNA sequence encoding the ribozyme gene was then incorporated into a mammalian expression vector (pH beta APr-1 neo) and transfected into the human pancreatic carcinoma cell line EPP85-181RDB, which is resistant to daunorubicin and expresses the MDR phenotype. The expressed ribozyme decreased the level of mdr1 mRNA expression, inhibited the formation of P-glycoprotein and reduced the cell's resistance to daunorubicin dramatically; this means that the resistant cells were 1,600-fold more resistant than the parental cell line (EPP85-181P), whereas those cell clones that showed ribozyme expression were only 5.3-fold more resistant than the parental cell line. Images Figure 1 Figure 3 Figure 2

Based on data from a large multicenter phase III trial (ToGA study) trastuzumab has very recently been approved by the EMEA for metastatic gastric cancer and adenocarcinoma of the gastro-esophageal junction. Only patients with tumors which over express Her2 as defined by IHC2+ and a confirmatory FISH+ result, or IHC 3+, determined by an accurate and validated assay are eligible for trastuzumab therapy. However, testing of Her2 status by immunohistochemistry (IHC) differs from breast cancer in core aspects: 1. IHC2+/3+ is scored even though membranous staining is incomplete if membrane staining is clearly detectable even at low magnification (2.5x/5x, 3+) or medium magnification (10x/20x, 2+). 2. Additionally, membrane staining at the appropriate intensity found in at least 10% of tumor cells is restricted to resection specimens. Evaluation of Her2 in situ hybridization (ISH) is similar to breast cancer with ratio values ofor =2.0 indicating Her2 gene amplification. Taking these modifications into account and defining the HER2 positive subgroup as IHC 3+ and IHC2+/FISH+, approximately 16% of gastric cancers are considered Her2 positive, affecting mainly tumor regions with intestinal (gland forming) type carcinoma. In contrast to breast cancer, up to one-third of gastric cancers show a heterogeneous Her2 status both at IHC and ISH levels which favors bright field ISH over FISH.

Although prostate cancer is of crucial impact as a common disease of men, numerous relationships remain unknown, particularly concerning its pathogenesis. A novel approach regarding the origin and development of prostate cancer is a phenomenon that has already been investigated in other human cancers: cancerogenesis due to chronic inflammation. Hence, the present review introduces the current state of research concerning the relationship between chronic prostatitis and prostate cancer. In addition to histological and biochemical features, the latest discoveries are discussed, including the relationship between the pathogenesis of prostate cancer and infection by the novel gammaretrovirus XMRV, similar to cervical cancer associated with HPV.

Five percent of cancer cases present as metastases. If the primary tumor cannot be identified after diagnostic workup, the disease is referred to as cancer of unknown primary (CUP) and is classified as C80.9 according to ICD-10. In Germany, CUP is among the ten most common causes of tumor-related death, with mortality similar to mortality in gastric or pancreatic cancer. Biopsies of the tumor manifestation are generally examined histopathologically and by immunohistochemistry (IHC). Gene expression profiling (GEP) is a new diagnostic technique that might further contribute to tumor specification.In a retrospective study, 43 CUP cases underwent central immunohistochemical review and centrally performed GEP using a classifier based on 495 genes. There was concordance between IHC, GEP and clinical picture in 54% of cases. In four cases, the combination of methods led to an unequivocal identification of the primary tumor.In conclusion, we regard detailed IHC workup and complementary GEP advisable for the purposes of targeted therapy, as well as to identify or exclude specific tumors in a CUP situation.

Chemotherapeutic agents have proven to be effective in the cure ofsome and the palliation of many human cancers. However, in the majority of lesions there develop tumor cell populations resistant to cytostatic drugs. This is considered to be one of the major causes of failure of clinical chemotherapy. Several mechanisms have been described by which the drug-insensitive tumor cells can resist the toxic agents, i.e. altered activity of cytoplasmic enzymes (e.g. 7-hydrofolatereductase, gluthatione-S-transferase, gluthatione-peroxidase, protein kinase C) (1, 3, 29, 32) and reduced intracellular drug toxification (2, 13), as well as stimulated DNA repair by altered activity of topoisomerase II, polymerase a or b and thymidylate synthase (19, 39, 45). Other mechanisms involve the overproduction of binding and transport proteins, e.g. Mr 170.000 P-glycoprotein, Mr 19.000 protein (34, 35, 42) combined with reduced net drug accumulation (16, 20), increased energy dependent efflux (24, 43) and gene amplification (6, 7, 17, 21, 22, 30, 36, 44). In addition, organelle-associated drug binding and extrusion by means of intracellular drug compartmentalization into vesicular structures have been described (4, 11, 14, 33, 40, 41). The development of acquired chemoresistance observed in vivo can be simulated in vitro by the incubation of tumor cells in stepwise enhanced concentration of cytostatic drugs. The associated changes of functional properties have been intensively studied using biochemical and molecular methods. However, morphological alterations of cellular structures in response to drug application have scarcely been investigated. The present paper summarizes some phenotypic and functional alterations due to cytostatic drug application in cell cultures of human carcinoma cell lines. In particular, differences of the morphologic appearance of sensitive vs. resistant cells are compared.

Lipoprotein(a), as an atherogenic particle, represents an independent risk factor for coronary heart disease. In the present study the morphological distribution of apoprotein (a) and apoprotein B within the arterial wall is described. Apoprotein B, a constituent of very low-density lipoprotein, low-density lipoprotein and lipoprotein(a) has previously been demonstrated in atheromatous lesions. Lipoprotein(a) possesses an additional protein, designated apoprotein (a). Autopsy material (n = 74) from the left coronary artery and from the thoracic aorta has been examined by means of immunohistochemistry and both apoprotein (a) and apoprotein B were detected, primarily associated with the extracellular matrix and accumulating in lesions in the arterial wall. The staining pattern for both antigens was almost always found to be congruent, suggesting that the detection of (a)-antigen has to be attributed at least in part to the presence of lipoprotein(a). It is concluded that both low-density lipoprotein and lipoprotein(a) have an important role in the pathogenesis of atherosclerosis.