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Colorectal Cancer Liver Metastases: Effects of Chemotherapy on Liver Parenchyma and Resections
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Current multimodal treatment of colorectal cancer liver metastasis often combines liver resections with preoperative chemotherapy with a 5-year survival of 40-50%. Preoperative chemotherapy includes conversion of initially non-resectable situation and control of micrometastatic disease. Despite its potential advantages also problems with associated steatosis, steatohepatitis and sinusoidal injury has been discussed. Paper I focused on prospective steatosis evaluation prior to resections using proton MR spectroscopy, most sensitive non-invasive method. Proton MR spectroscopy showed high concordance with digital quantification of steatosis and was also able to predict steatohepatitis with 100% sensitivity and 89% specificity without knowing lobular inflammation or hepatocyte ballooning. Paper II focused on portal vein hemodynamics changes in patients treated with oxaliplatin-based treatment and with sinusoidal injury. Magnetic resonance imaging flowmetry demonstrated portal vein dilatation associated with oxaliplatin treatment. Patients with SI showed a tendency towards decreased mean portal flow velocity. Portal vein flow was not changed. This may indicate that SI is associated with an increased resistance to blood flow in the liver parenchyma and stasis in splanchnic system. Paper III attempted to enlighten the effects of FOLFOX treatment on human liver tissue 6 weeks after treatment cessation by quantification of protein expression changes using label-free global proteome analysis. Deep proteome analysis identified 5891 proteins, where machine learning algorithm identified 3% of classifying proteins, associated with changes in DNA replication through upregulation of the minichromosome maintenance complex and with the innate immune response. Significant changes were observed in 1% of proteins, associated with DNA replication and cell cycle entry. Results support the hypothesis that liver has already regenerated from the FOLFOX treatment injury after 6 weeks. Paper IV aimed to identify possible patient, disease and chemotherapy characteristics associated with liver specific and severe general complications in a retrospective single centre cohort composed of 516 consecutive resections. Chemotherapy with more than 4 cycles of oxaliplatin was associated with post-hepatectomy hemorrhage. Underlying liver disease and diabetes mellitus were associated with 90-day mortality. Size of resection, intraoperative blood loss and transfusions were verified as independent predictors of liver specific complications to resections.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. , 53 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1041
National Category
Surgery
Identifiers
URN: urn:nbn:se:uu:diva-233790ISBN: 978-91-554-9066-9 (print)OAI: oai:DiVA.org:uu-233790DiVA: diva2:754320
Public defence
2014-11-22, Museum Gustavianum, Auditorium Minus, Akademigatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2014-10-30 Created: 2014-10-10 Last updated: 2015-01-23
List of papers
1. The value of pre-operative magnetic resonance spectroscopy in the assessment of steatohepatitis in patients with colorectal liver metastasis
Open this publication in new window or tab >>The value of pre-operative magnetic resonance spectroscopy in the assessment of steatohepatitis in patients with colorectal liver metastasis
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2012 (English)In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 56, no 3, 640-646 p.Article in journal (Refereed) Published
Abstract [en]

Background & Aims

Neoadjuvant chemotherapy prior to liver surgery for colorectal metastases can cause marked steatosis (⩾33%) and steatohepatitis defined by non-alcoholic fatty liver disease activity score (NAS) as adverse effects on liver parenchyma. The aim of this study was to evaluate the steatosis level prior to liver resection using proton magnetic resonance spectroscopy (1H MRS) and to compare it with digital quantification of steatosis (DQS) and “classical” histopathology.

Methods

1H MRS at 3T evaluated steatosis in 35 patients with colorectal liver metastasis, planned for liver resection. Non-tumorous liver parenchyma samples were obtained after surgery for classical histopathology and DQS utilising automated software for quantification of histopathological slides using image processing.

Results

Classical histopathology defined marked steatosis in nine patients. Histopathology was less reliable than DQS (interclass correlation coefficient – ICC 0.771) or 1H MRS (ICC 0.722) in steatosis estimation. 1H MRS showed very similar steatosis levels and high reliability compared to DQS (ICC 0.955). Steatohepatitis was observed in seven patients (NAS ⩾4) and 1H MRS was able to predict it with 100% sensitivity and 89% specificity at threshold 10.9%, without knowing lobular inflammation or hepatocyte ballooning. BMI was significantly higher in the groups with marked steatosis and steatohepatitis. Standard blood tests or chemotherapy had no predictive value.

Conclusions

1H MRS is a reliable non-invasive tool for steatosis assessment, and interestingly, it was able to predict steatohepatitis defined by NAS ⩾4 in patients planned for liver resection of colorectal metastases after neoadjuvant chemotherapy.

National Category
Medical and Health Sciences Basic Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-161000 (URN)10.1016/j.jhep.2011.10.006 (DOI)000301221200021 ()22027576 (PubMedID)
Available from: 2011-11-04 Created: 2011-11-04 Last updated: 2017-12-08Bibliographically approved
2. Magnetic resonance imaging flowmetry demonstrates portal vein dilatation subsequent to oxaliplatin therapy in patients with colorectal liver metastasis
Open this publication in new window or tab >>Magnetic resonance imaging flowmetry demonstrates portal vein dilatation subsequent to oxaliplatin therapy in patients with colorectal liver metastasis
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2013 (English)In: HPB, ISSN 1365-182X, E-ISSN 1477-2574, Vol. 15, no 4, 265-272 p.Article in journal (Refereed) Published
Abstract [en]

Objectives: 

Sinusoidal injury (SI) after oxaliplatin-based therapies for colorectal liver metastasis (CRLM) can increase postoperative morbidity. Preoperative methods to estimate SI are lacking. The aim of this study was to identify SI by evaluating portal vein haemodynamics.

Methods: 

Magnetic resonance imaging flowmetry (MRIF) was used to estimate portal vein haemodynamics in 29 patients with CRLM before liver surgery. Sinusoidal injury was evaluated from resected non-tumorous liver parenchyma according to the combined vascular injury (CVI) score of ≥3.

Results: 

All patients with SI (six of 29) received oxaliplatin; however, a significant association could not be proven (P= 0.148). Oxaliplatin-treated patients showed portal vein dilatation in both the SI and non-SI groups compared with patients who had not received oxaliplatin (Bonferroni corrected P= 0.003 and P= 0.039, respectively). Mean portal velocity tended to be lower in patients with SI compared with oxaliplatin-treated patients without SI (Bonferroni corrected P= 0.087). A mean portal velocity of ≤14.35 cm/s together with a cross-section area of ≥1.55 cm2 was found to predict SI with sensitivity of 100% and specificity of 78%.

Conclusions: 

Oxaliplatin treatment was associated with portal vein dilatation. Patients with SI showed a tendency towards decreased mean portal flow velocity. This may indicate that SI is associated with an increased resistance to blood flow in the liver parenchyma. Portal vein haemodynamic variables estimated by MRIF can identify patients without SI non-invasively.

National Category
Medical and Health Sciences Basic Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-190126 (URN)10.1111/j.1477-2574.2012.00540.x (DOI)000315902600004 ()
Conference
This manuscript was presented at the 10th World IHPBA Congress, Paris, 1–5 July 2012.
Available from: 2013-01-07 Created: 2013-01-07 Last updated: 2017-12-06Bibliographically approved
3. Global proteome changes in liver tissue 6 weeks after FOLFOX treatment of colorectal cancer liver metastases
Open this publication in new window or tab >>Global proteome changes in liver tissue 6 weeks after FOLFOX treatment of colorectal cancer liver metastases
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2016 (English)In: PROTEOMES, ISSN 2227-7382, Vol. 4, no 4, 30Article in journal (Refereed) Published
Abstract [en]

(1) Oxaliplatin-based chemotherapy for colorectal cancer liver metastasis is associated with sinusoidal injury of liver parenchyma. The effects of oxaliplatin-induced liver injury on the protein level remain unknown. (2) Protein expression in liver tissue was analyzed-from eight patients treated with FOLFOX (combination of fluorouracil, leucovorin, and oxaliplatin) and seven controls-by label-free liquid chromatography mass spectrometry. Recursive feature elimination-support vector machine and Welch t-test were used to identify classifying and relevantly changed proteins, respectively. Resulting proteins were analyzed for associations with gene ontology categories and pathways. (3) A total of 5891 proteins were detected. A set of 184 (3.1%) proteins classified the groups with a 20% error rate, but relevant change was observed only in 55 (0.9%) proteins. The classifying proteins were associated with changes in DNA replication (p < 0.05) through upregulation of the minichromosome maintenance complex and with the innate immune response (p < 0.05). The importance of DNA replication changes was supported by the results of Welch t-test (p < 0.05). (4) Six weeks after FOLFOX treatment, less than 1% of identified proteins showed changes in expression associated with DNA replication, cell cycle entry, and innate immune response. We hypothesize that the changes remain after recovery from FOLFOX treatment injury.

Keyword
oxaliplatin-based chemotherapy, protein expression, label-free liquid chromatography mass spectrometry, DNA replication, minichromosome maintenance complex, innate immune response, recovery of liver injury
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:uu:diva-233788 (URN)10.3390/proteomes4040030 (DOI)000388105200002 ()
Available from: 2014-10-10 Created: 2014-10-10 Last updated: 2016-12-20Bibliographically approved
4. Association between patient and chemotherapy characteristics with short-term outcomes of resections for colorectal cancer liver metastases.
Open this publication in new window or tab >>Association between patient and chemotherapy characteristics with short-term outcomes of resections for colorectal cancer liver metastases.
(English)Manuscript (preprint) (Other academic)
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-233789 (URN)
Available from: 2014-10-10 Created: 2014-10-10 Last updated: 2015-01-23

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