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1.  Mutated KRAS Results in Overexpression of DUSP4, a MAP-Kinase Phosphatase, and SMYD3, a Histone Methyltransferase, in Rectal Carcinomas 
Genes, chromosomes & cancer  2010;49(11):1024-1034.
Mutations of the KRAS oncogene are predictive for resistance to treatment with antibodies against the epithelial growth factor receptor in patients with colorectal cancer. Overcoming this therapeutic dilemma could potentially be achieved by the introduction of drugs that inhibit signaling pathways that are activated by KRAS mutations. To identify comprehensively such signaling pathways we profiled pretreatment biopsies and normal mucosa from 65 patients with locally advanced rectal cancer - 30 of which carried mutated KRAS - using global gene expression microarrays. By comparing all tumor tissues exclusively to matched normal mucosa, we could improve assay sensitivity, and identified a total of 22,297 features that were differentially expressed (adjusted P-value <0.05) between normal mucosa and cancer, including several novel potential rectal cancer genes. We then used this comprehensive description of the rectal cancer transcriptome as the baseline for identifying KRAS-dependent alterations. The presence of activating KRAS mutations is significantly correlated to an upregulation of 13 genes (adjusted P-value <0.05), among them DUSP4, a MAP-kinase phosphatase, and SMYD3, a histone methyltransferase. Inhibition of the expression of both genes has previously been shown using the MEK1-inhibitor PD98059 and the antibacterial compound Novobiocin, respectively. These findings suggest a potential approach to overcome resistance to treatment with antibodies against the epithelial growth factor receptor in patients with KRAS-mutant rectal carcinomas.
doi:10.1002/gcc.20811
PMCID: PMC3535184  PMID: 20725992
2.  Silencing of the Wnt transcription factor TCF4 sensitizes colorectal cancer cells to (chemo-) radiotherapy 
Carcinogenesis  2011;32(12):1824-1831.
A considerable percentage of rectal cancers are resistant to standard preoperative chemoradiotherapy. Because patients with a priori-resistant tumors do not benefit from multimodal treatment, understanding and overcoming this resistance remains of utmost clinical importance. We recently reported overexpression of the Wnt transcription factor TCF4, also known as TCF7L2, in rectal cancers that were resistant to 5-fluorouracil-based chemoradiotherapy. Because Wnt signaling has not been associated with treatment response, we aimed to investigate whether TCF4 mediates chemoradioresistance. RNA interference-mediated silencing of TCF4 was employed in three colorectal cancer (CRC) cell lines, and sensitivity to (chemo-) radiotherapy was assessed using a standard colony formation assay. Silencing of TCF4 caused a significant sensitization of CRC cells to clinically relevant doses of X-rays. This effect was restricted to tumor cells with high T cell factor (TCF) reporter activity, presumably in a β-catenin-independent manner. Radiosensitization was the consequence of (i) a transcriptional deregulation of Wnt/TCF4 target genes, (ii) a silencing-induced G2/M phase arrest, (iii) an impaired ability to adequately halt cell cycle progression after radiation and (iv) a compromised DNA double strand break repair as assessed by γH2AX staining. Taken together, our results indicate a novel mechanism through which the Wnt transcription factor TCF4 mediates chemoradioresistance. Moreover, they suggest that TCF4 is a promising molecular target to sensitize resistant tumor cells to (chemo-) radiotherapy.
doi:10.1093/carcin/bgr222
PMCID: PMC3254167  PMID: 21983179
3.  Gender-Specific Acute Organ Toxicity during Intensified Preoperative Radiochemotherapy for Rectal Cancer 
The Oncologist  2011;16(5):621-631.
Patients with locally advanced rectal cancer (cUICC stages II/III) are typically treated with preoperative 5-fluorouracil–based (5-FU–based) radiochemotherapy. However, trials are currently being conducted to improve the complete remission rates and the systemic control by combining 5-FU with oxaliplatin in order to identify the subgroups of rectal cancer patients at risk for high-grade toxicity. The results indicate that there are basic clinical parameters, such as gender and body mass index, that may be potential markers for generating individual risk profiles of radiochemotherapy-induced toxicity.
Learning Objectives
After completing this course, the reader will be able to: Describe present strategies of treatment of locally advanced rectal cancer and ongoing clinical trials, including neoadjuvant radiochemotherapy with 50.4 Gy and concomitant 5-FU +/− oxaliplatin.Define the basic clinical parameters, with special emphasis on gender and BMI, correlating with radiochemotherapy-associated side effects in rectal cancer patients and differences in severity of toxicity.
This article is available for continuing medical education credit at CME.TheOncologist.com
Patients with locally advanced rectal cancer (cUICC stages II/III) are typically treated with preoperative 5-fluorouracil–based (5-FU–based) radiochemotherapy (RCT). However, trials are currently being conducted to improve the complete remission rates and the systemic control by combining 5-FU with oxaliplatin. The primary objective was to identify the subgroups of rectal cancer patients who were at risk for high-grade toxicity.
All 196 patients who were included in the present study were treated with 50.4 Gy and chemotherapy that included either 5-FU (n = 115) or 5-FU+oxaliplatin (n = 81). The preoperative RCT was followed by a total mesorectal excision and adjuvant chemotherapy. Acute toxicity was monitored weekly and a toxicity grade ≥3 (Common Toxicity Criteria) for a skin reaction, cystitis, proctitis, or enteritis was defined as high-grade acute organ toxicity. After RCT with 5-FU+oxaliplatin, complete tumor remission was achieved in 13.6% of the patients and in 11.3% after RCT with 5-FU alone.
Complete irradiation dosages of 50.4 Gy were given to 99% (5-FU) and 95% (5-FU+oxaliplatin) of the patients. Concomitant chemotherapy was fully administered in 95% of the patients treated with 5-FU compared with the 84% of patients treated with 5-FU+oxaliplatin.
A significantly higher proportion of acute organ toxicity was found in the patients who were treated with 5-FU+oxaliplatin compared with those who were treated with 5-FU. Additionally, women with a low body mass index were at the highest risk for acute organ toxicity.
These results suggest that there are basic clinical parameters, such as gender and body mass index, that may be potential markers for generating individual risk profiles of RCT-induced toxicity.
doi:10.1634/theoncologist.2010-0414
PMCID: PMC3228181  PMID: 21558132
Rectal cancer; Gender effect; Radiochemotherapy; Toxicity; Body mass index
4.  A genomic strategy for the functional validation of colorectal cancer genes identifies potential therapeutic targets 
Summary/Abstract
Genes that are highly overexpressed in tumor cells can be required for tumor cell survival, and have the potential to be selective therapeutic targets. In an attempt to identify such targets, we combined a functional genomics and a systems biology approach to assess the consequences of RNAi-mediated silencing of overexpressed genes that were selected from 140 gene expression profiles from colorectal cancers (CRC) and matched normal mucosa. In order to identify credible models for in-depth functional analysis, we first confirmed the overexpression of these genes in 25 different CRC cell lines. We then identified five candidate genes that profoundly reduced the viability of CRC cell lines when silenced with either siRNAs or shRNAs, i.e., HMGA1, TACSTD2, RRM2, RPS2, and NOL5A. These genes were further studied by systematic analysis of comprehensive gene expression profiles generated following siRNA-mediated silencing. Exploration of these RNAi-specific gene expression signatures allowed the identification of the functional space in which the five genes operate, and showed enrichment for cancer specific signaling pathways, some known to be involved in CRC. By comparing the expression of the RNAi signature genes with their respective expression levels in an independent set of primary rectal carcinomas we could recapitulate these defined RNAi signatures, therefore establishing the biologically relevance of our observations. This strategy identified the signaling pathways that are affected by the prominent oncogenes HMGA1 and TACSTD2, established a yet unknown link between RRM2 and PLK1, and identified RPS2 and NOL5A as promising potential therapeutic targets in CRC.
doi:10.1002/ijc.25453
PMCID: PMC3008507  PMID: 20473941
Colorectal cancer; RNAi; functional genomics; systems biology; therapeutic targets
5.  Ultrasonic scalpel causes greater depth of soft tissue necrosis compared to monopolar electrocautery at standard power level settings in a pig model 
BMC Surgery  2012;12:3.
Background
Ultrasonic scalpel (UC) and monopolar electrocautery (ME) are common tools for soft tissue dissection. However, morphological data on the related tissue alteration are discordant. We developed an automatic device for standardized sample excision and compared quality and depth of morphological changes caused by UC and ME in a pig model.
Methods
100 tissue samples (5 × 3 cm) of the abdominal wall were excised in 16 pigs. Excisions were randomly performed manually or by using the self-constructed automatic device at standard power levels (60 W cutting in ME, level 5 in UC) for abdominal surgery. Quality of tissue alteration and depth of coagulation necrosis were examined histopathologically. Device (UC vs. ME) and mode (manually vs. automatic) effects were studied by two-way analysis of variance at a significance level of 5%.
Results
At the investigated power level settings UC and ME induced qualitatively similar coagulation necroses. Mean depth of necrosis was 450.4 ± 457.8 μm for manual UC and 553.5 ± 326.9 μm for automatic UC versus 149.0 ± 74.3 μm for manual ME and 257.6 ± 119.4 μm for automatic ME. Coagulation necrosis was significantly deeper (p < 0.01) when UC was used compared to ME. The mode of excision (manual versus automatic) did not influence the depth of necrosis (p = 0.85). There was no significant interaction between dissection tool and mode of excision (p = 0.93).
Conclusions
Thermal injury caused by UC and ME results in qualitatively similar coagulation necrosis. The depth of necrosis is significantly greater in UC compared to ME at investigated standard power levels.
doi:10.1186/1471-2482-12-3
PMCID: PMC3305372  PMID: 22361346
6.  A TNF-Regulated Recombinatorial Macrophage Immune Receptor Implicated in Granuloma Formation in Tuberculosis 
PLoS Pathogens  2011;7(11):e1002375.
Macrophages play a central role in host defense against mycobacterial infection and anti- TNF therapy is associated with granuloma disorganization and reactivation of tuberculosis in humans. Here, we provide evidence for the presence of a T cell receptor (TCR) αβ based recombinatorial immune receptor in subpopulations of human and mouse monocytes and macrophages. In vitro, we find that the macrophage-TCRαβ induces the release of CCL2 and modulates phagocytosis. TNF blockade suppresses macrophage-TCRαβ expression. Infection of macrophages from healthy individuals with mycobacteria triggers formation of clusters that express restricted TCR Vβ repertoires. In vivo, TCRαβ bearing macrophages abundantly accumulate at the inner host-pathogen contact zone of caseous granulomas from patients with lung tuberculosis. In chimeric mouse models, deletion of the variable macrophage-TCRαβ or TNF is associated with structurally compromised granulomas of pulmonary tuberculosis even in the presence of intact T cells. These results uncover a TNF-regulated recombinatorial immune receptor in monocytes/macrophages and demonstrate its implication in granuloma formation in tuberculosis.
Author Summary
Infection with mycobacteria results in a host response which results in the formation of granulomas, highly organized structures characterized by the presence of macrophages, which are considered to rely solely on invariant immune receptors. On the other hand, the presence of variable immune receptors is required for granuloma formation but this process is not solely dependent on T cells. Furthermore, TNF is required for the maintenance of the mycobacterial granuloma structure in humans. We now find evidence for subpopulations of human and mouse macrophages that express variable αβ T cell receptors (TCRαβ). Engagement of the macrophage-TCRαβ triggers CCL2 release and phagocytosis of baits directed to this receptor is enhanced. TCRαβ bearing macrophages accumulate in human tuberculosis granulomas and anti-TNF treatment of macrophages results in downregulation of the TCRαβ, which is associated with caspase 3 cleavage and suppression of TCRξ. Anti-TNF treatment reduces mycobacteria induced cluster formation of TCRαβ positive macrophages, which is in line with reduced granuloma formation in rag1–/–(T cell rag1+/+) and TNF–/–(T cell TNF+/+) chimeric mice. Consequently, both chimeras show reduced CCL2 staining after mycobacterial infection. In summary, we have identified a recombinatorial immunoreceptor in monocytes/macrophages and demonstrate its implication in mycobacterial infection.
doi:10.1371/journal.ppat.1002375
PMCID: PMC3219713  PMID: 22114556
7.  Thymidylate Synthase as a Prognostic Biomarker for Locally Advanced Rectal Cancer after multimodal Treatment 
Annals of Surgical Oncology  2011;18(9):2442-2452.
Purpose
For years, 5-fluorouracil (5-FU) has been the backbone of radiochemotherapy (RCT) of locally advanced rectal cancer. Its main target, thymidylate synthase (TS), is speculated to be an important biomarker for response prediction and long-term prognosis. In this study, we analyzed TS expression in the rectal cancer tissue of 208 patients to evaluate its predictive/prognostic potential.
Methods
All patients included were diagnosed with locally advanced adenocarcinoma of the rectum (UICC II and III) and were treated within randomized clinical trials of the German Rectal Cancer Study Group. Preoperative RCT (50.4 Gy and concomitant either 5-FU or 5-FU and oxaliplatin) was administered in 167 patients followed by surgical resection with total mesorectal excision (TME). Another 41 patients received postoperative RCT. TS levels and further clinicopathological parameters were assessed in univariate and multivariate analyses. Additionally, a TS gene polymorphism was analyzed with respect to the intratumoral protein levels.
Results
Low TS expression in pretreatment biopsies correlated with impaired patient survival (p = 0.015). Analysis of a 28-bp repeat revealed a correlation between the *3/*3 genotype and high TS expression in pretherapeutic biopsies. In this study, a correlation of TS expression and grade of RCT-induced tumor regression was not found. Histopathological examination confirmed a complete tumor remission in 16 patients (9.6%).
Analyses of the resection specimen indicated an unfavorable prognosis for patients with low intratumoral TS expression in case of detected lymph node metastases (p = 0.04).
Conclusions
TS can serve as a prognostic biomarker indicating an unfavorable prognosis for patients with low TS expression.
Electronic supplementary material
The online version of this article (doi:10.1245/s10434-011-1608-4) contains supplementary material, which is available to authorized users.
doi:10.1245/s10434-011-1608-4
PMCID: PMC3162628  PMID: 21347782
8.  The plasminogen activator inhibitor system in colon cancer cell lines is influenced by the CO2 pneumoperitoneum 
Purpose
Laparoscopic surgery in the treatment of colon carcinoma causes pH value alterations as well as changes in fibrinolytic activity. This results in enhanced proliferation of colon carcinoma cells in vitro and also in enhanced growth of liver metastasis when compared to isobaric (gasless) laparoscopy in vivo. So far, the direct influence of CO2 pneumoperitoneum on the invasiveness and metastatic capabilities of colon cancer cells remains unclear. We therefore evaluated transcripts of the uPA system.
Methods
The influence of CO2 pneumoperitoneum on the gene expression of plasminogen activator inhibitor-1 (PAI-1), urokinase-type plasminogen activator (uPA), and tissue-type plasminogen activator (tPA) was investigated in colon carcinoma cell lines (HT116, SW48, and WiDr) and mesothelial cells employing a pneumoperitoneum chamber in vitro. Quantitative gene expression data were collected using real-time RT-PCR and statistical analysis was performed by means of analysis of variance and Bonferroni correction.
Results
The expression of uPA and PAI-1 was increased in colon carcinoma cell lines when cultivated at pH 6.1, a value corresponding to intraabdominal pH values during CO2 insufflation. Elevated PAI-1 mRNA levels were also observed when CO2 was simultaneously applied with a pressure of 10 mmHg. In contrast, there were no significant changes in mesothelial cells in the investigated parameter.
Conclusion
The conditions of CO2 pneumoperitoneum cause changes in the expression of genes controlling the fibrinolytic activity. The increase of PAI-1 and uPA can contribute to the enhancement of metastasis and invasive potential of tumour cells. Therefore, changes in the conditions of laparoscopy may well optimise laparoscopic therapy in colon cancer.
doi:10.1007/s00384-010-1062-y
PMCID: PMC3015214  PMID: 20931209
CO2 pneumoperitoneum; Metastasis; Plasmin activator system; Tumour cell lines
9.  Liver sinusoidal endothelial and biliary cell repopulation following irradiation and partial hepatectomy 
AIM: To investigate whether irradiation (IR) and partial hepatectomy (PH) may prepare the host liver for non-parenchymal cell (NPC) transplantation.
METHODS: Livers of dipeptidyl peptidase IV (DPPIV)-deficient rats were pre-conditioned with external beam IR (25 Gy) delivered to two-thirds of the right liver lobules followed by a one-third PH of the untreated lobule. DPPIV-positive liver cells (NPC preparations enriched for liver sinusoidal endothelial cells (LSECs) and hepatocytes) were transplanted via the spleen into the recipient livers. The extent and quality of donor cell engraftment and growth was studied over a long-term interval of 16 wk after transplantation.
RESULTS: Host liver staining demonstrated 3 different repopulation types. Well defined clusters of donor-derived hepatocytes with canalicular expression of DPPIV were detectable either adjacent to or in between large areas of donor cells (covering up to 90% of the section plane) co-expressing the endothelial marker platelet endothelial cell adhesion molecule. The third type consisted of formations of DPPIV-positive duct-like structures which co-localized with biliary epithelial CD49f.
CONCLUSION: Liver IR and PH as a preconditioning stimulus enables multiple cell liver repopulation by donor hepatocytes, LSECs, and bile duct cells.
doi:10.3748/wjg.v16.i31.3928
PMCID: PMC2923767  PMID: 20712054
Cell transplants; Dipeptidyl peptidase IV protein; Endothelial cells; Liver cell transplantation; Liver irradiation; Liver repopulation
10.  Chromosomal copy number changes of locally advanced rectal cancers treated with preoperative chemoradiotherapy 
Cancer Genetics and Cytogenetics  2009;193(1):19-28.
Introduction
Standard treatment of rectal cancer patients comprises preoperative chemoradiotherapy followed by radical surgery. However, clinicians are faced with the problem that response rates vary from one individual to another. Predictive biomarkers would therefore be helpful.
Materials and Methods
In order to identify genomic imbalances that might assist in stratifying tumors into responsive or non-responsive, we used metaphase comparative genomic hybridization to prospectively analyze pre-therapeutic biopsies from 42 patients with locally advanced rectal cancers. These patients were subsequently treated with 5-FU based preoperative chemoradiotherapy.
Results
Based on downsizing of the T-category, 21 rectal cancers were later classified as responsive, while 21 were non-responsive. Comparing these two groups, we could show that gains of chromosomal regions 7q32-q36 and 7q11-q31, and amplifications of 20q11-q13 were significantly associated with responsiveness to preoperative chemoradiotherapy (P<0.05). However, the probability to detect these copy number changes by chance is high (P=0.21).
Conclusion
Our primary results suggest that pre-therapeutic evaluation of chromosomal copy number changes may be of value for response prediction of rectal cancers to preoperative chemoradiotherapy. This will require validation in a larger cohort of patients.
doi:10.1016/j.cancergencyto.2009.03.016
PMCID: PMC2714587  PMID: 19602460
Rectal cancer; 5-FU-based preoperative chemoradiotherapy; therapeutic response; copy number changes; response prediction
11.  Preoperative Chemoradiotherapy in Locally Advanced Rectal Cancer: Correlation of a Gene Expression-Based Response Signature with Recurrence 
Cancer Genetics and Cytogenetics  2009;190(2):57-65.
Background
Preoperative chemoradiotherapy is recommended for locally advanced rectal cancer (UICC stage II/III). We recently demonstrated that responsive and non-responsive tumors showed differential expression levels of 54 genes. In this follow-up study, we investigated the relationship between this gene-set and disease-free (DFS) and overall survival (OS).
Methods
Pre-therapeutic biopsies from 30 participants in the CAO/ARO/AIO-94 trial of the German Rectal Cancer Study Group were analyzed using gene expression microarrays. Statistical analysis was performed to identify differentially expressed genes between recurrent and non-recurrent tumors and to correlate these changes with disease recurrence and outcome.
Results
After a median follow-up of 59 months, seven of eight patients with recurrent disease belonged to the group of non-responders, while one responsive tumor recurred. Response to chemoradiotherapy was significantly correlated with an improved DFS (log rank p=0.028), while the OS did not differ significantly (p=0.11). Applying a class comparison analysis we identified 20 genes that were differentially expressed between recurrent and non-recurrent tumors at p<0.001. Analyzing the first two principal components of the 54 genes previously identified to predict response, we observed that this response signature correlated with an increased risk of cancer recurrence.
Conclusions
These data suggest that the genetic basis of local response also affects the genetic basis of tumor recurrence, and we demonstrated that genes that are indicative of non-response to preoperative chemoradiotherapy might also be linked to an increased risk of tumor recurrence.
doi:10.1016/j.cancergencyto.2008.11.011
PMCID: PMC2766806  PMID: 19380020
Rectal cancer; gene expression profiling; 5-FU-based preoperative chemoradiotherapy; recurrence; prognosis
12.  Stage II/III rectal cancer with intermediate response to preoperative radiochemotherapy: Do we have indications for individual risk stratification? 
Background
Response to preoperative radiochemotherapy (RCT) in patients with locally advanced rectal cancer is very heterogeneous. Pathologic complete response (pCR) is accompanied by a favorable outcome. However, most patients show incomplete response. The aim of this investigation was to find indications for risk stratification in the group of intermediate responders to RCT.
Methods
From a prospective database of 496 patients with rectal adenocarcinoma, 107 patients with stage II/III cancers and intermediate response to preoperative 5-FU based RCT (ypT2/3 and TRG 2/3), treated within the German Rectal Cancer Trials were studied. Surgical treatment comprised curative (R0) total mesorectal excision (TME) in all cases. In 95 patients available for statistical analyses, residual transmural infiltration of the mesorectal compartment, nodal involvement and histolologic tumor grading were investigated for their prognostic impact on disease-free (DFS) and overall survival (OS).
Results
Residual tumor transgression into the mesorectal compartment (ypT3) did not influence DFS and OS rates (p = 0.619, p = 0.602, respectively). Nodal involvement after preoperative RCT (ypN1/2) turned out to be a valid prognostic factor with decreased DFS and OS (p = 0.0463, p = 0.0236, respectively). Persistent tumor infiltration of the mesorectum (ypT3) and histologic tumor grading of residual tumor cell clusters were strongly correlated with lymph node metastases after neoadjuvant treatment (p < 0.001).
Conclusions
Advanced transmural tumor invasion after RCT does not affect prognosis when curative (R0) resection is achievable. Residual nodal status is the most important predictor of individual outcome in intermediate responders to preoperative RCT. Furthermore, ypT stage and tumor grading turn out to be additional auxiliary factors. Future clinical trials for risk-adapted adjuvant therapy should be based on a synopsis of clinicopathologic parameters.
doi:10.1186/1477-7819-8-27
PMCID: PMC2864265  PMID: 20388220
13.  Multimodal treatment options for bilobar colorectal liver metastases 
Langenbeck's Archives of Surgery  2010;395(6):633-641.
Purpose
We evaluated individualized multimodal oncological strategies in patients with bilobular colorectal liver metastases (biCRC-LM) as well as their effect on R0 resection rates, disease-free survival (DFS), and overall survival (OS).
Methods
Between January 2001 and December 2008, 64 patients were assigned to straightforward or two-stage liver resection ± preoperative 5-fluorouracil (5FU)-based chemotherapy (CTx). Postoperative strategy after R0-resection was either “wait and see” or “adjuvant” therapy (3 cycles of CTx or anti-carcinoembryonic antigen (CEA)-radioimmunotherapy with 131I-labetuzumab in a dose of 40–50 mCi/m2).
Results
Forty-three initially unresectable patients received preoperative CTx for downsizing of their biCRC-LM. Straightforward or two-stage liver resection was intended in 40 and 24 patients, respectively. Histopathologically confirmed R0-liver resection could be achieved in 47 patients. Surgical morbidity and mortality rates were 33% and 1.5%, respectively. Postoperatively, 26 patients received anti-cancer therapy (5 × CTx, 21 × anti-CEA-radioimmunotherapy). After R0-liver resection, median OS was significantly better compared to R1/R2 resections followed by palliative 5FU-CTx (38 versus 19 months, p = 0.035). There was no significant difference in DFS (p = 0.650) and OS (p = 0.435) between straightforward and two-stage liver resection. Compared to “wait and see” strategy, the application of postoperative therapy in adjuvant intent was associated with a better OS (p = 0.048).
Conclusion
Extensive liver resection within multimodal treatment concepts is justified in patients with biCRC-LM when complete resection of all metastases seems to be achievable.
doi:10.1007/s00423-010-0604-7
PMCID: PMC2908753  PMID: 20213463
Multimodal treatment; Two-stage hepatectomy; Portal vein ligation; Oncological strategy; Adjuvant therapy
14.  Preoperative Chemoradiotherapy Does Not Necessarily Reduce Lymph Node Retrieval in Rectal Cancer Specimens—Results from a Prospective Evaluation with Extensive Pathological Work-up 
Purpose
Preoperative chemoradiotherapy (CRT) is supposed not only to reduce lymph node metastases but also lymph node recovery in rectal cancer specimens. The objective of this prospective study was to determine the effects of chemoradiation on mesorectal lymph node retrieval under terms of a meticulous histopathological evaluation.
Methods
Specimens from 64 consecutive patients with stage II/III rectal cancer receiving preoperative 5-FU-based CRT were investigated. All patients were treated within the German Rectal Cancer Trial CAO/ARO/AIO-04. After surgery (including quality assessed total mesorectal excision), extensive pathological diagnostics was performed with embedding and microscopic evaluation of the whole mesorectal soft tissue compartment.
Results
A total number of 2,021 lymph nodes were recovered (31.6 per specimen) within pathological work-up. There was no significant correlation between the number of retrieved nodes and patient- as well as tumor-dependent parameters. Lymph node size constantly amounted for less than 0.5 cm. Twenty patients (31.3%) had persistent nodal metastases. A considerable incidence of residual micrometastatic involvement in lymph nodes <0.3 cm (in 9.4% of all patients) was detected by extensive pathologic work-up.
Conclusion
Reliable nodal staging with high numbers of detected nodes was feasible after neoadjuvant CRT. Micrometastases frequently occur in small lymph nodes detected by microscopic evaluation.
doi:10.1007/s11605-009-1057-6
PMCID: PMC2793396  PMID: 19830503
Locally advanced rectal cancer; Preoperative chemoradiotherapy; Total mesorectal excision; Pathologic diagnostics
15.  A catalogue of Triticum monococcum genes encoding toxic and immunogenic peptides for celiac disease patients 
Molecular Genetics and Genomics   2008;281(3):289-300.
The celiac disease (CD) is an inflammatory condition characterized by injury to the lining of the small-intestine on exposure to the gluten of wheat, barley and rye. The involvement of gluten in the CD syndrome has been studied in detail in bread wheat, where a set of “toxic” and “immunogenic” peptides has been defined. For wheat diploid species, information on CD epitopes is poor. In the present paper, we have adopted a genomic approach in order to understand the potential CD danger represented by storage proteins in diploid wheat and sequenced a sufficiently large number of cDNA clones related to storage protein genes of Triticum monococcum. Four bona fide toxic peptides and 13 immunogenic peptides were found. All the classes of storage proteins were shown to contain harmful sequences. The major conclusion is that einkorn has the full potential to induce the CD syndrome, as already evident for polyploid wheats. In addition, a complete overview of the storage protein gene arsenal in T. monococcum is provided, including a full-length HMW x-type sequence and two partial HMW y-type sequences.
Electronic supplementary material
The online version of this article (doi:10.1007/s00438-008-0412-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s00438-008-0412-8
PMCID: PMC2757618  PMID: 19104838
Einkorn wheat; Celiac disease; Gluten; Gliadins; Glutenins; Epitopes
16.  Predictive value of Ki67 and p53 in locally advanced rectal cancer: Correlation with thymidylate synthase and histopathological tumor regression after neoadjuvant 5-FU-based chemoradiotherapy 
AIM: To investigate the predictive value of Ki67 and p53 and their correlation with thymidylate synthase (TS) gene expression in a rectal cancer patient cohort treated according to a standardized recommended neoadjuvant treatment regimen.
METHODS: Formalin fixed, paraffin embedded pre-therapeutical tumor biopsies (n = 22) and post-therapeutical resection specimens (n = 40) from patients with rectal adenocarcinoma (clinical UICC stage II/III) receiving standardized neoadjuvant 5-fluorouracil (5-FU) based chemoradiotherapy were studied for Ki67 and p53 expression by immunohistochemistry and correlated with TS mRNA expression by quantitative TaqMan real-time PCR after laser microdissection. The results were compared with histopathological tumor regression according to a standardized semiquantitative score grading system.
RESULTS: Responders (patients with high tumor regression) showed a significantly lower Ki67 expression than non-responders in the pre-therapeutical tumor biopsies (81.2% vs 16.7%; P < 0.05) as well as in the post-therapeutical resection specimens (75.8% vs 14.3%; P < 0.01). High TS mRNA expression was significantly correlated with a high Ki67 index and low TS mRNA expression was significantly correlated with a low Ki67 index in the pre-therapeutical tumor biopsies (corr. coef. = 0.46; P < 0.01) as well as in the post-therapeutical resection specimens (corr. coef. = 0.40; P < 0.05). No significant association was found between p53 and TS mRNA expression or tumor regression.
CONCLUSION: Ki67 has, like TS, predictive value in rectal cancer patients after neoadjuvant 5-FU based chemoradiotherapy. The close correlation between Ki67 and TS indicates that TS is involved in active cell cycle processes.
doi:10.3748/wjg.14.1060
PMCID: PMC2689409  PMID: 18286688
p53; Ki67; Neoadjuvant treatment; Rectal cancer; Thymidylate synthase
17.  Liver transplantation as curative approach for advanced hepatocellular carcinoma: is it justified? 
Langenbeck's Archives of Surgery  2007;393(2):141-147.
Backgrounds
Liver transplantation is considered as one of therapeutic approaches to hepatocellular carcinoma (HCC). The present study aims to evaluate the efficacy of various therapeutic options for HCC.
Materials and methods
One hundred twenty patients with known HCC in various tumour stages were evaluated in the present study. Patients were treated either with primary tumour resection, transarterial chemoembolisation (TACE) or liver transplantation (LTx) by an interdisciplinary team.
Results
The overall 1-year and 5-year survivals of patients in LTx group were 95 and 57%, respectively, which were significantly higher than those in primary tumour resection group (65 and 33%, P < 0.01) and those in TACE group (44 and 4%, P < 0.01). In parallel, 1-year and 5-year tumour-free survivals of patients in LTx group (75 and 62%) were significantly higher than those in primary tumour resection group (50 and 11%, P < 0.01). There were no significant differences in 1- and 5-year survivals of patients with early tumour stage received LTx or primary tumour resection, whereas patients in advanced tumour stage based on pathological findings of explanted liver significantly benefited from LTx as compared to primary resection.
Conclusions
LTx can be a curative approach for patients with advanced HCC without extrahepatic metastasis. However, organ shortage is a major limiting factor in the selection of HCC patients for LTx.
doi:10.1007/s00423-007-0250-x
PMCID: PMC3085731  PMID: 18043937
Hepatocellular carcinoma; Liver transplantation; Transarterial chemoembolisation; Tumour-free survival
18.  Implantation of a colorectal stent as a therapeutic approach in the treatment of esophageal leakage 
BMC Gastroenterology  2007;7:10.
Background
While the mortality of esophageal surgery has decreased due to technological advancements, there is still a complication rate of about 30%. One of the main complications is the anastomotic leakage associated with a significant rate of morbidity and mortality. To close the leakage the efficacy of self-expanding stents (SES) has been shown in different studies. However, the high rate of stent migration limits the use of commercial available stents. In our case we were faced with the problem that the diameter of all available stents was too small to attach tightly to the mucosal wall of the esophagogastric anastomosis.
Case presentation
We used, for the first time to our knowledge, a metal stent designed for colorectal application in an extensive anastomotic leak after esophageal resection in a patient with an esophageal cancer. After primary surgery with subtotal esohagectomy the anastomotic leak was stented endoscopically with a Polyflex self-expanding covered plastic stent after no response to intensive conventional management. Even though the stent was placed correctly, the diameter of the Polyflex stent was too small to attach onto the wall of the esophagogastric anastomosis. Again surgery was performed with a thoracal resection of the esophageal remnant and a hand made anastomosis. Unfortunately, again an anastomotic leak was detected soon after. To close the leak we decided to use a covered colorectal stent (Hanarostent) with an inner diameter of 30 mm. Sixteen weeks later the stent was extracted and complete mucosal healing of the esophageal leak was observed.
Conclusion
The stent implantation with a large wide diameter offers a good chance to close more extensive leaks and prevent stent migration.
doi:10.1186/1471-230X-7-10
PMCID: PMC1831780  PMID: 17367525
19.  Patients without hepatocellular carcinoma progression after transarterial chemoembolization benefit from liver transplantation 
AIM: To assess the outcome of patients, who under-went transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) and subsequently liver transplantation (OLT) irrespective of tumor size when no tumor progression was observed.
METHODS: Records, imaging studies and pathology of 84 patients with HCC were reviewed. Ten patients were not treated at all, 67 patients had TACE and 35 of them were listed for OLT. Tumor progression was monitored by ultrasound and AFP level every 6 wk. Fifteen patients showed signs of tumor progression without transplantation. The remaining 20 patients underwent OLT. Further records of 7 patients with HCC seen in histological examination after OLT were included.
RESULTS: The patients after TACE without tumor progression underwent transplantation and had a median survival of 92.3 mo. Patients, who did not qualify for liver transplantation or had signs of tumor progression had a median survival of 8.4 mo. The patients without treatment had a median survival of 3.8 mo. Independent of International Union Against Cancer (UICC) stages, the patients without tumor progression and subsequent OLT had longer median survival. No significant difference was seen in the OLT treated patients if they did not fulfill the Milan criteria.
CONCLUSION: Selection of patients for OLT based on tumor progression results in good survival. The evaluation of HCC patients should not only be based on tumor size and number of foci but also on tumor progression and growth behavior under therapy.
doi:10.3748/wjg.v13.i5.761
PMCID: PMC4066010  PMID: 17278200
Liver transplantation; Hepatocellular carcinoma
20.  Comparison of Systems for Identification and Differentiation of Species within the Genus Yersinia 
Journal of Clinical Microbiology  1998;36(11):3366-3368.
Of four tested identification systems (API 20E, API Rapid 32 IDE, Micronaut E, and the PCR-based Yersinia enterocolitica Amplification Set), API 20E is still the system of choice for identifying pathogenic Yersinia isolates. It provides the highest sensitivity both at the genus and at the species level and has the best cost-effectiveness correlation.
PMCID: PMC105332  PMID: 9774596
21.  Evaluation of Liver Function Tests to Predict Operative Risk in Liver Surgery 
HPB Surgery  1995;9(1):13-18.
Despite numerous studies in the past it is not possible yet to predict postoperative liver failure and safe limits for hepatectomy. In this study the following liver function tests ICG-ER (indocyaninegreen elimination rate), GEC (galactose elimination capacity) and MEGX-F (monoethylglycinexylidid formation) are examined with regard to loss of liver tissue and prediction of operative risk. Liver function tests were assessed in 20 patients prior to liver resection and on the 10th. postoperative day. Liver and tumor volume were measured by ultrasound and pathologic specimen and the parenchymal resection rate was calculated. In patients without cirrhosis (n = 10) ICG-ER and MEGX-F remained unchanged after resection, GEC was reduced but did not correspond to the resection rate. Patients with cirrhosis (n = 10) had a significantly lower ICG-ER and GEC before resection than patients without cirrhosis. After resection these tests were unchanged. Patients with liver related complications and cirrhosis (n = 5) had lower ICG-ER and GEC than patients with cirrhosis and no complications. In the postoperative course all liver function tests in these patients were significantly lower compared to preoperative results. Comparing liver function tests ICG serves best to indicate postoperative liver failure. Liver function tests do not correspond with loss of liver tissue.
doi:10.1155/1995/47538
PMCID: PMC2443760  PMID: 8857448

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