Distinct galactofuranose antigens in the cell wall and culture supernatants as a means to differentiate Fusarium from Aspergillus species.

Detection of carbohydrate antigens is an important means for diagnosis of invasive fungal infections. For diagnosis of systemic Aspergillus infections, galactomannan is commonly used, the core antigenic structure of which consists of chains of several galactofuranose moieties. In this study, we provide evidence that Fusarium produces at least two distinct galactofuranose antigens: Smaller amounts of galactomannan and larger quantities of a novel antigen recognized by the monoclonal antibody AB135-8. In A. fumigatus, only minor amounts of the AB135-8 antigen are found in supernatants and in the apical regions of hyphae. A galactofuranose-deficient A. fumigatus mutant lacks the AB135-8 antigen, which strongly suggests that galactofuranose is an essential constituent of this antigen. Using a combination of AB135-8 and a galactomannan-specific antibody, we were able to unambiguously differentiate A. fumigatus and Fusarium hyphae in immunohistology. Moreover, since Fusarium releases the AB135-8 antigen, it appears to be a promising target antigen for a serological detection of Fusarium infections.

Microenvironment-induced CREPT expression by cancer-derived small extracellular vesicles primes field cancerization.

Rationale: Cancer local recurrence increases the mortality of patients, and might be caused by field cancerization, a pre-malignant alteration of normal epithelial cells. It has been suggested that cancer-derived small extracellular vesicles (CDEs) may contribute to field cancerization, but the underlying mechanisms remain poorly understood. In this study, we aim to identify the key regulatory factors within recipient cells under the instigation of CDEs. Methods: In vitro experiments were performed to demonstrate that CDEs promote the expression of CREPT in normal epithelial cells. TMT-based quantitative mass spectrometry was employed to investigate the proteomic differences between normal cells and tumor cells. Loss-of-function approaches by CRISPR-Cas9 system were used to assess the role of CREPT in CDEs-induced field cancerization. RNA-seq was performed to explore the genes regulated by CREPT during field cancerization. Results: CDEs promote field cancerization by inducing the expression of CREPT in non-malignant epithelial cells through activating the ERK signaling pathway. Intriguingly, CDEs failed to induce field cancerization when CREPT was deleted, highlighting the importance of CREPT. Transcriptomic analyses revealed that CDEs elicited inflammatory responses, primarily through activation of the TNF signaling pathway. CREPT, in turn, regulates the transduction of downstream signals of TNF by modulating the expression of TNFR2 and PI3K, thereby promoting inflammation-to-cancer transition. Conclusion: CREPT not only serves as a biomarker for field cancerization, but also emerges as a target for preventing the cancer local recurrence.

Methylated NEUROD1 promoter is a marker for chemosensitivity in breast cancer.

PURPOSE: Chemotherapy can be an integral component of the adjuvant management strategy for women with early stage breast cancer. To date, no tool is available to predict or monitor the efficacy of these therapies. The aim of this proof-of-principle study was to assess whether NEUROD1 DNA methylation is able to predict the response to neoadjuvant and adjuvant chemotherapy. EXPERIMENTAL DESIGN: Recently, we showed that NEUROD1 DNA is differentially methylated in neoplastic versus nonneoplastic breast tissue samples. In this study, we used MethyLight and analyzed NEUROD1 methylation in (a) 74 breast cancer tissue samples, (b) two independent sets of pretreatment core biopsies of 23 (training set) and 21 (test set) neoadjuvantly treated breast cancer patients, and (c) pretherapeutic and posttherapeutic serum samples from 107 breast cancer patients treated with adjuvant chemotherapy. RESULTS: High-grade tumors showed higher NEUROD1 methylation levels. Estrogen receptor-negative breast cancers with high NEUROD1 methylation were 10.8-fold more likely to respond with a complete pathologic response following neoadjuvant chemotherapy. Patients with positive serum pretreatment NEUROD1 methylation, which persisted after chemotherapy, indicated poor relapse-free and overall survival in univariate and multivariate analyses (relative risk for relapse, 6.2; 95% confidence interval, 1.6-24; P = 0.008, and relative risk for death, 14; 95% confidence interval, 1.6-120; P = 0.02). CONCLUSIONS: These data support the view that NEUROD1 methylation is a chemosensitivity marker in estrogen receptor-negative breast cancer.

EpCAM overexpression is associated with high-grade urothelial carcinoma in the renal pelvis.

BACKGROUND: EpCAM serves as an attractive target for immunotherapy due to its expression on the surface of most epithelial cancer cells. Urothelial carcinoma of the renal pelvis (RP-UC) comprises 2.4-4.6% of tumors of the lower urinary tract. To assess the expression of EpCAM in RP-UC a retrospective study was performed. PATIENTS AND METHODS: Tumor tissue from 42 patients with RP-UC was selected from the archives of the Institute of Pathology, Medical University of Innsbruck, Austria. EpCAM expression was demonstrated by immunohistochemistry using the mouse monoclonal antibody ESA. RESULTS: EpCAM overexpression was significantly associated with high grade and invasive behaviour (p = 0.014 and p = 0.029) and the presence of lymph node metastases (p = 0.031), but not with the extent of nodal involvement (p = 0.12). CONCLUSION: In RP-UC, EpCAM overexpression is associated with an aggressive tumor phenotype. The association of EpCAM overexpression with the presence of lymph node metastasis may be of prognostic and therapeutic relevance.

Immunosuppressive Therapy Improves Both Short- and Long-Term Prognosis in Patients With Virus-Negative Nonfulminant Inflammatory Cardiomyopathy.

BACKGROUND: Inflammatory cardiomyopathy (infl-CMP) is characterized by increased cardiac inflammation in the absence of viruses, ischemia, valvular disease, or other apparent causes. Studies addressing the efficacy of immunosuppressive therapy in patients with infl-CMP are sparse. This study retrospectively investigates whether immunosuppressive agents on top of heart failure therapy according to current guidelines improves cardiac function and long-term outcome in patients with infl-CMP. METHODS AND RESULTS: Within the Innsbruck and Maastricht Cardiomyopathy Registry, a total of 209 patients fulfilled the criteria for infl-CMP using endomyocardial biopsy (≥14 infiltrating inflammatory cells/mm2). A total of 110 (53%) patients received immunosuppressive therapy and 99 (47%) did not. To correct for potential selection bias, 1:1 propensity score matching was used on all significant baseline parameters, resulting in a total of 90 patients per group. Baseline characteristics did not significantly differ between both patient groups, reflecting optimal propensity score matching. After a median follow-up of 31 (15-47) months, immunosuppressive therapy resulted in an improved long-term outcome (eg, heart transplantation-free survival) as compared with standard heart failure therapy alone (Log-rank P=0.043; hazard ratio, 0.34 [95% CI, 0.17-0.92]) and in a significant larger increase of left ventricular ejection fraction after a mean of 12 months follow-up, as compared with patients receiving standard heart failure treatment only (12.2% versus 7.3%, respectively; P=0.036). CONCLUSIONS: To conclude, this study suggests that immunosuppressive therapy in infl-CMP patients results in an improved heart transplantation-free survival as compared with standard heart failure therapy alone, underscoring the urgent need for a large prospective multicenter trial.

Periacinar retraction clefting in proliferative prostatic atrophy and prostatic adenocarcinoma.

AIMS: To evaluate the presence and extent of periacinar retraction clefting in proliferative prostatic atrophy and carcinoma in radical prostatectomy specimens. METHODS: Atrophic foci and neoplastic glands were analysed in specimens from 50 patients who underwent radical prostatectomy. Analysed atrophic glands were classified in two main groups, proliferative atrophy (PA) and proliferative inflammatory atrophy (PIA); each group was subclassified into simple atrophy (SA) and postatrophic hyperplasia (PAH). According to the presence and extent of periacinar retraction clefting, atrophic and neoplastic glands were classified as: group 1, glands without clefts or with clefts affecting 50% of the circumference in <50% of examined glands; and group 3, glands with clefts that affected >50% of the circumference in >or=50% of examined glands. RESULTS: Forty-four (88.0%) atrophic foci were without periacinar clefts or clefts were present in less than half of the gland circumference (group 1). In 6 (12.0%), atrophic foci clefts affected >50% of gland circumference (groups 2 and 3). Forty-five (90.0%) carcinomas were with clefts which affected more than 50% of gland circumference (groups 2 and 3); and in five carcinomas only, clefts were not found or affected <50% of gland circumference (group 1). CONCLUSION: Results indicate that periacinar retraction clefting represents a reliable criterion in differential diagnosis between proliferative atrophy and carcinoma.

Circulating tumor-specific DNA: a marker for monitoring efficacy of adjuvant therapy in cancer patients.

Adjuvant systemic therapy (a strategy that targets potential disseminated tumor cells after complete removal of the tumor) has clearly improved survival of patients with cancer. To date, no tool is available to monitor efficacy of these therapies, unless distant metastases arise, a situation that unavoidably leads to death. We analyzed RASSF1A DNA methylation in pretherapeutic sera and serum samples collected 1 year after surgery from 148 patients with breast cancer who were receiving adjuvant tamoxifen; 19.6% and 22.3% of patients with breast cancer showed RASSF1A DNA methylation in their pretherapeutic and 1-year-after serum samples, respectively. RASSF1A methylation 1 year after primary surgery (and during adjuvant tamoxifen therapy) was an independent predictor of poor outcome, with a relative risk (95% confidence interval) for relapse of 5.1 (1.3-19.8) and for death of 6.9 (1.9-25.9). Measurement of serum DNA methylation allows adjuvant systemic treatment to be monitored for efficacy: disappearance of RASSF1A DNA methylation in serum throughout treatment with tamoxifen indicates a response, whereas persistence or new appearance means resistance to adjuvant tamoxifen treatment. It remains to be seen whether modifications made in adjuvant therapeutic strategies based on detection of circulating nucleic acids will improve survival as well as quality of life.

Hedgehog signaling in small-cell lung cancer: frequent in vivo but a rare event in vitro.

The hedgehog (HH) signaling pathway plays multiple roles during embryonic development and increasing evidence suggests that this embryonic pathway is involved in development and progression of several human cancers including those of the brain, skin, lung and gastrointestinal tract. To investigate HH signaling activity in small-cell lung cancer (SCLC), we have performed gene expression analysis on members of the HH pathway on a panel of 20 SCLC cell lines. Sonic hedgehog (SHH) expression was detected in only DMS79 and GLC16 and only DMS114 expressed detectable protein levels of GLI1, one of the key transcription factors of the pathway. Involvement of HH signaling in SCLC proliferation was investigated in a subset of cell lines using the HH signaling inhibitor cyclopamine or small interfering RNA (siRNA) against GLI1. Cells expressing GLI1 responded only weakly to both cyclopamine and RNA interference, suggesting that HH signaling plays only a minor role in the growth of SCLC cell lines. To investigate HH pathway activity in vivo, GLI1 immunohistochemistry was performed on SCLC tumors. Interestingly, GLI1 was expressed in most SCLC tumors studied, indicating that HH signaling is important for in vivo growth of SCLC but establishment of cell lines from SCLC tumors may lead to loss of expression of key HH pathway members. Thus, the data support the idea that the HH pathway may be a therapeutic target in SCLC. However, the data also suggest that the SCLC cells can circumvent the apparent in vivo requirement of HH signaling.

Clinical evaluation of a Mucorales-specific real-time PCR assay in tissue and serum samples.

Molecular diagnostic assays can accelerate the diagnosis of fungal infections and subsequently improve patient outcomes. In particular, the detection of infections due to Mucorales is still challenging for laboratories and physicians. The aim of this study was to evaluate a probe-based Mucorales-specific real-time PCR assay (Muc18S) using tissue and serum samples from patients suffering from invasive mucormycosis (IMM). This assay can detect a broad range of clinically relevant Mucorales species and can be used to complement existing diagnostic tests or to screen high-risk patients. An advantage of the Muc18S assay is that it exclusively detects Mucorales species allowing the diagnosis of Mucorales DNA without sequencing within a few hours. In paraffin-embedded tissue samples this PCR-based method allowed rapid identification of Mucorales in comparison with standard methods and showed 91 % sensitivity in the IMM tissue samples. We also evaluated serum samples, an easily accessible material, from patients at risk from IMM. Mucorales DNA was detected in all patients with probable/proven IMM (100 %) and in 29 % of the possible cases. Detection of IMM in serum could enable an earlier diagnosis (up to 21 days) than current methods including tissue samples, which were gained mainly post-mortem. A screening strategy for high-risk patients, which would enable targeted treatment to improve patient outcomes, is therefore possible.

Treatment of patients with refractory metastatic cancer according to molecular profiling on tumor tissue in the clinical routine: an interim-analysis of the ONCO-T-PROFILE project.

INTRODUCTION: Patients with refractory metastatic cancer have been shown to benefit from molecular profiling of tumor tissue. The ONCO-T-PROFILE project was launched in March 2014 at the Innsbruck Medical University. Within 2 years our project aims to recruit 110 patients with stage IV cancer refractory to standard therapy. Our data presented here are based on an interim-analysis. METHODS: Tumor tissue specimens were submitted for molecular profiling to the certified laboratory (Caris Life Science, USA). Druggable tumor targets were selected based on biomarker status to agents with potential clinical benefit. Clinical benefit was defined as a PFS ratio (=PFS upon treatment according to the molecular profile/ PFS upon the last prior therapy) ≥ 1.3. RESULTS: As of April 2015, tumors from 50 patients have been molecularly profiled and one or more targets were detectable in 48 specimens (98%). So far, 19 (38%) patients have been treated according to their molecular tumor profile. To date, 8 (42%) patients have reached a PFS ratio of ≥ 1.3. CONCLUSIONS: We could show that molecular profiling is feasible in the clinical routine. A proportion of patients might benefit from an individualized treatment approach based on molecular profiling. As a result, we will proceed to enroll patients in ONCO-T-PROFILE.

Tetranectin in cerebrospinal fluid: biochemical characterisation and evidence of intrathecal synthesis or selective uptake into CSF.

BACKGROUND: Tetranectin (TN) is a 67 kDa glycoprotein thought to play a prominent role in the regulation of proteolytic processes via its binding to plasminogen and indirect activation of plasminogen. The TN concentration in serum is approximately 10 mg/l and is reduced in patients with several cancers. The TN concentration in the normal CSF has not been examined. METHODS: The TN concentration in the serum and CSF of 47 normal subjects without neurological disorders was established using a polyclonal sandwich ELISA. RESULTS: The median TN concentration (quartile range) was 10.8 mg/l (9.0-12.1) in serum and 0.43 mg/l (0.3-0.53) in CSF. The TN index median (quartile range), defined as (TN CSF concentration/TN serum concentration)/(Albumin CSF concentration/Albumin serum concentration), was found to be 5.5 (4.7-7.6), suggesting intrathecal synthesis or selective uptake of TN in CNS. Immunohistochemistry showed TN immunoreactivity in neurons and dendrites, but no staining in glial cells in the cerebrum and cerebellum. In plexus choroideus, the ependymal cells exhibited strong immunoreactivity. TN in serum and CSF were immunochemically identical and of similar size. CONCLUSION: TN is present in normal brain and CSF, and the TN index is very high, but further studies are necessary to decide whether TN is synthesised in the CNS or selectively transported over the blood-brain barrier.

The peroxisome proliferator-activated receptor gamma ligand 15-deoxy-Delta12,14-prostaglandin J2 induces vascular endothelial growth factor in the hormone-independent prostate cancer cell line PC 3 and the urinary bladder carcinoma cell line 5637.

Cyclopentenone-prostaglandin derivatives, including the peroxisome-proliferator activated receptor gamma (PPARgamma) ligand 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), inhibit tumor cell growth in vitro and in vivo. As 15d-PGJ2 was found to stimulate the expression of vascular endothelial growth factor (VEGF) in endothelial cells, we investigated whether 15d-PGJ2 induces this angiogenic factor in the human androgen-independent PC 3 prostate and the 5637 urinary bladder carcinoma cell line. In PC 3 cells, 15d-PGJ2 caused a dose-dependent increase in VEGF mRNA expression, as determined by RT-PCR. Stimulation started after 6 h, and after 72 h, VEGF mRNA expression reached a maximum of 3.3+/-0.3 U, 4.4+/-0.3 U and 6.1+/-0.1 U with 1, 5 and 10 microM 15d-PGJ2, respectively. Between 12-72 h, VEGF protein production was stimulated by up to 2-fold with 5 and 10 microM 15d-PGJ2 as assessed by ELISA in PC 3 cell-conditioned medium. In 5637 cells, 15d-PGJ2 did not alter VEGF mRNA expression for up to 72 h. Thereafter, VEGF mRNA expression was transiently increased from 2.3+/-0.8 U in control cells to 4.6+/-0.5 U in 1 microM and 5.9+/-0.6 U in 5 microM 15d-PGJ2-treated cells. VEGF protein production was only moderately stimulated (1.7-fold). 10 microM 15d-PGJ2 had no effect on VEGF mRNA expression in 5637 cells, but effectively reduced viability in both cell lines. 15d-PGJ2 also increased PPARgamma mRNA expression in both cell lines. While in PC 3 cells, stimulation of PPARgamma mRNA expression occurred after 72 h, in 5637 cells, a transient stimulation took place after 6 h (4-fold). We demonstrated that 15d-PGJ2 induces VEGF in PC 3 and 5637 cancer cells. This might be important if PG-analogues are considered as antitumor agents.

Catestatin--a novel neuropeptide in carcinoid tumors of the appendix.

BACKGROUND: The aim of the study was to investigate the immunohistochemical distribution of the novel neuropeptide catestatin in carcinoid tumors. Catestatin, a novel 21 amino acid neuropeptide derived from chromogranin A, was determined immunohistochemically in 30 carcinoid tumors of the appendix and various carcinoid tumors of other localities. MATERIALS AND METHODS: Paraffin-embedded tissues from 30 carcinoid tumors of the appendix and 16 other carcinoid tumors (5 bronchus-, 5 stomach-, 2 small bowel-, 4 large bowel carcinoid tumors) were incubated with antibodies specific for catestatin, chromogranin A and chromogranin B. Immunohistochemical staining of catestatin was compared to staining with chromogranin A and B. Western blot analysis was performed in one patient with ileal carcinoid. RESULTS: Thirty patients (20 women, 10 men) with carcinoid tumors of the appendix and 16 patients with other localized carcinoid tumors were investigated. Twenty-six of the appendiceal tumors were localized in the apex of the appendix and 4 tumors in the midportion; none of the tumors was localized at the base of the appendix. Median tumor diameter was 10.7 mm (range 4-18 mm). Immunoreactivity to catesatatin was positive in 28 patients (negative in 2, 0-10% in 11 patients, 11-50% in 14 patients, 51-100% in 3 patients). In 16 patients with carcinoid tumors in various other localizations, catestatin was also expressed. Western blot analysis of ileal carcinoid showed abundant catestatin reactivity with accelerated processing of chromogranin A in the tumor tissue. CONCLUSION: Catestatin derived from chromogranin A, which is the most widely distributed marker of neuroendocrine tumors, is expressed in high frequency in carcinoid tumors of the appendix (93.3%).

Neuroendocrine tumors and second primary malignancy--a relationship with clinical impact?

BACKGROUND: Neuroendocrine tumors (NET) are frequently associated with synchronous or metachronous secondary primary malignancies (SPM). The aim of this study was to report on 14 patients with NET and SPM from a series of 96 patients with NET. PATIENTS AND METHODS: Fourteen patients with NET and synchronous or metachronous SPM were reviewed for primary site and characteristics of NET and associated SPMs as well as the outcome of these combined malignancies. RESULTS: From 1987 to 2002, 14 (14.6%) out of 96 patients with NET were identified with SPM. The median age of the patients at diagnosis of NET was 69 years (range: 56-86 yrs). There were nine female and five male patients. The localization of NET was: four in appendix, three ileum, two duodenum, one stomach, one jejunum, one pancreatic tail, one rectum and one lung. Five patients had synchronous SPM (two colon cancers with one double colon cancer, one gastric cancer, one bladder cancer, one ovarian cancer) and nine metachronous SPM (two basal cell carcinomas, one colon cancer, two breast cancer, one gastric MALT-lymphoma, one ductal pancreatic adenocarcinoma, one bladder cancer, one hepatocellular carcinoma), three months to five years after diagnosis of NET. Five patients died of metastatic tumor (three SPM: 1, 7, 10 yrs; two NET: 1, 9 yrs), two patients died of other causes (1, 7 yrs), three patients are alive with metastatic tumor (two NET: 5, 6 yrs; one SPM: 10 yrs) while four patients are tumor-free (6 ms, 2, 9, 10 yrs). CONCLUSION: NET is associated to a high degree with gastrointestinal and genitourinary SPM. In 5/14 (36%) patients SPM was diagnosed synchronously, while in 8/14 (57%) patients SPM was diagnosed metachronously. In 8/14 patients (57%) primary symptoms were caused by SPM. As a consequence, every NET should be regarded as an index tumor and risk-adapted follow-up with thorough investigation, mainly of the GI and genitourinary tracts, is to be recommended.

Her2/neu expression in C-cell hyperplasia and medullary thyroid carcinomas.

Medullary thyroid carcinomas (MTC) are rare neoplasms derived from the calcitonin-producing thyroid parafollicular C-cells. Interestingly about 20% of cases are related to inherited tumor syndromes. As precursor lesion, C-cell hyperplasia can be detected in numerous MTCs. In our series of 6 patients with MTC, including 5 patients with adjacent C-cell hyperplasia, Her2/neu levels were immunohistochemically evaluated on formalin-fixed, paraffin-embedded tissues using c-erbB-2/Her-2/neu Oncoprotein Ab-17 monoclonal antibody(mAb). Statistically, a highly significant correlation was found between high Her2/neu levels and extrathyroidal growth. C-cell hyperplasias always presented with higher amounts of stained cells than their corresponding invasive MTCs. Whereas in hyperplastic areas large stained cell clusters were found, the invasive tumors showed mainly single cells reacting in areas of variable size. These results present the impact of Her2/neu oncoprotein concerning development and biological behaviour, especially aggressive growth, of invasive MTCs and suggest a major role of hyperplastic C-cell areas in the development of these malignant tumors.

Her2/neu expression in poorly-differentiated and anaplastic thyroid carcinomas.

The Her2/neu expression in poorly-differentiated thyroid carcinomas (PDTC) and in anaplastic thyroid cancer (ATC) was investigated retrospectively. Tumors of 25 patients suffering from PDTC and 25 from ATC were evaluated, including 15 cases of PDTC with highly-differentiated tumor parts. Her2/neu levels were immunohistochemically detected on formalin-fixed, paraffin-embedded tissues using c-erbB-2/Her2/neu Oncoprotein Ab-17 monoclonal antibody(mAb). In statistical analysis using 1-way ANOVA, Her2/neu protein overexpression was highly significantly correlated with the differentiation status of the investigated tumor parts. Whereas ATCs showed only few positive tumor cells, PDTCs presented with large reacting tumor areas and highly-differentiated parts of PDTCs revealed the highest staining intensity. These findings suggest a decreasing impact of Her2/neu oncoproteins correlating to dedifferentiation, reflecting the aggressive biological behaviour of these tumors.

MNGIE Syndrome: Liver Cirrhosis Should Be Ruled Out Prior to Bone Marrow Transplantation.

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is an autosomal recessive mitochondriopathy caused by loss-of-function mutations in the thymidine phosphorylase gene. The disease leads to premature death and is characterized by gastrointestinal dysmotility and cachexia, external ophthalmoplegia, a sensorimotor neuropathy, and leukoencephalopathy. Bone marrow transplantation (BMT) is the only potentially curative treatment that can achieve a sustained biochemical correction of the metabolic imbalances.We report a 23-year-old male homozygous for the c.866A > C, p.Glu289Ala mutation of the TYMP gene, who presented with fatty liver and cachexia. Laboratory examinations were unremarkable except for increased transaminase activities. Grade II fibrosis and steatosis was found in an initial and a follow-up liver biopsy 4 years later. Myeloablative conditioning and BMT was performed 10 years after initial presentation due to the progressive weight loss and polyneuropathy. Pre-transplant liver staging was normal except for an elevated transient elastography of 31.6 kPa. Severe ascites developed after transplantation and liver function deteriorated progressively to liver failure. Despite engraftment on day +15, the patient died on day +18 from liver failure. Autopsy revealed micronodular liver cirrhosis, and postmortem diagnosis of acute-on-chronic liver failure was done.This case illustrates the difficulties and importance of diagnosing liver cirrhosis in MNGIE. Before BMT, patients must be carefully evaluated by transient elastography, liver biopsy, or assessment of hepatic venous pressure gradient. In patients with liver cirrhosis, further studies should evaluate if liver transplantation may be an alternative to BMT. Considerable amounts of thymidine phosphorylase are expressed in liver tissue which may prevent accumulation of toxic metabolites.

Models of partnership between the pharmaceutical and diagnostics industries around companion diagnostics for cancer and beyond.

An increase of targeted anticancer therapies has led to the beginning of a new era of cancer treatment, partly by replacing classical chemotherapies, partly supplementing these. Whereas for some substances only clinical experiences are relevant for treatment decisions, for some major cancer groups predictive markers are known that indicate probable tumor responses. To identify the latter, a need for companion diagnostics is given, often already existing as successful cooperation between pharmaceutical and diagnostic industries. This editorial focuses on the impact of companion diagnostic tests in personalized anticancer medicine, reporting recent advances in identifying and characterizing tumor subgroups responding to selected drugs. The most successful targeted therapies are directed against the EGFR/Her-2/neu receptors with regard to their downstream molecules in major cancer groups, including breast, gastric, lung and colorectal carcinomas. The development of biomarkers provides great opportunities to identify subpopulations with differential drug responses. On the one hand patients themselves are gaining major advantages of personalized and better tolerable cancer treatment, on the other hand, owing to very focused targeted therapies, these developments make possible cost-intensive targeted drug investigations and trials, especially in a situation of limited healthcare budgets.

EpCAM expression in primary tumour tissues and metastases: an immunohistochemical analysis.

AIMS: Epithelial cell adhesion molecule (EpCAM) is a cell surface protein with oncogenic features that is expressed on healthy human epithelia and corresponding malignant tumours. EpCAM expression frequently correlates with more aggressive tumour behaviour and new EpCAM-specific therapeutic agents have recently been approved for clinical use in patients with cancer. However, no consensus exists on how and when to evaluate EpCAM expression in patients with cancer. MATERIAL AND METHODS: EpCAM expression was assessed by a well-established immunohistochemical staining protocol in 2291 primary tumour tissues and in 108 metastases using the EpCAM-specific antibody clone VU1D9. A total immunostaining score was calculated as the product of a proportion score and an intensity score. Four expression subgroups (no, weak, moderate and intense) were defined. As described previously, the term 'EpCAM overexpression' was reserved for tissues showing a total immunostaining score >4. RESULTS: EpCAM was highly expressed in most tumours of gastrointestinal origin and in some carcinomas of the genitourinary tract. However, hepatocellular carcinomas, clear cell renal cell cancer, urothelial cancer and squamous cell cancers were frequently EpCAM negative. EpCAM expression in breast cancer depended on the histological subtype; lobular histology usually showed no or weak expression. Most metastases were EpCAM positive and they frequently reflected the expression phenotype of the primary tumour. CONCLUSION: EpCAM expression was detected on adenocarcinomas of various primary sites. If EpCAM-specific antibodies are intended to be used in patients with cancer, we recommend prior immunohistochemical evaluation of EpCAM expression, particularly in patients with renal cell cancer, hepatocellular carcinoma, urothelial carcinoma, breast cancer and squamous cell carcinomas.