[Show abstract][Hide abstract] ABSTRACT: In recent years spectral histopathology (SHP) is established as label free method, to identify cancer within tissue. Here, this approach is extended. It is not only used to identify tumour tissue with a sensitivity of 94 % and a specificity of 100 %, but in addition the tumour grading is determined. Grading is a measure how much the tumour cells differ from the healthy cells. The grading refers to G1 (well differentiated) over G2 (moderately differentiated) to G3 (poorly differentiated) and in rare cases to G4 (anaplastic). The grading is prognostic and is needed for the therapeutic decision of the clinician. The presented results showed a nice agreement between the annotation by the SHP and by the pathologists. A correlation matrix is presented. The presented results show, that SHP provide prognostic values in colon cancer, which are obtained label free and automated. It might become an important automated diagnostic tool at the bedside in precision medicine.
No preview · Article · Dec 2015 · Faraday Discussions
[Show abstract][Hide abstract] ABSTRACT: Background:
In recent years, hyperspectral microscopy techniques such as infrared or Raman microscopy have been applied successfully for diagnostic purposes. In many of the corresponding studies, it is common practice to measure one and the same sample under different types of microscopes. Any joint analysis of the two image modalities requires to overlay the images, so that identical positions in the sample are located at the same coordinate in both images. This step, commonly referred to as image registration, has typically been performed manually in the lack of established automated computational registration tools.
We propose a corresponding registration algorithm that addresses this registration problem, and demonstrate the robustness of our approach in different constellations of microscopes. First, we deal with subregion registration of Fourier Transform Infrared (FTIR) microscopic images in whole-slide histopathological staining images. Second, we register FTIR imaged cores of tissue microarrays in their histopathologically stained counterparts, and finally perform registration of Coherent anti-Stokes Raman spectroscopic (CARS) images within histopathological staining images.
Our validation involves a large variety of samples obtained from colon, bladder, and lung tissue on three different types of microscopes, and demonstrates that our proposed method works fully automated and highly robust in different constellations of microscopes involving diverse types of tissue samples.
Full-text · Article · Dec 2015 · BMC Bioinformatics
[Show abstract][Hide abstract] ABSTRACT: The reported prevalence of focal liver lesions in adult patients and children is different. The article discusses pediatric liver tumors under the criteria of histopathology and contrast enhanced ultrasound (CEUS) features. Aim of this article is also to support the already established Pediatric Registry of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) to collect data on safety and applications of ultrasound contrast agents in children (www.efsumb.org).
No preview · Article · Nov 2015 · Zeitschrift für Gastroenterologie
[Show abstract][Hide abstract] ABSTRACT: Hilar cholangiocarcinoma (CC) is non-resectable in the majority of patients often due to intrahepatic extension along bile duct branches/segments, and even after complete resection (R0) recurrence can be as high as 70%. Photodynamic therapy (PDT) is an established palliative local tumor ablative treatment for non-resectable hilar CC. We report the long-term outcome of curative resection (R0) performed after neoadjuvant PDT for downsizing of tumor margins in seven patients (median age 59 years) with initially non-resectable hilar CC. Photofrin(®) was injected intravenously 24-48 h before laser light irradiation of the tumor stenoses and the adjacent bile duct segments. Major resective surgery was done with curative intention six weeks after PDT. All seven patients had been curatively (R0) resected and there were no undue early or late complications for the neoadjuvant PDT and surgery. Six of seven patients died from tumor recurrence at a median of 3.2 years after resection, the five-year survival rate was 43%. These results are comparable with published data for patients resected R0 without pre-treatment, indicating that neoadjuvant PDT is feasible and could improve overall survival of patients considered non-curatively resectable because of initial tumor extension in bile duct branches/segments-however, this concept needs to be validated in a larger trial.
Preview · Article · Nov 2015 · International Journal of Molecular Sciences
[Show abstract][Hide abstract] ABSTRACT: Objectives:
Oral squamous cell carcinomas, and tongue malignancies in particular, are among the most common tumors of the oral cavity. Classification for therapeutic and prognostic purposes is routinely made using the tumor, node, metastasis (TNM) system; however, current definitions do not include tumor thickness. We therefore aimed to identify variables associated with survival, and to evaluate the correlation between tumor thickness and the occurrence of lymph node metastasis.
Patients and methods:
All patients undergoing radical tumor resection for squamous cell carcinomas of the tongue between 2000 and 2012 were included. Specimens were analyzed histopathologically and co-variables were interpreted. Follow-up was performed clinically and radiologically for at least 3years according to current guidelines.
We included 492 patients who had a median follow-up of 70months. Variables associated with survival (p<0.05) were age, tumor stage, N stage, UICC (Union for International Cancer Control) stage, tumor grade, and recurrence. In the receiver operating characteristic curve and Youden-Index analyses, the optimal tumor thickness cut-off was 8mm to detect significant differences in overall survival.
We highlight the importance of tumor thickness as a predictive variable in tongue cancer. Specifically, a cut-off point of 8mm allowed for a more accurate and statistically precise prediction of lymph node metastasis. These findings could supplement the current classification of tongue cancers and form the basis for treatment.
[Show abstract][Hide abstract] ABSTRACT: The gastrointestinal hormone GLP-1 is released from enteroendocrine L-cells and augments postprandial insulin secretion. In patients with type 2 diabetes, the incretin effect is markedly diminished. It is unclear, whether this is due to a reduction in the abundance of L-cells in the intestine.
[Show abstract][Hide abstract] ABSTRACT: Background:
The definition of a best maintenance strategy following combination chemotherapy plus bevacizumab in metastatic colorectal cancer is unclear. We investigated whether no continuation of therapy or bevacizumab alone are non-inferior to fluoropyrimidine plus bevacizumab, following induction treatment with a fluoropyrimidine plus oxaliplatin plus bevacizumab.
In this open-label, non-inferiority, randomised phase 3 trial, we included patients aged 18 years or older with histologically confirmed, previously untreated metastatic colorectal cancer, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, adequate bone marrow, liver, and renal function, no pre-existing neuropathy greater than grade 1, and measurable disease, from 55 hospitals and 51 private practices in Germany. After 24 weeks of induction therapy with either fluorouracil plus leucovorin plus oxaliplatin or capecitabine plus oxaliplatin, both with bevacizumab, patients without disease progression were randomly assigned centrally by fax (1:1:1) to standard maintenance treatment with a fluoropyrimidine plus bevacizumab, bevacizumab alone, or no treatment. Both patients and investigators were aware of treatment assignment. Stratification criteria were response status, termination of oxaliplatin, previous adjuvant treatment with oxaliplatin, and ECOG performance status. At first progression, re-induction with all drugs of the induction treatment was a planned part of the protocol. Time to failure of strategy was the primary endpoint, defined as time from randomisation to second progression after maintenance (and if applicable re-induction), death, or initiation of further treatment including a new drug. Time to failure of strategy was equivalent to time to first progression for patients who did not receive re-induction (for any reason). The boundary for assessment of non-inferiority was upper limit of the one-sided 98·8% CI 1·43. Analyses were done by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov, number NCT00973609.
Between Sept 17, 2009, and Feb 21, 2013, 837 patients were enrolled and 472 randomised; 158 were randomly assigned to receive fluoropyrimidine plus bevacizumab, 156 to receive bevacizumab monotherapy, and 158 to receive no treatment. Median follow-up from randomisation is 17·0 months (IQR 9·5-25·4). Median time to failure of strategy was 6·9 months (95% CI 6·1-8·5) for the fluoropyrimidine plus bevacizumab group, 6·1 months (5·3-7·4) for the bevacizumab alone group, and 6·4 months (4·8-7·6) for the no treatment group. Bevacizumab alone was non-inferior to standard fluoropyrimidine plus bevacizumab (hazard ratio [HR] 1·08 [95% CI 0·85-1·37]; p=0·53; upper limit of the one-sided 99·8% CI 1·42), whereas no treatment was not (HR 1·26 [0·99-1·60]; p=0·056; upper limit of the one-sided 99·8% CI 1·65). The protocol-defined re-induction after first progression was rarely done (30 [19%] patients in the fluoropyrimidine plus bevacizumab group, 67 [43%] in the bevacizumab monotherapy group, and 73 [46%] in the no treatment group. The most common grade 3 adverse event was sensory neuropathy (21 [13%] of 158 patients in the fluoropyrimidine plus bevacizumab group, 22 [14%] of 156 patients in the bevacizumab alone group, and 12 [8%] of 158 patients in the no treatment group).
Although non-inferiority for bevacizumab alone was demonstrated for the primary endpoint, maintenance treatment with a fluoropyrimidine plus bevacizumab may be the preferable option for patients following an induction treatment with a fluoropyrimidine, oxaliplatin, and bevacizumab, as it allows the planned discontinuation of the initial combination without compromising time with controlled disease. Only a few patients were exposed to re-induction treatment, thus deeming the primary endpoint time to failure of strategy non-informative and clinically irrelevant. Progression-free survival and overall survival should be considered primary endpoints in future trials exploring maintenance strategies.
RochePharma AG and AIO Studien gGmbH.
Full-text · Article · Sep 2015 · The Lancet Oncology
[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.
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.
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).
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.
No preview · Article · Aug 2015 · Zentralblatt fur Chirurgie, Supplement
[Show abstract][Hide abstract] ABSTRACT: Benign hepatic tumors are commonly observed in adults, but rarely reported in children. The reasons for this remain speculative and the exact data concerning the incidence of these lesions are lacking. Benign hepatic tumors represent a diverse group of epithelial and mesenchymal tumors. In pediatric patients, most benign focal liver lesions are inborn and may grow like the rest of the body. Knowledge of pediatric liver diseases and their imaging appearances is essential in order to make an appropriate differential diagnosis. Selection of the appropriate imaging test is challenging, since it depends on a number of age-related factors. This paper will discuss the most frequently encountered benign liver tumors in children (infantile hepatic hemangioendothelioma, mesenchymal hamartoma, focal nodular hyperplasia, nodular regenerative hyperplasia, and hepatocellular adenoma), as well as a comparison to the current knowledge regarding such tumors in adult patients. The current emphasis is on imaging features, which are helpful not only for the initial diagnosis, but also for pre- and posttreatment evaluation and follow-up. In addition, future perspectives of contrast-enhanced ultrasound (CEUS) in pediatric patients are highlighted, with descriptions of enhancement patterns for each lesion being discussed. The role of advanced imaging tests such as CEUS and magnetic resonance imaging, which allow for non-invasive assessment of liver tumors, is of utmost importance in pediatric patients, especially when repeated imaging tests are needed and radiation exposure should be avoided.
Full-text · Article · Jul 2015 · World Journal of Gastroenterology
[Show abstract][Hide abstract] ABSTRACT: Current evidence suggests that complete mesocolic excision (CME) for right-sided colon cancer could be beneficial in terms of long-term survival. However, CME is a considerably more complex operation than standard right hemicolectomy; this is especially true for the laparoscopic approach. Consequently, we have explored a new laparoscopic approach that provides surgical radicality at the mesenteric root on the one hand and maximum safety on the other hand.
The key feature of the uncinate process first approach (UFA) is the commencement of the dissection at the fourth part of the duodenum using a medial to lateral approach, thus mobilizing the whole mesenteric root posteriorly before the central parts of the mesenteric vessels are accessed. Twenty-eight selected patients with right-sided colon cancer underwent surgery using the UFA and were compared with 51 patients who underwent an open CME procedure (CON). In 11/28 and 51/51 patients in the UFA and CON groups, respectively, a planimetric assessment of the specimen was performed.
Surgical time was longer (144.8 vs. 202.5 min; p < 0.000) and postoperative stay shorter (8.0 vs. 10.5 days; p < 0.01) for the laparoscopic approach. The area of the resected mesentery (UFA, 15,097 mm(2); CON, 15,788 mm(2); p = 0.47) and the lymph node count (UFA, 59.0; CON, 51.0; p = 0.09) was not significantly different; additionally, no difference was observed regarding anastomotic leakage (both n = 0) and postoperative mortality (UFA, 0/28; CON, 1/51; p = 1.0).
Laparoscopic right hemicolectomy with CME using the UFA provides adequate radicality according to the CME principles and seems feasible and as safe as an open technique. However, future trails will have to demonstrate whether the theoretical advantages of the UFA, with a higher degree of mobility and accessibility of the mesenteric root, translate into a significant clinical benefit, especially relative to the other laparoscopic techniques.
No preview · Article · Jul 2015 · Surgical Endoscopy
[Show abstract][Hide abstract] ABSTRACT: The chemosensory capacity of the somatosensory system relies on the appropriate expression of chemoreceptors, which detect chemical stimuli and transduce sensory information into cellular signals. Knowledge of the complete repertoire of the chemoreceptors expressed in human sensory ganglia is lacking. This study employed the next-generation sequenc-ing technique (RNA-Seq) to conduct the first expression analysis of human trigeminal ganglia (TG) and dorsal root ganglia (DRG). We analyzed the data with a focus on G-protein coupled receptors (GPCRs) and ion channels, which are (potentially) involved in chemo-sensation by somatosensory neurons in the human TG and DRG. For years, transient receptor potential (TRP) channels have been considered the main group of receptors for chemosensation in the trigeminal system. Interestingly, we could show that sensory ganglia also express a panel of different olfactory receptors (ORs) with putative chemosensory function. To characterize OR expression in more detail, we performed microarray, semi-quantitative RT-PCR experiments, and immunohistochemical staining. Additionally, we analyzed the expression data to identify further known or putative classes of chemoreceptors in the human TG and DRG. Our results give an overview of the major classes of chemore-ceptors expressed in the human TG and DRG and provide the basis for a broader understanding of the reception of chemical cues.
[Show abstract][Hide abstract] ABSTRACT: Blood-based early detection of breast cancer has recently gained novel momentum, as liquid biopsy diagnostics is a fast emerging field. In this study, we aimed to identify secreted proteins which are up-regulated both in tumour tissue and serum samples of breast cancer patients compared to normal tissue and sera. Based on two independent tissue cohorts (n = 75 and n = 229) and one serum cohort (n = 80) of human breast cancer and healthy serum samples, we characterised AGR3 as a novel potential biomarker both for breast cancer prognosis and early breast cancer detection from blood. AGR3 expression in breast tumours is significantly associated with oestrogen receptor α (P<0.001) and lower tumour grade (P<0.01). Interestingly, AGR3 protein expression correlates with unfavourable outcome in low (G1) and intermediate (G2) grade breast tumours (multivariate hazard ratio: 2.186, 95% CI: 1.008-4.740, P<0.05) indicating an independent prognostic impact. In sera analysed by ELISA technique, AGR3 protein concentration was significantly (P<0.001) elevated in samples from breast cancer patients (n = 40, mainly low stage tumours) compared to healthy controls (n = 40). To develop a suitable biomarker panel for early breast cancer detection, we measured AGR2 protein in human serum samples in parallel. The combined AGR3/AGR2 biomarker panel achieved a sensitivity of 64.5% and a specificity of 89.5% as shown by receiver operating characteristic (ROC) curve statistics. Thus our data clearly show the potential usability of AGR3 and AGR2 as biomarkers for blood-based early detection of human breast cancer.