Η λαπαροσκοπική γαστρική παράκαμψη κατά Roux-en-Y είναι μία από τις πιο ευρέως χρησιμοποιούμενες βαριατρικές επεμβάσεις για την αντιμετώπιση της νοσογόνου παχυσαρκίας. Η απώλεια βάρους μετά από βαριατρικού τύπου επεμβάσεις έχει συσχετισθεί με τις επερχόμενες μεταβολές των γαστρεντερικών ορμονών, που έχει δειχθεί ότι συνδέονται με τον έλεγχο του μεταβολισμού και της όρεξης. Σκοπός: Η μελέτη της επίδρασης της εκτομής του θόλου του στομάχου σε ασθενείς με νοσογόνο παχυσαρκία που υποβάλλονται σε λαπαροσκοπική γαστρική παράκαμψη στην έκκριση των ορμονών, τα επίπεδα της γλυκόζης αλλά και την απώλεια βάρους. Μέθοδος: Δώδεκα ασθενείς υποβλήθηκαν σε λαπαροσκοπική γαστρική παράκαμψη και δώδεκα σε λαπαροσκοπική γαστρική παράκαμψη και εκτομή του θόλου του στομάχου. Όλοι οι ασθενείς μελετήθηκαν προοπτικά πρίν και τρείς, έξι και δώδεκα μήνες μετά την επέμβαση. Η συλλογή των δειγμάτων έγινε μετά από δωδεκάωρη νηστεία και 30, 60 και 120 λεπτά μετά την χορήγηση πρότυπου γεύματος θερμιδικού φορτίου 300 Kcal. Αποτελέσματα: Το σωματικό βάρος και ο δείκτης μάζας σώματος μειώθηκαν σημαντικά (p<0.001) και στις δύο ομάδες χωρίς όμως διαφορές μεταξύ των ομάδων. Για την ομάδα της γαστρικής παράκαμψης τα επίπεδα γκρελίνης νηστείας μειώθηκαν στους τρείς μήνες μετεγχειρητικά και αυξήθηκαν στούς δώδεκα μήνες σε επίπεδα υψηλότερα σε σχέση με τα προεγχειρητικά (p<0.01), αντίθετα, μετά από λαπαροσκοπική γαστρική παράκαμψη και εκτομή του θόλου, τα επίπεδα γκρελίνης νηστείας μειώθηκαν σημαντικά και παρέμειναν χαμηλά σε όλες τις χρονικές στιγμές της μελέτης (p<0.01). H μεταγευματική απόκριση του PYY, του GLP-1 και της ινσουλίνης ενισχύθηκαν μετεγχειρητικά (p<0.01) και στις δύο επεμβάσεις αλλά η απόκριση ήταν σημαντικά μεγαλύτερη και τα μεταγευματικά σάκχαρα χαμηλότερα μετά από γαστρική παράκαμψη και εκτομή του θόλου του στομάχου (p for interaction <0.05). Μετεγχειρητικά οι μεταβολές της γκρελίνης συσχετίστηκαν αρνητικά με τις μεταβολές του GLP-1. Συμπεράσματα: Η εκτομή του θόλου του στομάχου σε ασθενείς που υποβάλλονται σε λαπαροσκοπική γαστρική παράκαμψη οδηγεί σε χαμηλότερα βασικά επίπεδα γκρελίνης, σε μεγαλύτερη μεταγευματική απόκριση GLP-1, PYY και ινσουλίνης και σε χαμηλότερα σάκχαρα σε σχέση με την λαπαροσκοπική γαστρική παράκαμψη. Η εκτομή του θόλου του στομάχου με συνοδό γαστρική παράκαψη μπορεί να αποδειχθεί μια πολύ χρήσιμη καινούργια χειρουργική τεχνική για την αντιμετώπιση της νοσογόνου παχυσαρκίας και του σακχαρώδη διαβήτη τύπου ΙΙ. / Background: Laparoscopic Roux-en Y-Gastric bypass (LRYGBP) is the commonest available option for the surgical treatment of morbid obesity. Weight loss following bariatric surgery has been linked to changes of gastrointestinal peptides, shown to be implicated also in metabolic effects and appetite control. The purpose of this study was to evaluate whether gastric fundus resection in patients undergoing LRYGBP enhances the efficacy of the procedure in terms of weight loss, glucose levels and hormonal secretion. Methods: 12 patients underwent LRYGBP and 12 patients LRYGBP plus gastric fundus resection (LRYGBP+FR). All patients were evaluated before and at 3, 6, and 12 months postoperatively. Blood samples were collected after an overnight fast and 30, 60 and 120 min after a standard 300 kcal mixed meal. Results: Body weight and body mass index decreased markedly and comparably after both procedures. Fasting ghrelin decreased three months after LRYGBP, but increased at 12 months to levels higher than baseline while after LRYGBP+FR was markedly and persistently decreased. Postprandial GLP-1, PYY and insulin responses were enhanced more and postprandial glucose levels were lower after LRYGBP+FR compared to LRYGBP. Postoperatively, ghrelin changes correlated negatively with GLP-1 changes. Conclusions: Resection of the gastric fundus in patients undergoing LRYGBP was associated with persistently lower fasting ghrelin levels, higher postprandial PYY, GLP-1 and insulin responses and lower postprandial glucose levels compared to LRYGBP. These findings suggest that fundus resection in the setting of LRYGBP may be more effective than RYGBP for the management of morbid obesity and diabetes type 2.

O objetivo do presente trabalho foi avaliar o valor diagnóstico e o impacto na modificação da conduta terapêutica do ultra-som intra-operatório (UIO) na cirurgia por neoplasia de fígado, vias biliares e pâncreas, comparando-se achados da avaliação pré-operatória de rotina com métodos de imagem convencionais (tomografia computadorizada e ressonância magnética) com achados obtidos por meio da exploração cirúrgica (inspeção e palpação). Foram analisados, retrospectivamente, exames realizados em 49 pacientes, sendo 15 portadores de neoplasia hepática secundária; 14, de neoplasia hepática primária; 14, de tumor neuroendócrino pancreático e seis de neoplasia cística pancreática. No grupo de pacientes com neoplasia hepática e de vias biliares, a TC identificou 65% dos tumores; a exploração cirúrgica, 69,5% e o UIO, 95,2%. Houve mudança da conduta, em decorrência dos achados do UIO, em 34,4% dos pacientes. No grupo de tumores neuroendócrinos pancreáticos, a TC identificou corretamente 44,4% dos tumores; a RM, 60,9%; a exploração cirúrgica com palpação, 72,7% e o UIO, 100%. Houve mudança de conduta em 42,9% dos pacientes. No grupo de neoplasia cística, o UIO não acrescentou informação adicional relevante em relação à TC e à RM, exceto no paciente com neoplasia papilífera intraductal. Apesar do grande avanço nos métodos de avaliação por imagem pré-operatórios e mesmo com toda a expertise do cirurgião, os resultados mostram que o UIO modifica positivamente o planejamento cirúrgico em um número significativo de pacientes, devendo, portanto fazer parte integrante da avaliação intra-operatória dos pacientes candidatos à ressecção hepática por neoplasia primária ou secundária e da cirurgia de neoplasia endócrina pancreática / Intraoperative sonography (IOU) is an imaging modality that has been showing rapid growth in the last decade that can has a variety of applications in different surgical specialities, particularly in abdominal surgery. The purpose of this study was to analyze the use o IOU in the setting of surgery for liver, biliary and pancreatic malignancies. To achieve that, the findings of routine preoperative state-of the-art imaging modalities (CT and MRI) and the findings of surgical exploration (inspection and palpation) were compared to those of IOU. The impact of IOU on preoperative plans based on CT and MRI and on management after surgical exploration were studied as well 49 patients were retrospectively studied. Of those 15 had metastatic liver disease and 14 primary liver cancer; 14 had pancreatic neuroendocrine tumours and 6 had cystic pancreatic neoplasms. In the group of hepatic and biliary malignancies CT identified 65% of the tumours, surgical exploration identified 69.5% and IOU 95.2% (including 3 false positives). IOU determined a change in management in 34.4% of the patients. In the group of pancreatic neuroendocrine tumours the rates of identification were 27.3% for CT, 60.9% for MRI, 72.7% for surgical exploration and 100% for IOU, with an alteration in surgical plans in 42.9% of patients after IOU. In the case of patients with cystic pancreatic neoplasia, IOUS did not add any relevant additional information in relation to CT or MRI, with exception to one patient that had a papiliferous intraductal neoplasia. In spite of the great advances on preoperatory imaging modalities and of the possibility of direct surgical exploration, IOU has shown that it positively modifies surgical planning. For that reason, it should be included as an essential adjunct in the intraoperatory evaluation of patients with pancreatic endocrine neoplasia and of candidates for hepatic resection in cases of primary and secondary malignancies

Racional: O carcinoma hepatocelular é uma neoplasia maligna agressiva com elevada morbidade e mortalidade. Objetivo: Revisão da literatura sobre o diagnóstico e o manejo do carcinoma hepatocelular nos vários estágios da doença. Método: Revisão da literatura utilizando a base Medline/PubMed e literatura adicional. Resultados: O carcinoma hepatocelular é geralmente complicação da cirrose hepática. As hepatites virais crônicas B e C também são fatores de risco para o surgimento do carcinoma hepatocelular. Quando associado à cirrose hepática, o carcinoma hepatocelular geralmente surge a partir da evolução de um nódulo regenerativo hepatocitário que sofre degeneração maligna. O diagnóstico é efetuado através de tomografia computadorizada de abdome com contraste endovenoso (efeito wash in e wash out), e a ressonância magnética pode auxiliar nos casos que não possam ser definidos pela tomografia computadorizada. O único tratamento potencialmente curativo para o carcinoma hepatocelular é a ressecção do tumor, seja ela realizada através de hepatectomia parcial ou de transplante. Infelizmente, apenas cerca de 15% dos carcinomas hepatocelulares são passíveis de tratamento cirúrgico. Pacientes portadores de cirrose hepática estágio Child B e C não devem ser submetidos à ressecção hepática parcial. Para esses pacientes, as opções terapêuticas curativas restringem-se ao transplante de fígado, desde que selecionáveis para esse procedimento, o que na maioria dos países dá-se através dos Critérios de Milão (lesão única com até 5 cm de diâmetro ou até três lesões de até 3 cm de diâmetro). A sobrevida em 5 anos para pacientes transplantados para o carcinoma hepatocelular pode alcançar 70% Conclusão: Quando diagnosticado em seus estágios iniciais, o carcinoma hepatocelular é potencialmente curável. O conhecimento das estratégias de 17 diagnóstico e tratamento do carcinoma hepatocelular a fim propiciam sua identificação precoce e a indicação de tratamento apropriado. / Introduction: Hepatocellular carcinoma is an aggressive malignant tumor with high lethality. Aim: A literature review on diagnosis and management of hepatocellular carcinoma was performed. Methods: Literature review utilizing databases Medline/PubMed. Results: Hepatocellular carcinoma is a common complication of hepatic cirrhosis. Chronic viral hepatitis B and C also constitute as risk factors for development of hepatocellular carcinoma. In patients with cirrhosis, hepatocelular carcinoma usually develops from a malignant transformation of a dysplastic regenerative nodule. Diagnosis is confirmed through computed tomography scan with intravenous contrast (wash in and wash out effect), and magnetic resonance may be helpful in some instances. Curative treatment for hepatocellular carcinoma may be performed through partial liver resection or liver transplantation. Only 15% of all hepatocellular carcinomas are localized and amenable to operative treatment. Patients with Child C liver cirrhosis are not amenable to partial liver resections. The only curative treatment for hepatocellular carcinomas in patients with Child B or C cirrhosis is liver transplantation. In most countries, only patients with hepatocellular carcinoma under Milan Criteria (single tumor with up to 5 cm diameter or up to three nodules with a maximum diameter of 3 cm) are considered candidates for liver transplant. Five-year survival following liver transplantation for hepatocellular carcinoma may reach 70%. Conclusion: Hepatocellular carcinoma is a potentially curable neoplasm if discovered in its initial stages. Clinicians and surgeons should be familiar with strategies for early diagnosis and treatment of hepatocellular carcinoma as a way to decrease mortality associated with this malignant neoplasm.

Subglottic stenosis (SGS) is a narrowing of the airway in the region of the cricoid cartilage below the vocal folds and above the tracheal rings. Individuals with SGS experience difficulty breathing at rest and during exertion both of which become increasingly difficult with the level of stenosis severity. Some individuals also experience negative voice changes. Individuals whose stenoses significantly impact breathing generally require medical procedures or surgery, either balloon dilation or cricotracheal resection (CTR). CTR has been shown to improve patients' ability to breathe, but it can also result in permanent vocal changes. Alternatively, balloon dilation results in similar breathing improvements but for a relatively short period of time. Many studies have been published on the effectiveness of CTR; however, only a few have examined the effects of CTR on vocal production. The purpose of this study is to quantify the acoustic and auditory-perceptual features of subglottic stenosis and examine possible acoustic and auditory-perceptual changes in voice production following a revised CTR aimed to minimize voice impact in a group of women. A retrospective chart review identified women with idiopathic SGS who received revised CTR at The University of Utah Voice Disorders Center between 2008 and 2014. Presurgical and postsurgical groups included patients with both pre and post recordings (n = 11) as well as patients with only pre (n = 6) or post (n = 9) recordings. Acoustic quantification of voice signal periodicity, as well as cepstral, spectral, and fundamental frequency (F0) analyses were performed. Auditory-perceptual ratings of overall quality and monotonicity were performed. Cross-sectional and pre-post surgery analyses were completed. Aggregate analyses revealed that both pre and posttreatment SGS patients demonstrated voice disorders in the mild to moderate severity range. Pre-post comparisons indicated no significant voice change after surgery. Mean fundamental frequency decreased from 215 Hz (SD = 40 Hz) to 201 Hz (SD = 65 Hz). Voice disorder severity based on the cepstral spectral index of dysphoniaTM for sustained vowels decreased (i.e., improved) from 41 (SD = 41) to 25 (SD = 21) points. Semitone standard deviation (2.2 semitones) was equivalent from pretreatment to posttreatment. Auditory-perceptual ratings demonstrated similar results. These preliminary results indicate that the revised CTR procedure is promising in minimizing adverse voice effects. Future research is needed to determine causative factors for pretreatment voice disorders, as well as to optimize treatments in this population.

The Relationship Between Central Venous Catheter and Post-operative Complications in Patients Undergoing Hepatic Resection David C. O’Connor, Ph.D., DNAP, CRNA A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University Virginia Commonwealth University, 2018 Dissertation Chair: Clarence J. Biddle, Ph.D., CRNA Hepatic resection is indicated for primary and secondary malignancies. Use of a low central venous pressure technique is associated with decreased blood loss in these cases. This technique has evolved; central venous catheters and high dose morphine are no longer used, and patients are extubated earlier. The purpose of this study is to assess a relationship between these changes and outcomes. Central venous pressure has fallen out of favor as an accurate fluid measurement. Central venous catheters are associated with many complications. Outcomes in patients undergoing hepatic resection have improved over 20 years at one high volume institution. Guided by Donabedian’s theory of measuring outcomes, a non-randomized, non-experimental, retrospective, cohort design was conducted. The independent variables were intraoperative insertion of a central venous catheter, use of morphine, and time of extubation. The dependent variables were superficial and deep wound infections, number and severity of complications. The population sample is patients who submitted to partial hepatectomy at Memorial Sloan Kettering Cancer Center from 2007-2016. Data was obtained from hepatobiliary and anesthesia databases at Memorial Sloan Kettering Cancer Center. Data of 2518 from a possible 3903 patients were analyzed with chi square, univariate, Poisson and multivariate regressions. Univariate analysis for presence of CVC was significant for 90-day mortality (p 0.013). Use of morphine was significant for superficial wound infection (p 0.035), and a decrease in complications (p <.001). Amount of morphine was associated with fewer severe complications (p <.001). Incidental findings included a relationship between gender, total amount of fluids and number of segments resected. The significance of CVC with 90-day mortality was eliminated with stepwise multivariate regression. The findings support the change in anesthetic practice with clinical significance. Incidental findings regarding fluids and segments are supported in the literature. Future research should include goal directed fluid therapy and investigation of the relationship between gender and outcomes.

Repair of double-strand DNA breaks (DSBs) by the homologous recombination (HR) pathway results in crossovers (COs) required for a successful first meiotic division. DSB resection is the nucleic degradation of DSB ends to expose 3’ single strand DNA (ssDNA), an intermediate required for HR. To investigate genes involved in meiosis, a forward genetic screen was performed to search for novel genes or informative new mutant alleles of known genes. Mre11 is one member of the MRX/N (Mre11-Rad50-Xrs2/Nbs1) complex required for meiotic DSB formation and for resection in budding yeast. In Caenorhabditis elegans, evidence for the MRX/N’s role in DSB resection is limited. We isolated the first separation of function allele in C. elegans , mre 11(iow1), isolated from our forward genetic screen. The mre-11(iow1) mutants are specifically defective in meiotic DSB resection but not in DSB formation. The mre 11(iow1) mutants display chromosomal fragmentation and aggregation in late prophase I. Recombination intermediates and crossover formation is greatly reduced in mre 11(iow1) mutants. Irradiation induced DSBs during meiosis fail to be repaired from the early to middle prophase I in mre 11(iow1) mutants. Our data suggest that some DSBs in mre 11(iow1) mutants are repaired by the non homologous end joining (NHEJ) pathway because removing NHEJ partially suppresses some meiotic defects conferred by mre 11(iow1). In the absence of NHEJ and a functional MRX/N, meiotic DSBs are channeled to an EXO 1 dependent form of recombination repair. Overall, our analysis supports a role for MRE-11 in the resection of DSBs in early to middle meiotic prophase I and in blocking NHEJ. A reverse genetic screen and a yeast two hybrid screen were performed to search for genes with genetic and/or physical interactions with mre-11. The reverse genetic screen isolated a novel meiotic gene, nhr-2, as a partial suppressor of the meiotic defects conferred by mre-11(iow1). The yeast two hybrid screen identified kin-18 interacting with mre-11. KIN-18 is the C. elegans homolog of mammalian Thousand And One kinase (TAO) kinase. KIN-18/TAO is MAPK kinase kinase whose meiotic role was unknown. We have found that KIN-18 is essential for normal meiotic progression as kin-18 mutants exhibit accelerated meiotic recombination, ectopic germ cell differentiation, and enhanced levels of germline apoptosis. In C.elegans MPK-1 activation in late pachytene is required for physiological apoptosis (nuclei removed by apoptosis serve as nursing cells for oocytes) and oocyte differentiation. The kin-18 mutants also showed absence of MPK-1 activation and aberrant MPK-1 activation that includes ectopic activation in the wrong regions in the germline or more than one time of activation. The progression defects in kin-18 mutants are suppressed by inhibiting an upstream activator, KSR-2, of the canonical MPK-1 signaling. Our data suggest KIN-18 affects meiotic progression by modulating the timing of MPK-1 activation. This regulation ensures the proper timing of recombination and normal apoptosis, which is required for the formation of functional oocytes. Meiosis is a conserved process; revealing that KIN-18 is a novel regulator of meiotic progression in C. elegans will motivate hypothesis for TAO kinase’s role in the germline development in higher eukaryotes. Meiosis is a crucial for sexually reproducing organisms to maintain ploidy level from one generation to the next. Accurate chromosome segregation in the meiosis requires meiotic recombination between homologous chromosomes. Failure in recombination can lead to abnormal segregation of chromosomes in meiosis, which leads to aneuploidy. Anueploidy is a leading cause of miscarriages and attributes to chromosomal related birth defects. Meiotic recombination starts with programmed DNA double strand breaks (DSBs), followed by repair of these DSBs by homologous recombination (HR) pathway. One key step in HR is resection, a process to covert DSB ends into single strand DNA (ssDNA). To broaden our understanding of meiotic DSB resection, we used a nematode, C. elegans, as a model to investigate genes in DSB resection. We have isolated a specific mutant allele of a meiotic gene, mre-11. Our data suggest meiotic DSB resection in C. elegans requires collaboration of mre-11 and another gene exo-1; efficient resection of DSB ends is important to safeguard repair of DSB by HR against other illegitimate repair pathway. In addition, we identified a gene kin-18 by looking for genes interacting with mre-11. Characterization of kin-18 show meiotic recombination is tightly coordinated with germ cell progression. Our analysis provides significant improvement in the understanding of meiotic recombination in C. elegans. Given the high conservation of the two genes, mre-11 and kin-18, our finding may be applied to other organisms.

Various techniques are used to transect the liver. With increase in laparoscopic liver resections (LLR), it is of even more interest to develop surgical techniques to minimize bleeding and the risk for gas embolism during transection. Instrument like argon enhanced coagulator provides good hemostasis but increases the danger of gas embolism. The CO2 pneumoperitoneum that is routinely used in most types of laparoscopic surgery can be modified by the use of different gas pressure. It can be assumed that different pressure influences bleeding but also the risk for gas embolism. In presented porcine studies, three instrumental combinations have been studied. In study I sixteen piglets were randomized to LLR with either the cavitron ultrasonic aspirator (CUSA™) in combination with vessels sealing system (Ligasure™) or with CUSA™ and ultrascision scissors (Autosonix™), with the endpoints of intra-operative bleeding and gas embolism.  In study IV sixteen piglets were randomized to LLR either with staple device (Endo-GIA™) or the Ligasure™ - CUSA™ combination with same primary endpoints and additionally secondary endpoints of effect on gas-exchange, systemic- and pulmonary hemodynamic. Focusing on intra-abdominal pressure (IAP) in study II, sixteen piglets were randomized to LLR with an IAP of either 8 or 16 mmHg.  Primary endpoints were bleeding and gas embolism and secondary endpoints, effect on gas-exchange, systemic- and pulmonary hemodynamic. In study III effect of argon gas was tested during LLR. Sixteen piglets were randomized to either argon pneumoperitoneum or CO2 pneumoperitoneum. Primary endpoints were effect on gas-exchange, systemic- and pulmonary hemodynamic. In presented studies, we tested efficacy and safety of different techniques for LLR. CUSA™ can be used in combination with either Ligasure™ or Autosonix™. However, Ligasure™ reduces the amount of bleeding. The recent introduction of staplers seems promising with a further reduction in bleeding, gas embolism, and operating time. The IAP influences both the amount of bleeding as well as gas embolism. It seems reasonable to use a higher IAP to decrease bleeding with caution and with close monitoring for gas embolism. Argon gas embolism gives more extensive effect on gas-exchange and hemodynamic and should probably be avoided in this type of surgery.

Ulcerative colitis is a chronic inflammatory disease that mainly affects the colon and rectum. Onset of disease is most common between the ages of 15-35 years. There is an observed increased risk of colorectal cancer associated with the disease. The risk is often described to be 2% after 10 years, 8% after 20 years and 18% after 30 years disease. Since 1977, all known patients with ulcerative colitis in the catchment area of Örnsköldsvik Hospital have been invited to attend a colonoscopic surveillance programme. At endpoint of the studies included in this thesis there were 214 patients that had attended the surveillance programme. The aims of these studies have been to evaluate the efficiency of the surveillance programme, analyse the impact of findings of DNA aneuploidy, and determine the outcome for patients that underwent limited resections instead of complete proctocolectomy. Further, we have studied the long-term outcome for patients who had an early onset of disease and analysed the expression of cytokeratin 7 and 20 in respect to findings of dysplasia, DNA aneuploidy and colorectal cancer. At the end of the studies the prevalence for ulcerative colitis was 261/100 000 and the incidence rate was 7.6/100 000/year. During the period 1977-2005, four patients died of ulcerative colitis. Nine colorectal cancers were diagnosed in eight patients, one of whom died of the cancer. Fifty-two patients had findings of dysplasia and five of these patients developed colorectal cancer. In the subgroup of patients studied (N= 147) for DNA aneuploidy, 20 were found to have specimens with DNA aneuploidy on at least one occasion. The sensitivity of aneuploidy for development of dysplasia (LGD or higher) was found to be 0.50 and the specificity 0.94. The investigation of the outcome for the patients that underwent limited resections of the colon or rectum showed that none of the patients under surveillance died of colorectal cancer or metachronous cancer in their remaining colon or rectum. A separate study concerning early onset of ulcerative colitis revealed no particular increased risk of colorectal cancer in this cohort but a fairly high incidence of primary sclerosing cholangitis was seen. In the analyses of cytokeratins it was found that 7 out of 10 patients with low-grade dysplasia and 3 of 6 with high-grade dysplasia were positive for CK7. Our results indicate a possible relationship between the expression of CK7 and CK20 and neoplastic development of colorectal mucosa in patients with ulcerative colitis. The studies on which this thesis is based, were performed on a relatively small number of patients, however the time of observation was long and, most importantly, the patients were from a well defined catchment area. We conclude that the surveillance programme has been efficient in minimising the risk of lethal colorectal cancer. Analysing DNA ploidy helps to target the patients that need more attention but the method cannot stand alone. Our study on cytokeratins points to a relationship between dysplasia and CK7 but the results are preliminary and further studies needs to be done. We have shown that it is safe to do a limited colorectal resection in respect to lethal colorectal cancer. Early onset of ulcerative colitis as a risk factor for colorectal cancer was not found in the group we have studied, which could be due to effective surveillance and/or medication. A fairly high operation rate in this group may also have contributed. The most important variable in the beneficial outcome regarding lethal colorectal cancer in these studies is, in our opinion, the outstanding compliance of the patients to the colonoscopic surveillance programme.

This is a prospective, non-randomized pilot study comparing the cost-utility of hepatic resection, radiofrequency ablation (RFA), systemic chemotherapy, and symptom control only for the treatment of colorectal liver metastases. Seven patients underwent hepatic resection, 7 underwent RFA, 20 received chemotherapy, and 6 received symptom control alone. Liver resection provided an average of 2.51 QALY’s compared to 1.99 QALY’s for RFA, and 1.18 QALY’s for chemotherapy, and 0.82 QALY’s for symptom control alone. The costs were $20,122, $ 15,845, $15,069, and $3,899, respectively. The cost-utilities of liver resection and RFA were similar at $8,027 and $7,965 per QALY, respectively, although patients receiving RFA generally had more advanced disease. The cost-utility of chemotherapy was $12,751/QALY and the cost-utility of symptom control alone was $4,788/QALY. RFA is still a relatively new. However, if long-term survival proves promising, it may prove to be a viable alternative to liver resection. / May 2006

Homologous recombination (HR) repair is critical for the maintenance of genomic stability, as it is involved in the precise repair of DNA double-strand breaks (DSBs) using an intact homologous template for repair. The initiation of 5' strand resection of DNA ends is a critical determinant in this process, which commits cells to HR repair and prevents repair by non-homologous end joining (NHEJ). The human single-stranded DNA (ssDNA) binding complexes, RPA and SOSS1, are involved in regulating DSB signaling and HR repair. In this study, I demonstrate a novel function of SOSS1 in HR repair, in which SOSS1 stimulates hExo1-dependent resection. Despite its poor activity in binding duplex DNA, SOSS1 facilitates hExo1 recruitment to duplex DNA ends and promotes its activity in resection independently of MRN in vitro. MRN(X) is a highly conserved complex that is involved in the early steps of HR repair by regulating DSB resection. MRN interacts with CtIP and constitutes resection machinery that can perform limiting processing on DNA ends. In this study, I also examine the biochemical activities of MRN and CtIP in DSB resection through reconstituted in vitro assays. I show that the ATP-dependent DNA unwinding activity of MRN is responsible for overcoming Ku inhibition of hExo1- and Dna2/BLM-dependent resection activity in vitro. I propose that this unwinding step displaces Ku away from the DNA ends and facilitates the recruitment of hExo1 to the DNA ends for efficient resection. In addition, I show that CtIP can promote overcoming the inhibitory effect of Ku in resection together with MRN. Further, I demonstrate that MRN nuclease activity is required for efficient processing of covalent adducts from DNA ends in vitro, suggesting that the nucleolytic removal of covalent adducts by MRN generates free ends for hExo1- and Dna2/BLM binding. Overall, this study provides mechanistic insight into the regulation of DSB resection in human cells. / text