[Show abstract][Hide abstract] ABSTRACT: Introduction & Objectives
The non-invasive detection of bladder cancer (BC) and the identification of patients with a high risk for cancer progression remains a challenge in BC diagnostics. Here we present the identification of soluble betaIGH3 in urine as a sensitive and specific biomarker of high grade BC.
Material & Methods
Urine samples from patients with primary BC and population controls were collected. Differential protein expression analysis in urine was carried out by antibody arrays. Results were verified in an additional set of urine samples obtained from 63 BC patients and 95 population controls using ELISA. Additionally, urine samples from 28 patients with acute inflammation of the bladder (urological hospital controls) were analysed to further verify the usefulness of betaIGH3 for BC diagnosis and molecular characterization.
After identification of betaIGH3 using antibody arrays, subsequent verification by ELISAs showed that urinary betaIGH3 was found to be significantly higher in patients with primary bladder cancer (median 1262.8pg/mg creatinine) in comparison to population controls (median 76.8pg/mg creatinine) and urological hospital controls (median 339.6pg/mg creatinine; p≤0.001). Thereby, we found a notable difference of betaIGH3 values between low and high grade BC with increased median levels in high grade tumours (549.7pg/mg vs. 9390.6pg/mg). Additional analysis (receiver operating characteristic curves) showed an increased sensitivity and specificity of betaIGH3 towards high grade tumours with area under curve levels of 0.87 and 0.94 compared to hospital and population controls. All these differences were conserved after adjustment for important confounders including age, sex, smoking status and tumour grading.
We were able to identify and confirm soluble betaIGH3 as a promising biomarker candidate for high grade BC. Thereby, betaIGH3 was capable of distinguishing BC patients from urological hospital and population controls. Thus, analysis of betaIGH3 offers a significant step forward in non-invasive BC diagnosis.
6th European Multidisciplinary Meeting on Urological Cancer, Lisbon, Portugal; 11/2014
[Show abstract][Hide abstract] ABSTRACT: Lynch syndrome is the most frequent hereditary cancer syndrome, accounting for approximately 3-5 % of all colorectal cancers. In addition, it is the most frequent predisposing hereditary cause of endometrial cancer and is also associated with gastric cancer, ovarian cancer, cancer of the urinary tract as well as several other cancers. In clinical practise Lynch syndrome is frequently not detected and many clinicians admit uncertainties regarding diagnostic procedures. Also, counselling of patients is considered difficult regarding therapeutic - especially prophylactic surgical and chemopreventive options and recommendations. Based on a review of available literature we discuss optimized strategies for improved detection of suspected Lynch syndrome patients. The aim of this review is to establish a clinical algorithm of how to proceed on a diagnostic level and to discuss surgical options at the time of a colorectal cancer. In order to identify patients with Lynch syndrome, family history should be ascertained and evaluated in regards to fulfilment of the Amsterdam-II- and/or the revised Bethesda criteria. Subsequently immunohistochemical staining for the mismatch-repair-genes, BRAF testing for MLH1 loss of expression, as well as testing for microsatellite instability in some, followed by genetic counselling and mutation analysis when indicated, is recommended. Pathological identification of suspected Lynch syndrome is readily feasible and straightforward. However, the need of performing these analyses in the tumor biopsy at the time of (gastroenterological) diagnosis of CRC neoplasia is essential, in order to offer patients the option of a prophylactically extended surgery and - as recommended in the German S3 guidelines - to discuss the option of a merely prophylactical hysterectomy and oophorectomy (if postmenopausal) in women. Close cooperation between gastroenterologists, pathologists and surgeons is warranted, so that patients may benefit from options of extended or prophylactically extended surgery at the time of diagnosis of a colorectal primary. Patients nowadays must be involved in informed decision-making regarding prophylactic or extended prophylactic surgery at the time of a colorectal primary. To date, however, limitations in daily clinical practise, the failure to assess family history and the lack of awareness of this important hereditary syndrome is the major asset leading to severe underdiagnosis and putting to risk the indexpatients themselves and their families to (metachronous) CRC and the associated extracolonic cancers. If at all tumors of patients fulfilling Bethesda criteria will be analysed for MSI in the surgical specimen and therefore Lynch syndrome patients are not given the opportunity to opt for extended surgery. In clinical experience the postoperative MSI-analysis is inconsistently performed - even if the Bethesda criteria are fulfilled - and in case of suspected Lynch syndrome genetically counselling is not consistently recommended. Therefore affected cancer patients are left unaware of their increased genetic risk and in average 3 high-risk gene carriers per family miss the opportunity to actively engage in the recommended screening program.
[Show abstract][Hide abstract] ABSTRACT: The S3 guidelines for pancreatic cancer were revised in 2013. Besides the oncological and palliative therapy modalities and surgical therapy, the guidelines for pathologists in topic 3 were updated. The modifications essentially concern the histopathological assessment of surgical specimens and in particular the circumferential resection margin and the R classification. In addition, the current recommendations were amended by recommendations concerning the pathohistological records, which should include the lymph node ratio in the future.
[Show abstract][Hide abstract] ABSTRACT: Ductal adenocarcinoma of the pancreas is the fourth most common cause of death from cancer in men and women in Germany: about 15 000 persons die of this disease each year.
[Show abstract][Hide abstract] ABSTRACT: A 28-year-old man presented with loss of appetite, night sweats, eczema, and axillary and inguinal lymph node swelling. The tentative diagnosis of malignant lymphoma was made. To confirm the diagnosis, extirpation of a lymph node and a skin biopsy were performed. Systemic treatment with methylprednisolone resulted in an improvement of eczema and lymph node swelling. Because of the histological findings and clinical course, we diagnosed dermatopathic lymphadenopathy, also known as Pautrier-Woringer syndrome.
[Show abstract][Hide abstract] ABSTRACT: Malignant peripheral nerve sheath tumors (MPNST) account for up to 10% of all malignant soft tissue tumors in adults. Insufficient data are available on diagnosis, differential diagnosis and treatment modalities as well as prognosis.
Examining our sarcoma database from 1991 to 2004, we evaluated 65 patients with histologically-proven MPNST in terms of clinical, histopathological as well as prognostic factors.
The median age was 54 years, the gender ratio was equal, the follow-up 36 months. Extremities were involved in 75% of cases, the trunk in 15% and the head in 9% respectively. A total of 9% of our patients presented with disease-positive lymph nodes, in 28%, distant metastases (primarily lung) occurred. A primary closure was performed in 60%; in 22%, a tendon transfer and flap coverage was necessary. In 11% of cases, the final treatment was amputation. The initial diagnoses which had to be revised during re-evaluation was 32.3%. The 5-year disease-free survival rate was 49%. Overall, 27% of patients first operated on at our Institution experienced local recurrence. The only significant negative prognostic factor for survival was occurrence of metastases.
Our data indicate, that MPNST are tumor entities with a high rate of initial diagnoses that subsequently need to be adjusted (32%). Therefore, reference pathology should be requested. Tumor localization close to major nerves often results in functional restrictions after tumor resection. Because of the low mean life expectancy, early functional reconstructions by tendon transfer should be performed instead of nerve repair. Despite less radical tumor excision with often marginal resections, the survival rate is comparable to that of the literature where patients were treated with more radical procedures.
Anticancer research 02/2014; 34(2):777-83. · 1.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Targeting the centromers of chromosomes 3, 7, 17 (CEP3, 7, 17) and the 9p21-locus (LSI9p21) for diagnosing bladder cancer (BC) is time- and cost-intensive and requires a manual investigation of the sample by a well-trained investigator thus overall limiting its use in clinical diagnostics and large-scaled epidemiological studies. Here we introduce a new computer-assisted FISH-spot analysis tool enabling an automated, objective and quantitative assessment of FISH patterns in the urinary sediment. Utilizing a controllable microscope workstation, the microscope software Scan^R was programmed to allow automatic batch-scanning of up to 32 samples and identifying quadruple FISH signals in DAPI-scanned nuclei of urinary sediments. The assay allowed a time- and cost-efficient, automated and objective assessment of CEP3, 7 and 17 FISH signals and facilitated the quantification of nuclei harboring specific FISH patterns in all cells of the urinary sediment. To explore the diagnostic capability of the developed tool, we analyzed the abundance of 51 different FISH patterns in a pilot set of urine specimens from 14 patients with BC and 21 population controls (PC). Herein, the results of the fully automated approach yielded a high degree of conformity when compared to those obtained by an expert-guided re-evaluation of archived scans. The best cancer-identifying pattern was characterized by a concurrent gain of CEP3, 7 and 17. Overall, our automated analysis refines current FISH protocols and encourages its use to establish reliable diagnostic cutoffs in future large-scale studies with well-characterized specimens-collectives.
Biochemical and Biophysical Research Communications 01/2014; · 2.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background & Aims
Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in combination with cytopathology is the optimal method for diagnosis and staging of pancreatic ductal adenocarcinoma (PDAC) and other pancreatic lesions. Its clinical utility, however, can be limited by high rates of indeterminate or false negative results. We aimed to develop and validate a microRNA (miRNA)-based test to improve preoperative detection of PDAC.
Levels of miRNAs were analyzed in a central clinical laboratory by relative quantitative PCR in 95 formalin-fixed, paraffin-embedded (FFPE) specimens and 228 samples collected by EUS-FNA during routine evaluations of patients with solid pancreatic masses at 4 institutions in the United States, 1 in Canada, and 1 in Poland.
We developed a 5-miRNA expression classifier, consisting of MIR24, MIR130B, MIR135B, MIR148A, and MIR196, that could identify PDAC in well-characterized FFPE specimens. Detection of PDAC in EUS-FNA samples increased from 78.8% by cytology analysis alone (95% confidence interval [CI], 72.2%–84.5%) to 90.8% when combined with miRNA analysis (95% CI, 85.6%–94.5%). The miRNA classifier correctly identified 22 additional true PDAC cases among 39 samples initially classified as benign, indeterminate, or non-diagnostic by cytology. Cytology and miRNA test results were each significantly associated with PDAC (P<.001), with positive predictive values >99% (95% CI, 96%–100%).
We developed and validated a 5 miRNA classifier that can accurately predict which preoperative pancreatic EUS-FNA specimens contain PDAC. This test might aid in the diagnosis of pancreatic cancer by reducing the number of FNAs without a definitive adenocarcinoma diagnosis, thereby reducing the number of repeat EUS-FNA procedures.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 01/2014; · 5.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Osteosarcomas of the craniomaxillofacial region in adults are rare malignant tumors with many sites of origin. The purpose of this study was to analyze the outcome of adult patients suffering from osteosarcomas and investigate whether neoadjuvant chemotherapy would be beneficial to overall outcome.
The medical records of 36 patients treated during 2002-2012 were reviewed. All patients suffered from primary osteosarcomas of the craniomaxillofacial region.
The mean survival of patients was 64.49 ± 23.52 months. The 2- and 5-year overall survival rates in the neoadjuvant treatment group were 100 and 66.7 %; in the surgery only group, the overall survival rates were 66.7 and 41.7 %, respectively. The neoadjuvant treatment (p = 0.017), tumor size (p = 0.004), tumor location (p = 0.02), and age (p < 0.0001) were significant parameters influencing survival, whereas other tumor-related or demographic factors had no significant influence on survival.
Early identification of osteosarcoma of the craniomaxillofacial region and combined treatment by neoadjuvant chemotherapy with radical surgery are the most important strategies in dealing with these sarcomas. If possible, this treatment option should be followed unless contraindicated by other factors.
Journal of Cancer Research and Clinical Oncology 11/2013; · 2.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The interdisciplinary guidelines at the S3 level on the diagnosis of and therapy for hepatocellular carcinoma (HCC) constitute an evidence- and consensus-based instrument that is aimed at improving the diagnosis of and therapy for HCC since these are very challenging tasks. The purpose of the guidelines is to offer the patient (with suspected or confirmed HCC) adequate, scientifically based and up-to-date procedures in diagnosis, therapy and rehabilitation. This holds not only for locally limited or focally advanced disease but also for the existence of recurrences or distant metastases. Besides making a contribution to an appropriate health-care service, the guidelines should also provide the foundation for an individually adapted, high-quality therapy. The explanatory background texts should also enable non-specialist but responsible colleagues to give sound advice to their patients concerning specialist procedures, side effects and results. In the medium and long-term this should reduce the morbidity and mortality of patients with HCC and improve their quality of life.
Zeitschrift für Gastroenterologie 11/2013; 51(11):1269-326. · 1.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chemotherapy for soft tissue sarcomas remains unsatisfactory due to their low chemosensitivity. Even the first line chemotherapeutic agent doxorubicin only yields a response rate of 18-29%. The antibiotic salinomycin, a potassium ionophore, has recently been shown to be a potent compound to deplete chemoresistant cells like cancer stem like cells (CSC) in adenocarcinomas. Here, we evaluated the effect of salinomycin on sarcoma cell lines, whereby salinomycin mono- and combination treatment with doxorubicin regimens were analyzed.
To evaluate the effect of salinomycin on fibrosarcoma, rhabdomyosarcoma and liposarcoma cell lines, cells were drug exposed in single and combined treatments, respectively. The effects of the corresponding treatments were monitored by cell viability assays, cell cycle analysis, caspase 3/7 and 9 activity assays. Further we analyzed NF-kappaB activity; p53, p21 and PUMA transcription levels, together with p53 expression and serine 15 phosphorylation.
The combination of salinomycin with doxorubicin enhanced caspase activation and increased the sub-G1 fraction. The combined treatment yielded higher NF-kappaB activity, and p53, p21 and PUMA transcription, whereas the salinomycin monotreatment did not cause any significant changes.
Salinomycin increases the chemosensitivity of sarcoma cell lines - even at sub-lethal concentrations - to the cytostatic drug doxorubicin. These findings support a strategy to decrease the doxorubicin concentration in combination with salinomycin in order to reduce toxic side effects.
BMC Cancer 10/2013; 13(1):490. · 3.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Octreotide is suggested to harden the pancreas, thus facilitating the construction of a pancreatic anastomosis and lowering the risk of postoperative fistula. We tested the hypothesis that intra-arterial application of octreotide in the gastroduodenal artery during pancreatectomy may increase pancreatic hardness.
A single-center, prospective, double-blinded, randomized controlled trial with parallel assignment was conducted. Patients planned for a pancreatoduodenectomy or a total pancreatectomy, who had a palpatory and durometer proven (<40 Shore units) soft pancreas, were assigned to receive intraoperatively either 5 mL 500µg octreotide or 5 mL 0.9% saline solution as a bolus injection in the gastroduodenal artery. Pancreatic hardness was measured before, early, and late after intervention. The investigator performing the durometer measurements and pathologist were masked to group assignment. The primary outcome was increased pancreatic hardness. Analysis was by intention to treat. This trial is registered at http://www.clinicaltrials.gov (ID NCT01400100).
A total of 12 patients received octreotide and 13 received saline solution. Pancreatic hardness marginally increased in the octreotide group: 0.67 ± 2.3 Shore units, whereas it decreased in the control group: -2.15 ± 2.7 Shore units. The difference was statistically significant, p = 0.029 (95% confidence interval = -4.87 to -0.77). Histology did not find any correlate for this clinically irrelevant hardening effect.
A single bolus application of octreotide did not deliver a clinically relevant increase in pancreatic hardness. Future studies on the hardening effect of octreotide should employ repeated or continuous preoperative administration of this drug.
Scandinavian journal of surgery: SJS: official organ for the Finnish Surgical Society and the Scandinavian Surgical Society 09/2013; 102(3):164-70. · 1.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The MRE11/RAD50/NIBRIN complex, a protein complex that repairs DNA double-strand breaks, could serve as an early marker for new lesions in pancreatic cancer. We determined the expression of MRE11, RAD50 and NIBRIN, and their possible prognostic value regarding survival. Forty-one patients with ductal adenocarcinoma of the pancreas were included. All underwent curative surgery. Immunohistochemistry was performed for MRE11, RAD50 and NIBRIN. Subsequent analyses were based on a modified immunoreactive score. Statistical analysis was conducted using the statistics program "R". The mean follow-up period was 509 days. The mean age of the patients was 67±8 years, male=56%, female=44%. Eighty-seven percent underwent a Kausch-Whipple procedure, whereas a left side resection was performed in 22% of patients. Positive lymph nodes were found in 80% of cases, and patients were staged UICC IIa (12%), IIb (56%) and IV (29%). Overall significant results were found for MRE11 (p=0.02) and NIBRIN (p=0.01) expression and postoperative survival. We found a significant relation between the expression of MRE11, NIBRIN and the postoperative survival of patients with ductal adenocarcinoma. The link between the expression of the MRN complex, ATM and pancreatic cancer can be used to develop new treatment options for pancreatic carcinoma.
Pathology - Research and Practice 07/2013; · 1.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Spectral histopathology (SHP) is an emerging tool for label free annotation of tissue. While FTIR based SHP provides fast annotation of larger tissue sections, Raman based SHP is slower but achieves a 10 times higher spatial resolution as compared to FTIR. Usually NIR excitation is used for Raman measurements on biological samples. Here, for the first time 532 nm excitation is used to annotate colon tissue by Raman SHP. Excellent data quality is obtained, which resolves for example erythrocytes and lymphocytes. In addition to Raman scattering auto-fluorescence is observed. We found that this auto-fluorescence overlaps spatially with the fluorescence of antibodies against p53 used in routine immunohistochemistry in surgical pathology. This fluorescence indicates nuclei of cancer cells with mutated p53 and allows new label free assignment of cancer cells. These results open new avenues for optical diagnosis by Raman spectroscopy and autofluorescence.