| 1. |
- Gad, Helge, et al.
(author)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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In: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Journal article (peer-reviewed)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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| 2. |
- Strömberg, Cecilia
(author)
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Aspects of treatment of common bile duct stones
- 2011
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Doctoral thesis (other academic/artistic)abstract
- Background: Gallstone disease is a major cause of morbidity and at least 10 000 cholecystectomies are performed annually in Sweden. At the time of surgery about 5-15% of the patients also have common bile duct stones (CBDS). Introduction of new techniques like Endoscopic Retrograde CholangioPancreatography (ERCP) and laparoscopy have changed the treatment for these patients. Aims: To analyze how CBDS has been treated in Sweden 1965-2009 and to calculate mortality connected to the different procedures, to assess the risk of malignancy after ERCP in benign disease and identify risk factors for death within 90 days. To evaluate the short term clinical outcome and identify risk-factors for failure in laparoscopic transcystic common bile duct exploration (LTCE). Methods: Data on all patients with an in-patient procedure code of common bile duct exploration or ERCP 1965- 2009 were collected from the Swedish Hospital Discharge Register and those with a diagnosis of malignancy in the bile ducts, liver or pancreas were excluded. The outcome death was identified by cross-linkage to the Registry of Causes of Death and readmission in the Swedish Hospital Discharge Register. For assessment of cancer risk a cohort study of all patients in Sweden having had an ERCP before the end of 2003 without a diagnosis of malignancy at the time of the procedure or within two years after it was performed. To calculate mortality and analyze risk-factors for death after ERCP a case-control study based on the population of Stockholm 1990-2003 was performed. Cases were defined as patients having died within 90 days of the procedure and controls were randomly chosen among those who did not die. Data were collected prospectively on patients having a cholecystectomy at S:t Göran’s Hospital 1994-2002, in 155 patients a LTCE were attempted and the outcome analyzed. Results: The Swedish Hospital Discharge Registry contained records of 126 885 procedures for treatment of common bile duct stones in 110 119 individuals, without a diagnosis of malignancy at the time of the procedure, during 1965-2009. The 90-day mortality was 0.24 % after open surgery, 0.90% after ERCP, 0.67% after combined procedures and 0% after laparoscopic surgery. After adjustment for confounding factors, mainly age and comorbidity, in the multivariate analyses there was no significant difference in mortality between open surgery and ERCP. The risk of malignancy in the bile ducts alone and in the bile ducts, liver and pancreas together was significantly elevated in the cohort of individuals having had an ERCP before 2003, irrespective of if an ES was performed or not. The risk of malignancy diminished with increasing follow-up time. Patients ever having had a cholecystectomy had a significantly lower risk of the studied malignancies. In Stockholm County during 1990-2003 the 90-day mortality after ERCP was 1.6%. Advanced age, severe comorbidity, high complexity of the procedure and the occurrence of a complication were associated to death within 90 days, whereas a previous cholecystectomy or the simultaneous performance of an endoscopic sphincterotomy reduced the risk. An attempt of transcystic CBD exploration with complete stone clearance in the 155 patients at S:t Göran’s Hospital could be fulfilled in 85 %. The median operating time was 184 minutes (range 89-384 minutes) and the median postoperative hospital stay was one day. There was a significant 3-fold increase in risk of failure of clearance of the bile ducts among patients with stones of >5 mm compared to patients with stones ≤5 mm. Conclusions: Common bile duct stones were mainly treated endoscopically. ERCP and open surgery were associated with a similar mortality after adjustment for confounding factors. Laparoscopic treatment was chosen in younger and healthier patients, probably with a less severe disease, and no 90-day mortality was recorded. The risk of malignancy in the bile ducts, liver or pancreas was elevated after ERCP in benign disease. However, ES did not seem to affect this risk. Old age and comorbidity were the main risk factors for death after ERCP but a complex procedure or the occurrence of a complication also seemed to increase short term mortality. The performance of a sphincterotomy may decrease the risk of death, possibly by facilitating adequate drainage. Previous cholecystectomy may also decrease the risk of dying after ERCP. Laparoscopic transcystic exploration of the CBD had a high frequency of stone clearance and low morbidity in the present study. Moreover, large stones were a risk factor for failure in stone clearance.
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| 3. |
- Strömberg, Cecilia, et al.
(author)
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Possible mortality reduction by endoscopic sphincterotomy during endoscopic retrograde cholangiopancreatography : a population-based case-control study.
- 2012
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In: Surgical Endoscopy. - : Springer Science and Business Media LLC. - 0930-2794 .- 1432-2218. ; 26:5, s. 1369-76
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Journal article (peer-reviewed)abstract
- BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is widely used for young patients, but ERCP and endoscopic sphincterotomy in particular are reported to be associated with increased complication and mortality rates. This study aimed to calculate mortality and to identify risk factors for death within 90 days after ERCP for nonmalignant disease.METHODS: From the Swedish Hospital Discharge Registry, the authors identified all individuals in Stockholm County who had undergone in-patient ERCP during 1990-2003. Among these individuals, they excluded those recorded in the Swedish Cancer Registry as having a diagnosis of malignancy in the liver, pancreas, or bile ducts. Cases, defined as patients who had died within 90 days after the procedure, were identified by cross-linkage to the causes of death registry. Control subjects were randomly sampled from the same cohort. The medical records were studied to discern risk factors for death after ERCP.RESULTS: The mortality rate was 1.6%. Advanced age, severe comorbidity, high complexity of the procedure, and occurrence of a complication were associated with death within 90 days, whereas a previous cholecystectomy or the simultaneous performance of an endoscopic sphincterotomy reduced the risk.CONCLUSIONS: Old age and comorbidity are the main risk factors for death after ERCP, but a complex procedure or the occurrence of a complication also seems to increase short-term mortality. The performance of a sphincterotomy may reduce the risk of death, possibly by facilitating adequate drainage. A previous cholecystectomy also may decrease the risk of death after ERCP.
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