[Show abstract][Hide abstract] ABSTRACT: Oncogenic Kras-activated robust Mek/Erk signals phosphorylate to the tuberous sclerosis complex (Tsc) and deactivates mammalian target of rapamycin (mTOR) suppression in pancreatic ductal adenocarcinoma (PDAC); however, Mek and mTOR inhibitors alone have demonstrated minimal clinical antitumor activity.
We generated transgenic mouse models in which mTOR was hyperactivated either through the Kras/Mek/Erk cascade, by loss of Pten or through Tsc1 haploinsufficiency. Primary cancer cells were isolated from mouse tumours. Oncogenic signalling was assessed in vitro and in vivo, with and without single or multiple targeted molecule inhibition. Transcriptional profiling was used to identify biomarkers predictive of the underlying pathway alterations and of therapeutic response. Results from the preclinical models were confirmed on human material.
Reduction of Tsc1 function facilitated activation of Kras/Mek/Erk-mediated mTOR signalling, which promoted the development of metastatic PDACs. Single inhibition of mTOR or Mek elicited strong feedback activation of Erk or Akt, respectively. Only dual inhibition of Mek and PI3K reduced mTOR activity and effectively induced cancer cell apoptosis. Analysis of downstream targets demonstrated that oncogenic activity of the Mek/Erk/Tsc/mTOR axis relied on Aldh1a3 function. Moreover, in clinical PDAC samples, ALDH1A3 specifically labelled an aggressive subtype.
These results advance our understanding of Mek/Erk-driven mTOR activation and its downstream targets in PDAC, and provide a mechanistic rationale for effective therapeutic matching for Aldh1a3-positive PDACs.
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[Show abstract][Hide abstract] ABSTRACT: The TNM classification is used to assess cancers of the oral cavity, and advancements in imaging techniques have revealed clear variations in tumor volume at presentation. This study therefore aimed to clarify whether preoperative imaging, with exact measurements of the tumor, could affect post-surgery survival after controlling for demographic, clinical, and tumor characteristics.
We included 437 patients with histologically confirmed, stage T1-4, N1-3, M0, invasive squamous cell carcinoma of the tongue. Participants were assessed for recurrence every 3 months for the first 2 years, every 6 months for another 2 years, and annually thereafter; routine computed tomography was performed annually. Associations were determined using the Kaplan-Meier estimator, univariate log-rank test, and Cox proportional hazards regression models.
The mean survival of all patients was 68.1 ± 48.2 months. The 2- and 5-year overall survival rates were 82.2 and 66.7 %, respectively. The mean primary tumor volume was 7.14 cm(3) with a range of 1.3-24.21 cm(3). The ROC curve and Youden Index analysis revealed that the optimal cutoff volume was between ≤5.9 and ≤18.3 cm(3) for three different volume groups (p < 0.0001). Large tumor volume was associated with a significantly poorer overall survival (p < 0.0001).
Tumor volume was significantly associated with the overall survival of patients. This has both prognostic and reconstructive implications that will affect health-related quality of life. In addition, this will inform surgical planning and the allocation of resources.
Journal of Cancer Research and Clinical Oncology 11/2014; · 3.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Complete mesocolic excision (CME) and central vascular ligation (CVL) for right-sided colon cancer may be superior to standard hemicolectomy in terms of oncological results. This hypothesis is currently being investigated in a large multicentre trial conducted by the authors of this paper (Resektatstudie). Because CVL in right-sided hemicolectomy is technically rather demanding the incidence of central node involvement is of special interest. Therefore, during the single centre pilot phase of our multicentre trial we have analysed the incidence of central lymph node metastasis in CME specimens. Patients: In 51 patients with right-sided colon adenocarcinoma (cT1-3, cM0) an open CME with CVL was performed. In the fresh specimen the central four centimetres of the ileocolic vessels that would have been presumably left in place during a standard hemicolectomy were marked with a suture. The lymph nodes in this segment were separately analysed. Results: In the CME specimen the mean lymph node count was 52.6 (range: 27-171). 35.0 % (range: 13.1-65.6 %) of the nodes were located in the central 4 cm segment. The proportion of patients with positive nodes was 25.5 % (13/51). Of all nodes 1.97 % (53/2686) were metastatic. In 3/51 (5.8 %) patients the central nodes were involved. In one patient the central nodes were the only metastatic site. UICC stage was influenced in two of the three patients who had central involvement (stage migration: UICC IIB to IIIB, UICC IIIB to IIIC). Conclusion: CME with CVL in right-sided colon adenocarcinoma increases the probability of complete removal of the local lymph node drainage and thus local metastatic lymph nodes. Considering this result an improvement of long-term survival by the CME procedure seems conceivable but needs to be confirmed by the current multicentre trial.
[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: 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 06/2014; · 2.28 Impact Factor
[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: GIST sind mesenchymale Tumoren, deren Ursprung in den interstitiellen Cajal-Zellen vermutet wird. Charakteristisch ist eine CD117-Expression, die auf einer aktivierenden Mutation des Tyrosinkinaserezeptors basiert, die zu einem unkontrollierten Proliferationsreiz und dem Verlust der Apoptosefunktion mit konsekutivem Tumorwachstum führt. Einige GIST sind CD117-negativ und weisen eine Mutation des PDGFRA-Gens („platelet derived growth factor receptor α“) auf. Die Bestimmung des c-KIT- bzw. PDGFRA-Status ist deshalb für die Diagnosestellung obligat. Klinisch gibt es 3 entscheidende Prognosefaktoren: Tumorgröße, -lokalisation und -mitoserate. Goldstandard für lokalisierte, resezierbare GIST ist die komplette chirurgische Resektion. In Abhängigkeit vom Rezidivrisiko erfolgt eine Therapie mit Imatinib (adjuvant 400 mg über 3 Jahre). Auch bei lokal fortgeschrittenen, inoperablen oder metastasierten GIST ist Imatinib je nach Mutationsstatus aktuelle Standardtherapie.
Gastrointestinal stromal tumors (GIST) are mesenchymal tumors arising form the interstitial cells of Cajal and are characterized by the expression of CD117 (c-kit). The CD117 expression is caused by an activating mutation of the tyrosine kinase receptor resulting in a loss of apoptosis and uncontrolled proliferation of the tumor. Some GIST are negative for CD117 and these tumors show a mutation in the platelet-derived growth factor receptor alpha (PDGFRA). Identification of the CD117 and PDGFRA mutations is obligatory to diagnose GIST. Clinical behavior depends on tumor size, tumor origin and frequency of mitoses. Currently, surgery represents the standard treatment for patients with localized resectable disease and an R0 resection is the goal. Depending on the risk of recurrence a therapy with imatinib will be started. The gold standard in adjuvant treatment is 400 mg imatinib for 3 years. In locally advanced inoperable or metastatic GIST and depending on the mutation imatinib is also the current standard treatment.
Der Onkologe 03/2014; 20(3):277-290. · 0.13 Impact Factor
[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. · 1.87 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