<p>Oncogenic mutations in KRAS are present in approximately 95% of patients diagnosed with pancreatic ductal adenocarcinoma (<b>PDAC</b>) and are considered the initiating event during the development of pancreatic intraepithelial neoplasia (<b>PanIN</b>) precursor lesions. While it is well established that KRAS mutations can drive the initiation of pancreatic oncogenesis, the effects of oncogenic KRAS signaling on regulation of phosphatases during this process is not fully appreciated. Protein Phosphatase 2A (<b>PP2A</b>) has been implicated in suppressing KRAS-driven cellular transformation. However, low PP2A activity is observed in PDAC cells compared to non-transformed cells, suggesting that suppression of PP2A activity is an important step in the overall development of PDAC. In the current study, we demonstrate that KRASG12D induces the expression of both Cancerous Inhibitor of PP2A (<b>CIP2A</b>), an endogenous inhibitor of PP2A activity, and the PP2A target, c-MYC. Consistent with these findings, KRASG12D sequestered the specific PP2A subunit responsible for c-MYC degradation, B56a, away from the active PP2A holoenzyme in a CIP2A-dependent manner. During PDAC initiation <i>in vivo</i>, knockout of B56a promoted KRASG12D tumorigenesis by accelerating acinar-to-ductal metaplasia (<b>ADM</b>) and the formation of PanIN lesions. The process of ADM was attenuated <i>ex vivo</i> in response to pharmacological re-activation of PP2A utilizing direct small molecule activators of PP2A (<b>SMAP</b>s). Together, the results of this study suggest that suppression of PP2A-B56a through KRAS signaling can promote Myc-driven initiation of pancreatic tumorigenesis.</p>

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Pancreatic cancer is the seventh leading cause of cancer related mortalities worldwide and incidences are increasing. The prognosis remains poor as the 5-year survival rate is below 10%. This can be partly explained by the silent progression of disease as most patients present with advanced disease at time of diagnosis. In turn, surgical resection, the only potential curative measure, is not possible in nearly 80% of cases due to the occurrence of distant metastasis and/or infiltration of major vessels in close proximity to the pancreas. In patients with localized but advanced disease, resectability can be achieved in some cases by initiation of a neoCTx. However, as neoCTx is commonly conducted by administering multi-drug treatments, severe side effects occur frequently, which require an adaption of drug doses administered. In this study, we revealed the negative impact of these drug dose changes during neoCTx on the patients´ treatment outcome. R0 resections were significantly less frequently observed, and the N-status significantly impacted by the tumor regression grade, which in turn trended towards minor response in the cohort of patients that did not sustain full dose course prior surgery. In turn, treatment of LA PDAC could be improved by increasing the proportion of patients that undergo neoCTx without any changes of the treatment schedule. Patient-derived PDAC organoid could serve as an avatar of patients´ tumor disease on which optimal treatment protocols could be tested. In this study, a large living PDAC PDO biobank successfully has been established from surgical resection specimens as well as EUS guided FNA samples. Subsequently, a new protocol for molecular subtyping of PDAC on organoids was established by assessing the expression level of KRT81 and CFTR, as a replacement for HNF1a, using IF staining. Strikingly, we observed identical PDAC subtypes in PDOs and their respective tissue of origin in nearly all cases. This observation allowed the assumption that PDOs could indeed be used as patient-individual avatars to identify treatment sensitivities and resistances, as they share fundamental molecular properties with the tissue they have been initiated from. Extensive pharmacotyping was performed for many PDO lines by testing the response behavior to the multi-drug regimens FOLFIRINOX and Gem/Pac, as well as their respective single drug compounds. As a result, we observed diverse response patterns for each PDAC PDO line. A poor response to FOLFIRINOX did not necessarily imply a resistance to Gem/Pac. PDO pharmacotyping could guide treatment decision making in the foreseeable future. Moreover, when the non-efficient drug was removed, no changes of overall efficacy of treatment in PDOs was observed, implying that additional therapy improvements could be possible using this ex vivo model. This observation was true for both commonly used chemotherapy protocols, FOLFIRINOX and Gem/Pac and could result in less drug mediated side effects under (neo)adjuvant CTx without impacting treatment efficacy. Yet, the main goal of this study was to assess if PDAC PDOs can be used to predict the neoCTx outcome of PDAC patients. All methods required to address this issue in a prospective clinical trial have been established as a protocol for PDAC PDOs initiation from minimal starting material has been established and subsequently improved resulting in take rates of up to 80%. To support this study, we successfully secured patient enrollment from a second clinical center, which will increase the number of recruited patients in the future. Unfortunately, at the time of writing this thesis, patient numbers were not sufficient to answer the question of the predictive value of PDAC PDOs in regard to the current standard of care.

P8 est un gène lié au stress cellulaire qui a été identifié et caractérisé dans notre laboratoire. Il est surexprimé dans diverses pathologies, et plus particulièrement dans l'adénocarcinome pancréatique. Notre étude se focalise sur le rôle de p8 dans la progression tumorale et la formation des métastases du cancer du pancréas. Dans ce travail, nous avons démontré, dans un premier temps, que p8 régule la migration, l'adhésion et l'invasion cellulaire induites par diverses molécules dont le TGF-&#946;1, par le biais de la GTPase CDC42, dont il contrôle l'expression et l'activité. Nous avons prouvé aussi que la présence de p8 est nécessaire pour la mise en place d'une transition épithélio-mésenchymateuse, facilitant ainsi l'action pro-tumorale du TGF-&#946;1. Enfin, une analyse morphologique d'adénocarcinomes pancréatiques humains et murins nous a permis d'identifier la présence de cellules « cannibales », déficientes en p8, capables de phagocyter et ainsi limiter la prolifération d'autres cellules. Nous avons décortiqué ce mécanisme au niveau moléculaire. Son étude nous a permis de conclure, qu'en absence de p8, une nouvelle transition de type épithélio-phagocytaire est instaurée, ayant comme résultat un cannibalisme cellulaire, potentialisé notamment par le TGF-&#946;1, qui agirait dans ce cas comme un agent anti-tumoral. L'avancée de ces résultats donne place à des nouvelles perspectives vis-à-vis de l'importance de p8, d'abord d'un point de vue moléculaire sur les actions pro et anti-tumorales du TGF-&#946;1, ensuite en tant que potentielle cible thérapeutique dans le cancer du pancréas. / P8 is a gene related to cellular stress, identified and characterized in our laboratory, and overexpressed in several diseases, especially in pancreatic cancer (PDAC). Our study focuses on the role of p8 in tumor progression and metastasis formation in PDAC. In this work, we have demonstrated that firstly, p8 regulates pancreatic cancer cell migration, invasion and adhesion, induced by several molecules like TGF-&#946;1, through CDC42, a small GTPase, whose expression and activation is controlled by p8. We also established that p8 is necessary to set up epithelial-to-mesenchymal transition, promoting TGF-&#946;1 pro-tumoral effects. Finally, morphological analysis of human and murine pancreatic cancer, allowed us to identify “cannibal” cells, in which p8 expression was absent, able to phagocytose another cells and in this way limit its proliferation. We dissected the mechanism involved in this process at the molecular level. This study led us to conclude that when p8 is absent, a new epithelial-to-phagocytic transition takes place, resulting in cell cannibalism, maximized by TGF-&#946;1 action that will play an anti-tumoral role. These results underscore, on one hand, the crucial role of p8, at the molecular level, over the pro and anti-tumoral effects of TGF-&#946;1 and on the other hand its potential role in pancreatic cancer therapy.

La progression maligne de l’adénocarcinome canalaire pancréatique (ADKP) s'accompagne d'une profonde réaction desmoplasique, limitant la vascularisation de la tumeur et de fait privant les cellules tumorales en nutriments, forçant les cellules tumorales à adapter leur métabolisme. L’objectif de thèse était de définir les changements métaboliques relatifs à l’ADKP. Par une analyse transcriptomique des tumeurs pancréatiques développées de manière spontanée chez les souris, nous avons établi le profil métabolique des ADKPs lié aux acides aminés au cours de leur progression. Ainsi, nous avons montré que les voies métaboliques de la proline et des acides aminés à chaînes branchées, en particulier le catabolisme de la leucine, sont celles étant les plus dérégulées dans l’ADKP. Concernant le métabolisme de la proline, nous avons montré que les cellules tumorales privées en nutriments capturent et utilisent le collagène, produit par les fibroblastes du stroma tumoral grâce à la macropinocytose, de façon le dégrader en proline. Aussi, l’inhibition de la dégradation de la proline entraine une diminution de la prolifération tumorale in vitro et in vivo. Concernant la leucine, nous montrons que l’élément clé de ce métabolisme est un de ces produits de dégradation finaux à savoir le β-hydroxybutyrate (βOHB) dont la production repose sur une enzyme cruciale : HMGCL. Dans nos travaux, nous démontrons que la suppression d’HMGCL dans les cellules d’ADKP humains entrave leurs capacités oncogéniques et métastatiques in vitro et in vivo. De plus, nous montrons in vivo que le βOHB augmente la croissance tumorale ainsi que la formation de métastases. / The malignant progression of pancreatic ductal adenocarcinoma (PDAC) is accompanied by a profound desmoplasia, depriving tumor cells from oxygen and nutrients, which forces tumor cells to adapt their metabolism to proliferate. The thesis purpose is to define the metabolic changes related to ADKP. Using a transcriptomic analysis of PDAC from mice model, we established the PDAC metabolic profile. Focusing on amino acid metabolic pathways, we identified the metabolic pathways of proline and the branched-chain amino acid, especially the leucine catabolism, as the most deregulated in ADKP compared to the normal pancreas. We demonstrated that tumor cells take up collagen-derived fibroblasts, thanks macropinocytosis, when they are nutrient deprived. Once collagen is internalized, its subsequent digestion supplies TCA with proline. Also, inhibition of proline degradation leads to a decrease in tumor proliferation in vitro and in vivo. We have shown leucine catabolism is specific to tumor cells and the final degradation products: the β-hydroxybutyrate (βOHB) appears as a key element of this metabolism. To produce βOHB, tumor cells use HMGCL, a crucial enzyme involved in leucine degradation. In our work we demonstrated that HMGCL suppression in PDAC cells decreases their oncogenic and metastatic capacities in vitro and in vivo. In addition, we have demonstrated in vivo that βOHB increases tumor growth and metastasis formation. Thus, our works show 1/ the metabolic plasticity of cells, 2/the influence of microenvironment on tumor cell metabolism, 3/ the importance to study tumor metabolism for the finding of new therapeutic targets.

Jährlich erkranken in Deutschland über 11.000 Patienten an Pankreaskarzinomen. Für die ganz überwiegende Mehrzahl dieser Patienten ist die Diagnosestellung gleichbedeutend mit einem Todesurteil innerhalb von wenigen Wochen, hauptsächlich bedingt durch das meist fortgeschrittene Krankheitsstadium bei Diagnosestellung sowie die relative Therapieresistenz des Tumors. Die vorliegende Arbeit faßt wissenschaftliche Untersuchungen zusammen, die in den zurückliegenden vier Jahren in Berlin zu dieser Thematik durchgeführt wurden. Stadienadaptiert wurden Behandlungskonzepte und klinische Studien entwickelt und durchgeführt, die von der adjuvanten Chemotherapie über ein Radiochemo-therapiekonzept bei lokal fortgeschrittenen Stadien hin zur Entwicklung einer neuen Zytostatika-Kombinationstherapie für die Behandlung metastasierter Pankreastumoren im Rahmen einer multinationalen Phase III Studie geführt haben. Neben diesen Schemata konnte auch eine wirksame Zweitlinientherapie geprüft werden. An Tumormaterial konnte gezeigt werden, daß sich keine Her2/neu-Überexpressionen bei Pankreastumoren nachweisen lassen, die therapeutisch nutzbar wären. Bei ca. 80 % aller Pankreaskarzinome lassen sich Mutationen des K-ras-Onkogens nachweisen. In Kooperation mit einer anderen Arbeitsgruppe wurde ein Verfahren entwickelt, mit dem sich qualitativ und semiquantitiativ schnell und zuverlässig ras-Mutationen nachweisen lassen. Diese klinischen Studienergebnisse geben Grund zur Hoffnung, die Prognose von Patienten mit Pankreaskarzinomen in den nächsten Jahren durch die hier vorgestellten Konzepte zu verbessern. Fortschritte im Verständnis der molekularen Karzinogenese, in Diagnostik und Therapie lassen in naher Zukunft Ergebnisse erwarten, die zumindest denen bei anderen soliden Tumoren nahekommen. Daher ist der vereinzelt noch verbreitete therapeutische Nihilismus bei der Behandlung des Pankreaskarzinoms als nicht länger gerechtfertigt und akzeptabel anzusehen. / In Germany, more than 11,000 patients are diagnosed with pancreatic cancer each year. For the vast majority, this means a death verdict within a few weeks, primarily due to the advanced stage of the disease at diagnosis and the relative chemoresistance of the tumor. This thesis summarizes the scientific work regarding pancreatic cancer that has been done within the last four years. Several clinical treatment concepts and studies were developed and conducted that covered the different stages of the disease, including adjuvant therapy, radiochemotherapy for locally advanced disease and a multinational phase III study for the patients with metastatic disease. In addition, an effective second line regimen was developed. Using tumor material, we found no overexpression of Her2/neu which would have been a therapeutically usable target. Mutations of the K-ras oncogene can be found in approximately 80% of patients with pancreas carcinoma. A method for a rapid and reliable qualitative and semiquantitative determination detection of ras mutations was developed in cooperation with another research group. The clinical results give rise to the hope that the prognosis of patients with pancreatic carcinoma can be improved during the next years using the concepts outlined above. Recent improvements in our understanding of the molecular carcinognesis together with advances in diagnostics and therapy give rise to the expectation that clinical results will be achievable that will be at least as good as those for other solid tumors. Therefore, nihilism regarding the treatment of pancreatic cancer that still can be found is no longer justifiable or acceptable.

Abstract Pancreatic cancer remains one of the deadliest malignancies, with dismal prognosis. Pancreatic cancer arises from precursor lesions called pancreatic intraepithelial neoplasia. Toll-like receptors (TLR) are receptors of the innate immunity responsible for initiating immune responses against invading pathogens. Their involvement in cancer progression is becoming evident. Hypoxia is a typical characteristic of pancreatic cancer and linked to poor prognosis. Typically, pancreatic cancer has an abundant desmoplastic stroma that contributes to the hypoxia and poor delivery of anti-tumor drugs to the cancer cells. Tenascin-C and fibronectin are proteins of the extracellular matrix. They are involved in normal organ development, but in recent years, their involvement in various cancers has become evident. This thesis examined the involvement of Toll-like receptors, hypoxia markers HIF-1alpha and Carbonic anhydrase 9 (CAIX) as well as stromal markers tenascin-C and fibronectin in pancreatic cancer. Furthermore, the prognostic effect of each protein was evaluated. The material consisted of whole section tissue samples of surgically treated patients with pancreatic ductal adenocarcinoma. The expression of the proteins was evaluated using immunohistochemical stainings. TLR, HIF-1alpha, CAIX, tenascin-C and fibronectin were all abundantly expressed in pancreatic cancer. High TLR9 associated with improved prognosis while weak HIF-1alpha indicated poor prognosis. In a subgroup analysis consisting of only T1 and T2 tumors, high tenascin-C associated with poor prognosis. There was no significant correlation between TLR and hypoxia marker expression. Based on these results, TLR2, TLR4 and TLR9 are expressed in pancreatic cancer, and high TLR9 associates with improved survival of the patients. Weak HIF-1alpha associated with poor prognosis, suggesting that other factors than hypoxia might be involved in the regulation of HIF-1alpha expression. Tenascin-C and fibronectin are not associated with patient prognosis in pancreatic cancer. / Tiivistelmä Haimasyövällä on kaikista syövistä yksi huonoimmista ennusteista. Haimasyöpä kehittyy tiehyidensisäisistä muutoksista, joita kutsutaan englanninkielisellä nimellä pancreatic intraepithelial neoplasia (PanIN). Tollin kaltaiset reseptorit (TLR) ovat luontaisen immuniteetin reseptoreja, ja niiden tehtävä on aloittaa elimistön puolustusvaste tunkeutuvia taudinaiheuttajia vastaan. Tollin kaltaisten reseptorien osuus on osoitettu eri syövissä. Hypoksia on tyypillistä haimasyövälle, ja se on yleensä yhteydessä huonontuneeseen ennusteen. Tyypillisesti haimasyövällä on voimakas sidekudosreaktio, joka osaltaan lisää kasvaimen hapenpuutetta ja vaikeuttaa sytostaattien kulkeutumista syöpäsoluihin. Tenaskiini ja fibronektiini ovat solunulkoisen tilan proteiineja, jotka osallistuvat normaaliin elimistön kehitykseen. Viime aikoina niillä on huomattu olevan osuutta myös erilaisten syöpien kehittymiseen. Tässä väitöskirjassa on tutkittu Tollin kaltaisten reseptorien, hypoksiamerkkiaineiden HIF-1alpha ja hiilihappoanhydraasi 9 (CAIX) sekä sidekudosmerkkiaineiden tenaskiini ja fibronektiini ilmentymistä haimasyövässä. Lisäksi tutkimuksessa selvitettiin näiden proteiinien osuutta haimasyövän ennusteeseen. Tutkimuksen materiaali koostuu haimasyöpäpotilaiden syöpäkudosnäytteistä. Näytteinä käytettiin kokoleikenäytteitä. Näytteille tehtiin immunohistokemialliset värjäykset, joista eri proteiinien ilmentymistä arvioitiin. Tollin kaltaiset reseptorit, HIF-1alpha, CAIX, tenaskiini ja fibronektiini ilmenivät kaikki haimasyövässä. Korkea TLR9 oli yhteydessä parantuneeseen ennusteeseen, kun taas heikko HIF-1alpha oli yhteydessä huonontuneeseen ennusteeseen. Huomioitaessa vain T1- ja T2-kasvaimet korkea tenaskiini oli yhteydessä huonontuneeseen ennusteeseen. Tollin kaltaisten reseptorien ja hypoksiamerkkiaineiden välillä ei ollut merkittävää yhteyttä. Tulosten perusteella haimasyövässä on runsaasti Tollin kaltaisia reseptoreita, ja korkea TLR9 on yhteydessä parantuneeseen ennusteeseen. Matala HIF-1alpha on yhteydessä huonoon ennusteeseen. Tenaskiinilla ja fibronektiinilla ei ole vaikutusta potilaiden ennusteeseen.

Doctor of Philosophy / Introduction Cachexia is characterised by a marked weight loss and the presence of anorexia, anaemia, and asthenia. Although cachexia is often associated with the presence and growth of tumour and observed in solid tumours of the upper gastrointestinal tract, its presence is not unique to cancer and is often also present in most chronic, end-stage diseases processes. The loss of body fat, altered lipid metabolism, increase in the resting energy expenditure, and the increased loss of body protein the degree of which is associated with poor survival, are all hallmarks of this detrimental disease. The clinical aspects and consequences of cachexia can simply be summarised as morbidity, debilitating conditions, and mortality. The conditions such as loss of muscle mass, impaired muscle function, fatigue, reduced activity and functional capacity by themselves are enough to severely and significantly affect the patients’ QL. Although different interventional procedures and therapies are available for the treatment of cachexia and its symptoms, effective methods to evaluate their benefits and outcomes have not been tested or investigated. It was, therefore, the aim of this project to use body composition analysis as a clinical tool and evaluate the effectiveness and outcome of interventional and therapeutic procedures in three groups of patients with cancer. Methods Three patient groups were investigated: 1) patients with pancreatic cancer undergoing Whipple’s Procedure, 2) patients with pancreatic cancer undergoing cancer chemotherapy and receiving either EPA or placebo, and 3) patients with malignant mesothelioma undergoing cancer chemotherapy plus thalidomide or thalidomide alone. Body composition analysis techniques were used to assess the changes in TBN, TBF, TBK, and TBW. In addition, the body composition parameters together with clinical measures were also used to determine parameters influencing survival. The malignant mesothelioma patients were randomised into patients who received gemcitabine / cisplatin plus thalidomide and those who received thalidomide alone. The pancreatic cancer patients undergoing chemotherapy were randomised into the group who were receiving EPA and those who were receiving placebo. In addition, these patients were also investigated on the basis of their disease extent where they were separated into two groups of metastatic and locally advanced. Unpaired T-Test and ANOVA were used to determine differences between groups. Kaplan-Meier analysis and Cox’s Regression were used to assess survival in all three patient cohorts. The Whipple’s Procedure patients were separated into those who received a Clear Margin and those who received an Unclear Margin during their resection. Results 1) In the pancreatic cancer patients undergoing Whipple’s Procedure, compared to the base-line, there were highly significant changes in Weight (p=0.006), BMI (p=0.005), and FM (p=0.007) followed by significant changes in %BFat (p=0.016), TBK/Ht (p=0.021), LBM (By TBK) (p=0.023), LBM (Van Loan) (p=0.034), and LBM (Segal) (p=0.038) at the 14 week time-point. At the 26 weeks post-operative time point, the only significant changes were in the FM (p=0.012), %BFat (p=0.003), and BMI (p=0.027) parameters. There was also a deviation between the two groups in their TBN, LBM and TBW content observable in a long-term setting and fat content in the relatively shorter-term. Although the Unclear Margin group had lower body composition values, both groups seem to begin to gradually “equalise” around the 14 weeks post-operative time-point. The survival analysis results for the Whipple’s Procedure patients demonstrated that Margin Status (p=0.001), Fat Mass (p=0.003) and Age (p=0.081) were significant and could influence survival. 2) When the second cohort pancreatic cancer patients undergoing chemotherapy were analysed, they were initially separated according to the extent of their disease The results of the analyses of body composition changes between measurement time-points for the each group separately, suggested that the patients with locally advanced disease maintain their Weight, FM, and TBN but are more likely to have a lower TBW by the end of the four month of chemotherapy. However, the patients with metastatic pancreatic cancer maintain their TBW but are more likely to have a decreased fat compartment and a higher FFM. The QL analysis showed that the metastatic group are performing “worse” than the locally advanced group especially in term of their Dyspnoea, Nausea & Vomiting, and Sexuality. In addition, the Karnofsky score showed that the metastatic group are not performing as well as the locally advanced group. Furthermore, for the metastatic group there was an increase in the patients’ pain with a decline in mood and general performance as well as increase in gastrointestinal symptoms. Pain Card scores also showed a general increase for the metastatic group and a general decrease for the locally advanced group. When the pancreatic cancer patients undergoing chemotherapy were separated according to whether they received EPA or placebo, the results demonstrated that firstly, due to the fact that the patients were well randomised, the two groups commenced the trial with similar and statistically non-significantly different body composition parameters. Secondly, the two groups were also found to be statistically not different at their corresponding measurement time-points. And thirdly, the patients receiving placebo compared to those receiving EPA lost more Weight, and FM but less TBW throughout the trial. The TBK/Ht (p=0.044), TBK (p=0.042), and LBM (By TBK) (p=0.042), however, showed statistically significant differences where in all three parameters the EPA showed an increase compared to the base-line (pre-chemotherapy). Results of the survival analysis demonstrated that the use of EPA in this group of pancreatic cancer patients did not provide any benefit. In fact, as it was shown in the Kaplan-Meier plot, the group of patients receiving the EPA had a “worse” survival than the group receiving the placebo. The QL results showed that placebo group improved in their functional scales, but increased their Altered Bowel Habit scores with an increase in the perception of pain and decrease in relief from pain. The EPA group, however, showed a decrease in the Loss of Appetite, Dyspnoea, Pain, Pancreatic Pain, and Fatigue, and improvements in Role Functioning and Sexuality. 3) Results of the malignant mesothelioma patients demonstrated that both study arms show similar weight changes. In addition, body composition measurements indicated that the gemcitabine / cisplatin chemotherapy plus thalidomide group had a greater TBN loss and a greater TBW gain than the thalidomide-alone group. This loss of TBN and gain in TBW looked to be “concealed” in the weight. The results of the survival analysis carried out on the mesothelioma patient group suggested that haemoglobin levels (p=0.001), Age (p=0.007), and NI (p=0.008) are the parameters that can influence the survival of patients with malignant mesothelioma undergoing chemotherapy. Conclusions 1) The trend in body composition changes in the Whipple’s Procedure group showed that, although both groups may start with non-significantly different body composition, they tended to grow closer around the 14 week point indicating that the Clear Margin group may lose more than Unclear Margin group. The implications of these findings, therefore, were that once the most appropriate surgical procedure is performed, an adjuvant therapy regimen (such as chemotherapy) at around 14 weeks may have the most impact on the patient’s overall treatment outcome. 2) When the pancreatic cancer patients were separated by the extent of their disease, the results lead to the conclusion that the patients with locally advanced disease maintain their Weight, FM, and TBN but are more likely to have a lower TBW by the end of the four month of chemotherapy. However, the patients with metastatic pancreatic cancer maintain their TBW but are more likely to have a decreased fat compartment and a higher FFM. The QL analysis concluded that the results may point to a worsening and/or progressing disease which is consistent with classic metastatic disease aetiology. From the results of the pancreatic cancer patients undergoing cancer chemotherapy it was concluded that the use of EPA in this group of pancreatic cancer patients undergoing cancer chemotherapy with gemcitabine results in a non-significant reduction in weight loss, FM loss, and TBW gain with a statistically significant increase in FFM. The results of the survival analysis was, however, contradictory suggesting that patients receiving EPA may have a worse survival than the placebo group. The QL analysis here concluded that that EPA does improve the QL of this group of pancreatic cancer patients. 3) From the malignant mesothelioma group it was concluded that provided that the overall anti-cancer potential of gemcitabine / cisplatin plus thalidomide is comparable with that of thalidomide-alone, then by looking purely from the body composition angle one may be able to suggest the use of thalidomide alone in the treatment of malignant mesothelioma in this group of patients. From the results of the survival analysis, the fact that the Study Arm parameter did not reach statistical significance could indicate that survival in these patients is not affected by the presence or absence of chemotherapy with gemcitabine and cisplatin. The body composition techniques were used here as a tool to monitor changes in various body composition parameters to assess the outcomes, including survival, of the administration of different therapies and interventional procedures in these three groups of cancer patients. For these purposes, these techniques were demonstrated to be an effective and invaluable tool.

Objective: The aim of this study was to develop an immunomagnetic/real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay and assess its clinical value for the molecular detection of circulating tumor cells (CTCs) in peripheral blood of pancreatic cancer patients. Methods: The presence of CTCs was evaluated in 34 pancreatic cancer patients before systemic therapy and in 40 healthy controls, through immunomagnetic enrichment, using the antibodies BM7 and VU1D9 [targeting mucin 1 and epithelial cell adhesion molecule (EpCAM), respectively], followed by real-time RT-PCR analysis of the genes KRT19, MUC1, EPCAM, CEACAM5 and BIRC5. Results: The developed assay showed high specificity, as none of the healthy controls were found to be positive for the multimarker gene panel. CTCs were detected in 47.1% of the pancreatic cancer patients before the beginning of systemic treatment. Shorter median progression-free survival (PFS) was observed for patients who had at least one detectable tumor-associated transcript, compared with patients who were CTC negative. Median PFS time was 66.0 days [95% confidence interval (CI) 44.8–87.2] for patients with baseline CTC positivity and 138.0 days (95% CI 124.1–151.9) for CTC-negative patients (p = 0.01, log-rank test). Conclusion: Our results suggest that in addition to the current prognostic methods, CTC analysis represents a potential complementary tool for prediction of outcome in pancreatic cancer patients. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.