Cat scratch disease--heterogeneous in clinical presentation: five unusual cases of an infection caused by Bartonella henselae.

BACKGROUND: Cat-scratch disease (CSD) is common in children, however the wide spectrum of the clinical presentation of CSD may lead to delayed diagnosis. An atypical presentation of CSD includes in its differential diagnosis diseases such as tuberculosis, other mycobacterioses, Epstein-Barr-Virus infection (EBV) or malignant disease. Since, in a small number of cases, these diseases may be present concurrently with an active CSD, it is important to consider CSD early in the differential diagnosis and order the appropriate tests. These tests include serology and, where possible, histology including molecular diagnostic methods on tissue specimens. PATIENTS AND METHOD: We performed a case series of five patients treated in our hospital with a clinical diagnosis of cat-scratch disease, confirmed by serology. An analysis of the history and clinical symptoms associated specifically with an atypical presentation of CSD was performed. RESULTS: The clinical presentation of CSD no longer encompasses the original typical description from 1950, but rather presents with a wide spectrum of signs and symptoms, including the absence of a documented cat scratch, fever, primary lesions or peripheral lymphadenopathy. Low density lesions in spleen, liver and lymph nodes are typical findings in ultrasound, MRI, or CT. Ignoring CSD as a possibility in investigating possible malignancy or tuberculosis could lead to unnecessary hospitalisation and delay in the proper treatment. CONCLUSION: CSD should also be considered in differential diagnosis of any patient with intraabdominal lymphadenopathy, abdominal pain and fever of unknown origin. A careful history is important, however, often patients with CSD have no history of contact with cats. Therefore in atypical cases of CSD the finding of other clinical symptoms and performance of specific diagnostic tests is important. Our experience suggests that early serological testing for Bartonella henselae should be performed and may avoid invasive diagnostic procedures.

DKC1 overexpression associated with prostate cancer progression.

BACKGROUND: Dyskerin encoded by the DKC1 gene is a predominantly nucleolar protein essential for the formation of pseudouridine in RNA and the telomerase RNA subunit hTR. Inherited mutations inactivating dyskerin cause dyskeratosis congenita, a syndrome with progeroid features characterised by skin defects and haematopoiesis failure, as well as cancer susceptibility. In this study, we report DKC1 overexpression in prostate cancers. METHODS: Expression of DKC1 was measured by quantitative RT-PCR in prostate cancer tissues in relation to hTR and the proliferation marker MKI67. Effects of dyskerin downregulation on proliferation, apoptosis and senescence of prostate cancer cell lines were determined. RESULTS: DKC1 was significantly overexpressed in prostate cancers, particularly in high-stage and recurring cases, correlating moderately with hTR and MKI67. Dyskerin downregulation in prostate carcinoma cell lines by siRNA diminished cell proliferation, but elicited neither apoptosis nor senescence. Apoptosis induction by TNF-alpha or tunicamycin was not enhanced. Long-term downregulation led predominantly to cell shrinking and loss of adhesion. INTERPRETATION: DKC1 upregulation in prostate cancers is common and likely to be necessary for extensive tumour growth. The phenotype of prostate carcinoma cell lines after dyskerin downregulation suggests that its most critical function is sustaining protein biosynthesis. Intriguingly, compromised function and overexpression of dyskerin can both contribute to cancer development.

Chest wall and intrathoracic desmoid tumors: surgical experience and review of the literature.

Desmoid tumors are fibroblastic/myofibroblastic neoplasms, which originate from musculo-aponeurotic structures and are classified as deep fibromatoses. Despite their benign histologic appearance and lack of metastatic potential, desmoid tumors may cause aggres?sive local infiltrations and compression of surrounding structures. They are often associated with female gender, familial adenomatous polyposis (FAP) and sporadically may occur at sites of previous trauma, scars or irradiation. Molecular studies have demonstrated that these patients are associated with a bi-allelic APC mutation in the affected tissue. Radical tumor resection with free margins remains the first therapy of choice. In cases with anatomical or technical limitations for a wide excision, radiation therapy represents a proven and effective alternative or supplementary treatment.

Nitric oxide-mediated inhibition of androgen receptor activity: possible implications for prostate cancer progression.

Chronic inflammation increases the risk of cancer and many cancers, including prostate cancer, arise at sites of chronic inflammation. Inducible nitric oxide synthase (iNOS) is an enzyme dominantly expressed during inflammatory reactions. Although synthesis of high amounts of nitric oxide (NO) by iNOS has been demonstrated in pathophysiological processes, such as acute or chronic inflammation, autoimmune diseases or tumorigenesis, the role of iNOS activity in most of these diseases is poorly understood. Analysing prostate cancer biopsies by immunohistochemistry we found iNOS protein expression in tumor cells strongly paralleled by nitrotyrosine suggesting that iNOS is fully active. In vitro, NO inhibits androgen receptor-dependent promoter activity and prostate specific antigen production as well as DNA-binding activity of the androgen receptor (AR) in a concentration-dependent manner. Inhibition of the activity of androgen receptor-dependent reporter constructs is neither owing to diminished AR protein levels nor owing to an inhibition of its nuclear import. In addition, NO inhibits the proliferation of androgen receptor-positive prostate cancer cells significantly more efficiently than proliferation of androgen receptor-negative prostate cancer cells. In summary, our findings suggest that intratumoral iNOS activity favors development of prostate cancer cells that are able to proliferate androgen receptor-independently, thereby promoting prostate tumor progression.

Interobserver reproducibility of Gleason grading: evaluation using prostate cancer tissue microarrays.

OBJECTIVES: Due to PSA screening and increased awareness, prostate cancer (PCa) is identified earlier resulting in smaller diagnostic samples on prostate needle biopsy. Because Gleason grading plays a critical role in treatment planning, we undertook a controlled study to evaluate interobserver variability among German pathologists to grade small PCas using a series of tissue microarray (TMA) images. METHODS: We have previously demonstrated excellent agreement in Gleason grading using TMAs among expert genitourinary pathologists. In the current study, we identified 331 TMA images (95% PCa and 5% benign) to be evaluated by an expert PCa pathologist and subsequently by practicing pathologists throughout Germany. The images were presented using the Bacus Webslide Browser on a CD-ROM. Evaluations were kept anonymous and participant's scoring was compared to the expert's results. RESULTS: A total of 29 German pathologists analysed an average of 278 images. Mean percentage of TMA images which had been assigned the same Gleason score (GS) as done by the expert was 45.7%. GSs differed by no more than one point (+/-1) in 83.5% of the TMA samples evaluated. The respondents were able to correctly assign a GS into clinically relevant categories (i.e. <7, 7, >7) in 68.3% of cases. A total of 75.9% respondents under-graded the TMA images. Gleason grading agreement with the expert reviewer correlated with the number of biopsies evaluated by the pathologist per week. Years of diagnostic experience, self-description as a urologic pathologist or affiliation with a university hospital did not correlate with the pathologist's performance. CONCLUSION: The vast majority of participants under-graded the small tumors. Clinically relevant GS categories were correctly assigned in 68% of cases. This raises a potentially significant problem for pathologists, who have not had as much experience evaluating small PCas.

Modern therapy of rectal carcinoma.

Throughout the past decade the treatment of rectal carcinoma has improved remarkably. Today, individualized multimodality treatment allows local and distant tumor freedom with preservation of anorectal and genitourinary function in a majority of patients. Radiotherapy is elementary in reducing the risk of local recurrence whereas chemotherapy including promising novel agents prevents or eliminates distant metastases. However, surgery revolutionized by TME (total mesorectal excision) remains the only curative treatment for rectal carcinoma. In this study the authors review the developments as well as the current status of modern treatment for rectal carcinoma.

Validity of S-100 B in patients after brain radiation.

BACKGROUND: S-100B is a calcium binding acute phase protein and a potential biomarker for brain injury. In prior studies elevated plasma S-100B levels were detected in stroke and severe head trauma. The aim of this study was to evaluate whether S-100 B is elevated during cerebral radiotherapy and whether that is associated with adverse outcomes. MATERIAL AND METHODS: In this prospective pilot study, 45 patients (25 males, 20 females, median age 58 (17-81)) underwent cerebral radiation therapy because of a primary or metastaic cerebral malignancy. 39 patients were included in the evaluation. 6 patients died during the study period. S-100 plasma concentrations were measured with an electrochemiluminescence immunoassay on admission and weekly during radiation therapy for the duration of 6 weeks. In 10 healthy young volunteers (5 males, 5 females, median age 32 (28-36)) S-100 B plasma levels were measured weekly for 6 weeks as a negative control. Furthermore, in an active control 10 patients (4 males, 6 females, median age 68 (64-76)) with stroke (7 = major stroke, 3 = lacunar infarct) S- 100 B plasma levels were measured for 7 consecutive days after the event. RESULTS: During radiotherapy S-100 B plasma concentrations increased from median baseline values of 0.030 microg/l to 0.044 microg/l. For the time of radiation therapy most patients showed a mild increase, but absolute plasma values were still within the normal range. In the control group of healthy volunteers S-100 B remained unchanged. In stroke patients S-100 B increased to maximum values of 1.7 microg/l three days after the event. In the 3 patients with lacunar infarcts no increase of S-100 B levels could be detected. CONCLUSION: Brain irradiation leads to a mild increase of S-100 B plasma levels. However, the absolute rise was far weaker compared to that seen in major brain injuries.

Prognostic relevance of increased Rac GTPase expression in prostate carcinomas.

Rac proteins of the Rho-like GTPase family, including the ubiquitous Rac1, the hematopoiesis-specific Rac2, and the least-characterized Rac3 play a major role in oncogenic transformation, tumor invasion and metastasis. However, the prognostic relevance of Rac expression in human tumors has not been investigated yet. In the present study, Rac protein expression was analyzed in benign secretory epithelium, high-grade prostatic intraepithelium neoplasia (HG-PIN), and prostate carcinomas of 60 R0-resected radical prostatectomy specimens by semiquantitative immunohistochemistry. Thus, Rac proteins were significantly strongly expressed in HG-PIN (P < 0.001) and prostate carcinomas (P < 0.001) when compared with benign secretory epithelium. Accordingly, all tumor tissues analyzed by isoform-specific real-time PCR (n = 7) exhibited significantly higher RNA expression levels of Rac (i.e. sum of Rac1 and Rac3 expression levels) than the respective benign counterparts (P = 0.018) and this appeared to result mainly from increased expression of the Rac3 isoform as verified by immunoblotting. Univariate analyses showed statistically significant associations of increased Rac protein expression in prostate cancer (P = 0.045), preoperative prostate-specific antigen levels (P = 0.044), pT stage (P = 0.002), and Gleason score (P = 0.001) with decreased disease-free survival (DFS). This prognostic effect of increased protein expression of Rac remained significant even in a multivariate analysis including all these four factors (relative risk = 3.22, 95% confidence interval = 1.04-10.00; P = 0.043). In conclusion, our data suggest that increased Rac protein expression in prostate cancer relative to the corresponding benign secretory epithelium is an independent predictor of decreased DFS and appears to result mainly from increased expression of the Rac3 isoform.

Concomitant down-regulation of SPRY1 and SPRY2 in prostate carcinoma.

Sprouty proteins encoded by the SPRY genes act as modulators and feedback inhibitors of signalling by epidermal growth factor (EGF) and fibroblast growth factor (FGF). Overactivity of EGF and FGF signalling common in prostate cancer might therefore be exacerbated by Sprouty down-regulation. Indeed, down-regulation of SPRY1 and SPRY2 expression has been independently reported. We found both genes modestly down-regulated by microarray expression analysis of microdissected prostate cancers and by quantitative RT-PCR in macrodissected specimens compared with benign tissues. Importantly, the decreases paralleled each other and expression levels of both genes were significantly lower in cancers that recurred within the average follow-up period of 32 months. In contrast to a previous report, no hypermethylation was found to accompany down-regulation of SPRY2 in cancer tissues and cell lines. We additionally investigated the expression of an SPRY1 alternative transcript presumed to be specific for fetal tissues and found its expression moderately well correlated with expression of the standard transcript through diverse tissues and cell lines. The present study confirms and extends previous reports by demonstrating concomitant down-regulation and a significant association with recurrence of SPRY genes.

Heterogeneous response to differentiation induction in different clonal subpopulations of a rat rhabdomyosarcoma cell line (BA-HAN-1).

Three clonal subpopulations (A, B, C) isolated from the same rhabdomyosarcoma of the rat were tested and compared for their susceptibility to differentiation induction using retinoic acid (RA), dimethylformamide (DMF), and N-monomethylformamide (NMF). These subpopulations differ in that a block to spontaneous differentiation is imposed at different stages which are characteristic for each subpopulation. Whereas tumor cell proliferation was significantly inhibited (P less than 0.001) in all three subpopulations, the effects of RA, DMF, and NMF on tumor cell differentiation were strikingly heterogeneous. The response was most marked in subpopulation C, as evidenced by a significant increase in the number of terminally differentiated myotube-like giant cells (P less than 0.001) and in biochemical differentiation, as indicated by the creatine kinase activity (P less than 0.05). Between 5% (DMF and NMF) and 30% (RA) of the mononuclear cells in subpopulation C exhibited thick and thin myofilaments, which were never observed in the mononuclear cells of the control. In contrast, subpopulation A and B responded to RA, DMF, and NMF quite heterogeneously with an increase in biochemical differentiation, whereas terminally differentiated myotube-like giant cells were never observed. These results demonstrate that the therapeutic potential of differentiation induction in malignant tumors may be impaired by tumor heterogeneity.

Terminal differentiation and growth inhibition of a rat rhabdomyosarcoma cell line (BA-HAN-1C) in vitro after exposure to retinoic acid.

BA-HAN-1C is a clonal rat rhabdomyosarcoma cell line composed of proliferating mononuclear cells, which partly fuse to terminally differentiated postmitotic myotube-like giant cells. The exposure to retinoic acid in vitro resulted in time- and dose-dependent changes of both cell differentiation and cell growth. The mononuclear cells revealed bundles of newly formed thick and thin myofilaments, never observed in untreated cultures, and exhibited signs of contact inhibition. In addition, there was a statistically significant increase (P less than 0.001) in the number of terminally differentiated postmitotic myotube-like giant cells and in the creatine kinase activity (P less than 0.05) which was used as a biochemical differentiation marker. At the same time cell growth was significantly inhibited (P less than 0.001) in vitro and a decrease in plating efficiency, as well as in saturation density, was observed. These data demonstrate that retinoic acid can suppress cell growth and simultaneously initiate differentiation in a malignant mesenchymal tumor cell line. However, despite the clonal nature of BA-HAN-1C, the complete status of terminal differentiation was not achieved by all tumor cells. The reason why not all tumor cells responded to retinoic acid is unknown at the present time and will have to be the subject of further studies.

Multiple neuroendocrine tumors of the pancreas associated with pancreas divisum.

Pancreas divisum is the most common congenital anomaly of the pancreas, characterized by missing fusion of the ventral and dorsal pancreatic duct. It may cause pancreatitis, but is rarely associated with malignancy.We report herein for the first time the rare association, in a symptomless patient, of multiple neuroendocrine tumors of the pancreas with pancreas divisum and a failure of the exocrine system. Diagnosis was made incidentally by routine abdominal ultrasound. Laboratory examinations and a fine-needle aspiration revealed the neuroendocrine nature of the tumor. Spleen-preserving left pancreas resection was performed, with evidence of multiple neuroendocrine tumors of the pancreas with the typical histological characteristics. Eighteen months later the patient is still free of tumor burden.

Mechanisms of tumor metastasis: cell biological aspects and clinical implications.

The clinical course--and hence the prognosis--of patients suffering from malignant tumors are essentially determined by the capability of tumor cells to metastasize. During the past decade knowledge about genetic aberrations, as well as molecular and cell biological mechanisms which are involved in the regulation of tumor metastasis, has dramatically increased and consequently led to the development of new theoretical and experimental strategies in cancer treatment. The objective of this review is not only to give an overview about the principal cell biological and molecular mechanisms of tumor metastasis, but also to discuss potential therapeutical options resulting from this knowledge.

Differentiation induction in the human rhabdomyosarcoma cell line TE-671. A morphological, biochemical and molecular analysis.

In the clonal human rhabdomyosarcoma cell line TE-671-1A, the expression of genes implicated in myogenic differentiation was determined before and after exposure to the differentiation inducers retinoic acid (RA), sodium butyrate (NaBut) and N-monomethylformamide (NMF). Exposure to NaBut or RA resulted in a significant (NaBut: p < 0.0001; RA: p < 0.05) increase in biochemical differentiation paralleled by a significant (NaBut: p < 0.0001; RA: p < 0.0002) inhibition of proliferation. An increase in the relative number of myotube-like giant cells was observed after exposure to NaBut. Exposure to NMF proved to be least effective and produced a significant (p < 0.0001) inhibition of proliferation without increase in differentiation. On the molecular level, exposure to RA resulted in a moderate increase in RAR a mRNA expression, whereas CRABP mRNA remained constant. RAR beta and RAR gamma mRNA were not expressed. mRNA expression of c-raf, c-myc and c-Ki-ras remained constant before and after exposure to all inducers of differentiation. C-fos mRNA was not expressed. In summary, differentiation can successfully be induced in the human rhabdomyosarcoma cell line TE-671-1A by various inducers of differentiation. In contrast to other myogenic cell lines, however, the proto-oncogenes myc, fos and raf are not involved in the transmission of myogenic differentiation signals in TE-671-1A cells.

Effects of TNF-alpha and retinoic acid on the proliferation of the clear cell and chromophilic types of human renal cell carcinoma in vitro.

Since no effective therapeutic approach is known so far for metastatic renal cell carcinoma (RCC), we analyzed the anti-proliferative effects of TNF-alpha and retinoic acid (RA), applied either alone or in combination on 7 different RCC cell lines in vitro. In 5 out of 7 cell lines, a significant (p < 0.05) dose-dependent inhibition of tumor cell proliferation became evident after exposure to TNF-alpha, the response being of modest magnitude in 5 cell lines. In 2 cell lines the effects were more pronounced with a reduction of cell viability to 55 +/- 11% of the control. Northern blot analysis revealed no expression of TNF-alpha and p75 TNF-receptor in any cell line. All the cell lines showed p55 TNF-receptor mRNA. Scatchard analysis revealed no correlation between TNF-alpha receptor status and growth inhibitory response to TNF-alpha, the number of TNF-receptors per cell ranging from 0 to 3,976, and the affinity values from Kd = 0.621 nmol/l to Kd = 4.28 nmol/l. Exposure to RA alone resulted in significant (p < 0.05), but modest growth inhibition in 2 out of 7 cell lines with a reduction of cell viability to 83 +/- 1% of the control. In 2 out of 7 cell lines, combination of RA and TNF-alpha was significantly (p < 0.05) more effective than the single application of each compound. Northern blot analysis revealed no transcripts of CRABP I and retinoic acid receptor (RAR)-beta. All the cell lines expressed RAR-alpha mRNA and one cell line additionally expressed RAR-gamma mRNA. A correlation between RAR status and RA response was not seen.

Right atrial metastasis as primary clinical manifestation of hepatocellular carcinoma.

We present an 81-year-old man with right atrial metastasis associated with hepatocellular carcinoma. Antemortem diagnosis was made by two-dimensional echocardiography, cardiac catheterisation and computed tomography, followed by surgical intervention and histological examination of the right atrial tumour. To our knowledge, this is the second case with intravital diagnosis and histological confirmation.

Uptake and metabolism of retinoic acid induces inhibition of cell growth: a study in a rat rhabdomyosarcoma cell line (BA-HAN-1C) using nonlinear theoretical models.

Retinoic acid causes a significant inhibition of cell growth of the tumor cell line BA-HAN-1C. This growth inhibition is the same whether the cells are treated with a pulse dose of retinoic acid (RA) or continuously expand to RA. The determination of RA and its degradation products within the culture medium and in the cells showed that after 24 hours 13-cis-RA was the major retinoid in all cells (96 ng/10(6) cells); all-trans-RA represented 56 ng/10(6) cells. After 48 hours 4-hydroxy-RA and a small amount of 5,6-epoxy-RA was found in the cells and also in the culture medium. 4-hydroxy-RA increased up to 96 hours, whereas 13-cis- and all-trans-RA were not detectable in the cells after 96 hours. We conclude that the BA-HAN-1C cells take up and metabolize RA. Nonlinear fit analysis of the time behavior of the RA concentration in medium demonstrates that the RA uptake unexpectedly follows a mono-exponential time function. Discussion of the experimental results in connection with a proper compartment model shows that uptake and metabolism of RA cannot be described really by a first order kinetics. The mathematical analysis leads to a more complicated kinetic model with certain restrictions for the corresponding rate constants.

Graves' disease occurring after surgery of a multinodular goiter: a case report.

The transition of toxic or nodular goiter to Graves' disease is known as a rare side effect of (131)I therapy. Here, we report the case of a 46-year-old German female with posttherapeutical Graves' disease after surgery of a multinodular goiter. Although the major part of the thyroid was excised the patient suffered from manifest Graves' disease including typical clinical and laboratory findings. Prior to surgery, no TSH receptor antibodies were found, although low TPO antibody titres could already be detected. It may thus be assumed that the therapeutic manipulation elicited the key change towards a TSH receptor antibody production in a predisposed organ or alternatively deteriorated a mild unapparent pre-existing Graves' disease. It might be concluded that the possibility of posttherapeutical Graves' disease should be considered in the presence of TPO antibodies prior to the surgical intervention.

[Do we have to remove a painless collar swelling along the carotid artery?]. / Muss eine schmerzlose Schwellung entlang der A. carotis operiert werden?

Schwannoma are rare. We describe the clinical presentation, diagnostic workup and therapy in sympathetic chain schwannoma in a 54 year old patient. Besides the operative management the differential diagnosis of painless swelling at the carotid bifurcation are discussed.