Colonoscopy is used in colorectal cancer (CRC) screening either as an independent screening method (screening colonoscopy) or following a positive result of a primary screening test (eg. fecal occult blood test, FOBT). Preventive colonoscopy is the collective name for screening and FOBT+ colonoscopy. Due to the considerable variability in the detection of colorectal neoplasia between individual endoscopists, colonoscopy quality indicators were introduced. Adenoma detection rate (ADR) and polyp detection rate (PDR) are defined as the proportion of colonoscopies in which at least one adenoma (for ADR) or polyp (for PDR) was detected to the total number of colonoscopies performed. ADR is considered a key indicator of the quality of colonoscopy. Adenoma per colonoscopy (APC), defined as the total number of adenomas detected relative to the total number of colonoscopies performed, is the most accurate indicator currently available. However, APC limit values have not yet been set. Both ADR and APC are validated indicators, but their evaluation is time-consuming and personnel-intensive, which limits their use in clinical practice. The main purpose of the presented work is to simplify the monitoring of colonoscopy quality by introducing a more user-friendly indicator, which does not require histological...

Die Entwicklung moderner minimal-invasiver Diagnose- und Behandlungsverfahren auf dem Gebiet der kolorektalen Adenome und Karzinome ermöglicht eine effektive Überwachung von Risikopersonen, andererseits erfolgt durch die endoskopische Abtragung oder transanale bzw. TEM-technische Resektion von Adenomen bereits eine erhebliche Karzinomprävention. Die Einführung der laparoskopischen Technik bei der Resektion kolorektaler Tumoren könnte nach Evaluierung der bisherigen Ergebnisse zu einer weiteren Verringerung der Hospitalisierung und operationsassoziierten Morbidität der Patienten bei gleicher Prognose führen. Kennzeichnend für familiäre Formen des kolorektalen Karzinoms ist das hohe Risiko für die Entwicklung kolorektaler Tumoren, jedoch auch für weitere extrakolonische Neoplasien. Dies trifft für das hereditäre Nicht-Polyposis-assoziierte kolorektale Karzinom (HNPCC), die familiäre Polyposis (FAP) und die selteneren Formen wie Peutz-Jeghers-Syndrom und juvenile Polyposis zu. Die Anwendung der molekularen Diagnostik in diesen Familien ermöglicht durch die Identifizierung von Mutationsträgern und Nichtmutationsträgern einerseits die gezielte Eingliederung von Hochrisikopersonen (Mutationsträgern) in spezielle, auf das jeweilige Syndrom zugeschnittene Überwachungs- und Vorsorgeprogramme und erspart andererseits Personen mit durchschnittlichem Risiko (Nichtmutationsträgern) unnötige und teilweise invasive Diagnostik. Bezüglich des chirurgischen Vorgehens bei Patienten mit einer Form des hereditären kolorektalen Karzinoms gibt es bereits etablierte Verfahren, wie die Durchführung einer restaurativen Proktokolektomie bei der FAP, bei anderen Formen, wie bei HNPCC, sind diese noch in der Diskussion. Wesentliche Fortschritte bei der Prävention kolorektaler Tumoren sind in den nächsten Jahren möglicherweise auf dem Gebiet der Chemoprävention zu erwarten. / Development of modern, minimally invasive methods for diagnosis and treatment in the field of colorectal tumours enables an effective surveillance for persons at high risk as well as a distinct cancer prevention by endoscopic, transanal or TEM removal of colorectal adenomas. Introduction of laparoscopic techniques in the resection of colorectal tumours could entail, after evaluation of preliminary results, a decreased duration of hospitalisation and procedure-associated morbidity in patients with the same prognosis. The very high risk for development of colorectal tumours as well as for some extracolonic neoplasia is typical for familial colorectal cancer syndromes. This concerns hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, familial polyposis coli, and the infrequent forms like Peutz-Jeghers syndrome and juvenile polyposis. Molecular diagnostics has the power to identify carriers and noncarriers of a mutated gene in these families and therefore may permit clear-cut decisions regarding inclusion in special surveillance programmes, which is recommended for all persons at risk from affected families. Concerning the surgical approach in patients with hereditary colorectal cancer, well-accepted routine procedures like restorative proctocolectomy in familiar polyposis patients have already been established; in other forms like HNPCC the best surgical modality is still under discussion. Remarkable progress in the prevention of colorectal tumours could be expected from chemoprevention trials in the next years. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Die zytostatische Chemotherapie ist wesentlicher Bestandteil der palliativen Therapie von Patienten mit metastasiertem kolorektalen Karzinom. Gegenüber einer rein supportiven Behandlung verbessert eine auf 5-Fluorouracil (5-FU) basierende Chemotherapie die Lebensqualität und verlängert das Überleben der Patienten. 5- FU-Dauerinfusion moduliert mit Folinsäure ist die beste Grundlage für die Kombination mit Irinotecan oder Oxaliplatin. Randomisierte Studien zum Einsatz von Irinotecan zeigten signifikante Vorteile im Hinblick auf die Remissionsrate, das progressionsfreie Überleben und auch die mediane Überlebenszeit. Randomisierte Studien zum Einsatz von Oxaliplatin zeigten ebenfalls höhere Remissionsraten und ein verlängertes progressionsfreies Überleben ohne eine verlängerte Überlebenszeit nachweisen zu können. Heutzutage sollten alle Patienten mit einer Kombinationschemotherapie behandelt werden und im Verlauf ihrer Erkrankung, soweit möglich, alle zur Verfügung stehenden Medikamente erhalten. Nur dadurch können mediane Überlebenszeiten von über 20 Monaten erreicht werden. Der Einsatz oraler Fluoropyrimidine statt einer 5-FU-Dauerinfusion in Kombination mit Irinotecan und Oxaliplatin ist viel versprechend, jedoch Gegenstand laufender Studien. Monoklonale Antikörper gegen den EGF-Rezeptor bzw. gegen VEGF haben ebenfalls viel versprechende Ergebnisse gezeigt und werden wahrscheinlich die Behandlungsmöglichkeiten in der Zukunft wesentlich verbessern. / Systemic chemotherapy has a key role in the palliative treatment of patients with metastatic colorectal cancer. Compared to best supportive care, 5-fluorouracil (5-FU)-based therapy prolongs survival and improves quality of life. 5-FU continuous infusion modulated by Leukovorin (LV) is the optimal basis for a combination therapy with irinotecan or oxaliplatin. Randomized trials investigating the role of irinotecan in combination with 5-FU/LV relative to 5-FU/LV alone demonstrated a significant improvement in the response rate, progression free survival and overall survival. Randomized studies using oxaliplatin/ 5-FU/LV vs. FU/LV alone resulted in a higher response rate and longer progression-free survival while the overall survival was not significantly different. Today, all patients should receive combination treatment in first line and should be offered all active compounds during the course of their disease. Hereby, median survival times of more than 20 months are achievable. The use of oral fluoropyrimidines as a substitute of infusional 5-FU in combination with irinotecan or oxaliplatin is promising and subject of clinical trials. Monoclonal antibodies directed against the EGF-receptor or against VEGF have demonstrated interesting results and may be a treatment option in the future. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

In cancer diagnosis there is a goal of having the treatment being tailored to each patient. This in order to increase efficiency and reduce side effects. Using more data on each patient can help in achieving this. One such data source is histological images on tissues, such as lymph nodes. This report sets out to find a method in which such images on lymph nodes can be automatically segmented. This so that they can later be analysed and maybe tell in what stage a cancer is in. Such work is today done by hand, and this makes it a subjective process, that might differ between doctors and institutions. If there was a method done by a computer, the process would be replicable and objective. Also, a lot of time would be saved. The results show that such a method is reachable in this early stage of development. It is also quite efficient when segmenting the lymph node itself. The segmentation of smaller areas of the lymph nodes is not as efficient, but with further work in the area it might improve enough to be useful. Some issues are still had since the method relies in part on a person to decide a parameter in order to get a clean segmentation. The final conclusion is that one model is to prefer compared to the others and that further work on this might make it a useful tool in analysing histological images.

Vid cancerdiagnostisering av Lynch syndrom används immunohistokemisk färgning för undersökning av eventuell defekt hos mismatch repair-generna MLH1, MSH2, MSH6 och PMS2. Färgningen använder sig av antikroppar som undersöker om cellkärnor i vävnad har intakta eller förlorade proteinuttryck hos respektive gen. Syftet med studien var att utföra en antikroppsvalidering för att granska om de nuvarande Dako Link Ready-to-Use-antikropparna (Link RTU) och koncentrerade antikroppen Dako PMS2 1:40 kunde bytas ut till Dako Omnis Ready-to-Use-antikroppar (Omnis RTU). Omnis RTU-antikropparna är optimerade för det automatiserade analysinstrumentet Dako Omnis som används vid patologavdelning på Universitetssjukhuset Örebro. Tolv vävnader med colorektalcancer och två externa positiva kontroller färgades med samtliga antikroppar för respektive gen och en jämförelse mellan Link RTU samt Dako PMS2 1:40 gjordes mot Omnis RTU-antikropparna. De nya färgningarna med Omnis RTU bedömdes som sämre, likvärdig eller bättre infärgad. Om antikroppen färgade rätt målceller och med stark färgintensitet bedömdes den och motsvarande protokoll som godkänd. Resultatet visade att Omnis RTU för MLH1 gav en förbättrad färgning. Omnis RTU för MSH2 gav i majoritet en förbättrad färgning med något mer bakgrundsfärg än önskvärt. Omnis RTU för MSH6 gav en svagare infärgning i majoriteten av fallen och Omnis RTU för PMS2 gav i majoritet en förbättrad färgning, men med för mycket bakgrundsfärg. Slutsatsen var att Omnis RTU för MSH6 och PMS2 kräver vidare optimering av protokoll innan de används i laboratoriets rutinfärgning. Protokollet för Omnis RTU för MSH2 kan behöva en mindre justering för minskad bakgrundsfärg och Omnis RTU för MLH1 fungerar väl med det nuvarande protokollet. / Immunohistochemistry staining is used in diagnostics of Lynch Syndrome to investigate possible defects in the mismatch repair genes MLH1, MSH2, MSH6 and PMS2. Antibodies is used to examine whether cell nuclei in cancer tissue have intact or loss of protein expression in said genes. The aim of the study was to perform an antibody validation to examine if the current Dako Link Ready-to-Use antibodies (Link RTU) and the concentrated PMS2 antibody can be replaced with Dako Omnis Ready-to-Use antibodies (Omnis RTU) that are optimized for the analytical instrument Dako Omnis, which is used in Universitetssjukhuset Örebro. Twelve tissues with colorectal cancer and two external positive controls was stained with all antibodies for each gene. A comparison was done between the old antibodies and Omnis RTU, where Omnis RTU was judged to be worse, equivalent or better. The antibody and used protocol were approved of laboratory use if it stained the target cells with a strong intensity. The results showed that Omnis RTU MLH1 had an improved staining. Omnis RTU MSH2 had in majority an improved staining, but with slightly more background staining than preferred. Omnis RTU MSH6 had in majority a weak staining while Omnis RTU PMS2 had an improved staining but with too much background staining. The conclusion was that the protocols for Omnis RTU MSH6 and PMS2 needed further optimization before laboratory use. The protocol for Omnis RTU MSH2 may need a minor adjustment to reduce background staining, while Omnis RTU MLH1 works well with the current protocol.

Kolorektalcancer är den tredje vanligaste cancerformen hos både män och kvinnor i Sverige där storkärls invasion, venös invasion (VI), är en viktig prognostisk indikator. Noggrann bedömning av VI är särskilt viktigt för patienter med kolorektal cancer i stadium II eftersom det kan påverka beslutet att erbjuda adjuvant behandling. Histologisk bedömning av VI kan vara utmanande på rutinmässig Hematoxylin och Eosin färgning (H&E). Elastinfärgning med syfte att identifiera elastinfibrer i kärlväggen kan underlätta bedömning av VI. I dagsläget finns inte någon bra elastinfärgning som kan användas rutinmässigt hos klinisk patologi i Värmland, Centralsjukhuset Karlstad, prover måste skickas till annat laboratorium vilket är tidskrävande. Denna studie ska finna den optimala färgningsmetoden för elastin genom att utvärdera tre olika färgningsmetoder för elastin fibrer. Färgningens resultat bedömdes rent histokemiskt av överläkare enlig kriterierna, frånvaro av avsedda kärl (skala 0–1), specifik infärgning (skala 0–1), specifik infärgnings intensitet (skala 1–3) och ospecifik infärgning (skala 0–1) och data samlades för respektive metod. Resultatet tyder på att rent histokemiskt är den manuella elastinfärgning metoden från Region Jönköpings län konsekvent och visade signifikant skillnad. Därför metoden är potentiellt användbar för den större frågeställningen om storkärlsinväxt i kolorektal cancer samt rekommenderas starkt som en rutinmässig elastinfärgning till klinisk patologi i Värmland, Centralsjukhuset Karlstad. / The third most common form of cancer in both men and women in Sweden is Colorectal cancer. Prognostic indicators of colorectal cancer include Large vessel invasion and venous invasion (VI). Careful assessment of VI is of particular interest especially with patients having stage II colorectal cancer. This is because it may influence decisions to offer adjuvant therapy. Accurate histological assessment of VI can be challenging on routine hematoxylin and eosin staining. But staining that can identify the elastin fibers in the vessel can enhance the assessment of VI. Currently, there is not any good Elastin staining that can be routinely used in clinical pathology in Värmland, Karlstad Central Hospital. Therefore, samples are required to be sent to other laboratories which in effect is time consuming. This study is aimed at finding an optimal elastin staining method through evaluations of three different staining methods for elastin fibers. Staining results were assessed histochemically by the chief physician according to the following criteria, absence of intended vessels (scale 0–1), specific staining (scale 0–1), specific staining intensity (scale 1–3) and nonspecific staining (scale 0–1), while different data were collected for each method. The results indicate that purely histochemically, elastin staining-manual method Region Jönköping County is consistent and significant. Therefore, the method is potentially useful for the detection of colorectal cancer and is strongly recommended as a routine elastin staining for clinical pathology in Värmland, Karlstad Central Hospital.

Das metastasierende kolorektale Karzinom stellt eine große Herausforderung in der Krebstherapie dar. Verlässliche und effiziente Biomarker zur Prognose des Krankheitsverlaufes oder der Therapieantwort (Prädiktion) sind rar. Metastasis-associated in colon cancer 1 (MACC1) ist ein prognostischer, prädiktiver und kausaler Biomarker für verschiedene Tumorentitäten. Durch die Induzierung von Zielgenen, wie z.B. MET, beeinflusst es Signalwege wie MEK/ERK und AKT/β-catenin und fördert so Zellproliferation und -motilität sowie Tumorprogression und Metastasierung in vivo. Diese Arbeit sollte neue Strategien erforschen diese Prozesse durch die Inhibition von MACC1 auf Transkriptions- und Signaltransduktionsebene zu unterbinden. Mit zwei verschiedenen Screeningmethoden konnten wir Statine als potente transkriptionelle Inhibitoren von MACC1 als auch phosphotyrosin (pY)-abhängige Interaktionen von MACC1 mit essentiellen Signalmolekülen identifizieren: SHP2, GRB2, SHC1, PLCG1 und STAT5B. Statine verringerten MACC1-spezifische Proliferation und Koloniebildung in vitro als auch Tumor Wachstum und Metastasierung in vivo bei Dosen äquivalent der humanen Standardtherapie zur Blutlipidsenkung. Mutation der pY-Bindungsstellen reduzierte die Aktivität des MACC1-induzierten ERK Signalwegs sowie Zellmigration und -proliferation. Anhand unserer Daten orchestriert MACC1, abhängig von MET und EGFR, neue SHP2/SRC/ERK und PKA/SRC/CREB Signalkaskaden zu einem malignen Phänotyp. Gezielte Intervention restringierte die MACC1-abhängige Koloniebildung, was neue therapeutische Interventionspunkte identifiziert und eine hervorragende Basis für Untersuchungen zur Kombinationstherapie darstellt. Die weitere Erforschung der spatiotemporalen Organisation des MACC1 Signalosoms und assoziierter Signalkaskaden soll das volle therapeutische Potential von MACC1 ausschöpfen. Wir empfehlen zudem Statine in der Krebstherapie bzw. -prävention, besonders bei MACC1-stratifzierten Patienten, anzuwenden. / Metastatic colorectal cancer still represents a major challenge in therapy. Reliable and efficient biomarkers for early prognosis of disease course or treatment response (prediction) remain scarce. Metastasis-associated in colon cancer 1 (MACC1) has been established as prognostic, predictive and causal biomarker for several tumor entities. Its induction of target genes such as MET affects several signaling pathways including MEK/ERK and AKT/β-catenin. Thus, it promotes cellular proliferation and motility as well as tumor progression and metastasis formation in vivo. This study intended to explore new strategies to inhibit these processes by targeting MACC1 on transcriptional and signaling level. By two distinct screening methods, we identified statins as potent MACC1 transcriptional inhibitors as well as phosphotyrosine (pY)-dependent interactions of MACC1 with crucial signaling molecules: SHP2, GRB2, SHC1, PLCG1 and STAT5B. Statins showed MACC1-specific reduction of proliferation and colony formation in vitro as well as restriction of tumor growth and metastasis formation in vivo at doses equivalent to human standard lipid reduction therapy. Mutation of the pY-interaction sites abrogated MACC1-dependent ERK signaling as well as cell migration and proliferation. Our data further suggest that MACC1 governs SHP2/SRC/ERK and PKA/SRC/CREB axes conferring a malignant phenotype in response to MET and EGFR. Targeted intervention restricted MACC1-dependent colony formation which indicates new drug intervention points for MACC1 signaling and provides an excellent baseline for further investigations of combinatorial treatments. Additional research about the spatiotemporal organization of MACC1 signalosome formation and downstream signaling will reveal the entire potential of MACC1 as therapeutic target, whereas statins should already be considered for cancer therapy or prevention, especially in patients stratified for MACC1 expression.

Prediction of clinical outcome in cancer is usually achieved by histopathological evaluation of tissue samples obtained during surgical resection of the primary tumor. Traditional tumor staging (AJCC/UICC-TNM classification) summarizes data on tumor burden (T), presence of cancer cells in draining and regional lymph nodes (N) and evidence for metastases (M). However, it is now recognized that clinical outcome cansignificantly vary among patients within the same stage. Data collected from largecohorts of human cancers has demonstrated the impact of immune-classification, which has a prognostic value that may add largely to the significance of the AJCC/UICC TNM-classification. In our study we examined the immune cells that infiltrated the tumor tissues of colorectal and ovarian cancer patients. In a cohort of newly diagnosed colorectal cancer patients we examined the correlations between the KRAS mutational status, patterns of tumor-infiltrating immune cells and the presence of tumor recurrence. Our data suggest that colorectal cancer patients with low levels of tumor-infiltrating lymphocytes, a high CD1a/DC-LAMP tumor-infiltrating dendritic cells ratio, and a KRAS mutation in codon 13 are at a high risk of disease recurrence. In ovarian cancer patients we focused on the dynamics of the tumor-infiltrating...

Objective: Tumor metastasis and resistance to chemotherapy are two critical factors that contribute to the high death rate of colorectal cancer (CRC) patients. Metastasis is facilitated by the epithelial-mesenchymal transition (EMT) of tumor cells, which has emerged not only as a fundamental process during metastasis, but is also a key process leading to chemoresistance of cancer cells. However, the underlying mechanisms of EMT in CRC cell remain unknown. Here, we aim to assess the role of dual serine/threonine and tyrosine protein kinase (DSTYK) in CRC metastasis and chemoresistance. Methods: To study the role of DSTYK in TGF-β-induced EMT, we employed techniques including Crispr/Cas9 knockout (KO) to generate DSTYK KO cell lines, RT-PCR to detect the mRNA expression, immunofluorescence analyses, and western blots to detect protein levels of DSTYK in the following 4 cell lines: control LS411N-TβRII and LS411N-TβRII/DSTYK KO, control LS513 and LS513/DSTYK KO cells, treated with/without TGF-β. The effects of DSTYK on apoptosis were investigated by MTT assays, flow cytometry assays, and TUNEL assays. The expression of DSTYK in CRC patients and its correlation with EMT markers were determined by bioinformatics analysis. For in vivo analysis, both xenograft and orthotopic tumor mouse models were employed to investigate the function of DSTYK in chemoresistance and metastasis of tumors. Results: In this study, we demonstrate that the novel kinase DSTYK promotes both TGF-β-induced EMT and the subsequent chemoresistance in CRC cells. DSTYK KO significantly attenuates TGF-β–induced EMT and chemoresistance in CRC cells. According to the Gene Expression Omnibus (GEO) database, the expression of DSTYK is not only positively correlated to the expression of TGF-β, but proportional to the death rate of CRC patients as well. Evidently, the expression of DSTYK in the metastatic colorectal cancer samples from patients was significantly higher than that of primary colorectal cancer samples. Further, we demonstrate in mouse models that chemotherapeutic drug treatment suppresses the growth of DSTYK KO tumors more effectively than control tumors. Conclusion: Our findings identify DSTYK as a novel protein kinase in regulating TGF-β–mediated EMT and chemoresistance in CRC cells, which defines DSTYK as a potential therapeutic target for CRC therapy.

La chirurgie est le traitement principal du cancer colorectal (CCR). Une durée d'hospitalisation prolongée peut augmenter le risque de complications et d'inactivité physique, entraînant un déclin de la fonction physique. L'objectif de cette étude est de déterminer si la celle-ci peut prédire l’hospitalisation prolongée chez les patients atteints de CCR. Un total de 459 patients provenant de 7 cohortes a été analysé. Une régression logistique a été utilisée pour déterminer le risque d'hospitalisation prolongée (>3 jours) et une courbe ROC a été tracée pour établir la sensibilité/spécificité. Les variables sélectionnées comprenaient l'âge, le sexe, l'IMC, la présence de comorbidités, le statut ASA, le site tumoral, l'approche chirurgicale, la force de préhension, le test Timed-Up and Go, le test assis-debout de 30 secondes, le test de flexion des coudes de 30 secondes, le test de marche de 6 minutes (6MWT), le questionnaire CHAMPS et le SF-36. Les résultats démontrent que les patients atteints d'une tumeur rectale ont un risque 2,7 fois plus élevé d'appartenir au groupe d'hospitalisation prolongée que ceux atteints d'une tumeur du côlon (O.R. 2,7 ; C.I. 1,3-5,7, p=0,01). Pour chaque augmentation de 20 mètres dans le 6MWT, il y a une diminution de 9% du risque d'être dans le groupe d'hospitalisation prolongée (C.I. 1.03-1.17, p=0.00). Un seuil de 431 m peut prédire 70% des patients dans le groupe d'hospitalisation prolongée (AUC 0,71, C.I. 0,63-0,78, p=0,00). L'utilisation du 6MWT comme outil de dépistage de l'hospitalisation prolongée devrait être intégrée dans le parcours chirurgical préopératoire. / Surgery is the primary treatment for colorectal cancer. A prolonged Length of Stay (pLOS) can increase risk of complications and physical inactivity, leading to a decline in physical function. While promising results were seen from preoperative exercise training and post-operative functional recovery, the predictive potential of preoperative physical function has not yet been investigated. The objective of this study is to determine if preoperative physical function can predict pLOS in patients with for colorectal cancer. A total of 459 patients from 7 cohorts were analyzed. Logistic regression was used to determine risk of pLOS (>3 days), and ROC curve was plotted to establish sensitivity/specificity. Selected variables included age, sex, BMI, comorbidity, ASA status, tumor site, surgical approach, handgrip strength, Timed-Up and Go, 30-second Sit-to-Stand, 30-second Arm Curl Test, 6-Minute-Walking Test (6MWT), CHAMPS Physical Activity Questionnaire for Older Adult and 36-Item Short Form Survey. The results showed that patients with rectal tumor are 2.7x more at risk to be in the pLOS group compared to those with colon tumor (O.R. 2.7; C.I. 1.3-5.7, p=0.01). For every increment of 20 meters in 6MWT, there is a decreased risk of 9% of being in pLOS group (C.I. 1.03-1.17, p=0.00). A cut-off of 431m can predict 70% of patients in pLOS group (AUC 0.71 C.I 0.63-0.78, p=0.00). Tumor site (rectal) and 6MWT were significant predictors of pLOS. Using the 6MWT as a screening tool for pLOS with cut-off of 431 m should be implemented in the preoperative surgical pathway.