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Birgisson, H
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Publications (10 of 23) Show all publications
Birgisson, H., Tsimogiannis, K., Freyhult, E. & Kamali-Moghaddam, M. (2018). Plasma Protein Profiling Reveal Osteoprotegerin as a Marker of Prognostic Impact for Colorectal Cancer. Translational Oncology, 11(4), 1034-1043
Open this publication in new window or tab >>Plasma Protein Profiling Reveal Osteoprotegerin as a Marker of Prognostic Impact for Colorectal Cancer
2018 (English)In: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 11, no 4, p. 1034-1043Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Due to difficulties in predicting recurrences in colorectal cancer stages II and III, reliable prognostic biomarkers could be a breakthrough for individualized treatment and follow-up. OBJECTIVE: To find potential prognostic protein biomarkers in colorectal cancer, using the proximity extension assays. METHODS: A panel of 92 oncology-related proteins was analyzed with proximity extension assays, in plasma from a cohort of 261 colorectal cancer patients with stage II-IV. The survival analyses were corrected for disease stage and age, and the recurrence analyses were corrected for disease stage. The significance threshold was adjusted for multiple comparisons. RESULTS: The plasma proteins expression levels had a greater prognostic relevance in disease stage III colorectal cancer than in disease stage II, and for overall survival than for time to recurrence. Osteoprotegerin was the only biomarker candidate in the protein panel that had a statistical significant association with overall survival (P = .00029). None of the proteins were statistically significantly associated with time to recurrence. CONCLUSIONS: Of the 92 analyzed plasma proteins, osteoprotegerin showed the strongest prognostic impact in patients with colorectal cancer, and therefore osteoprotegerin is a potential predictive marker, and it also could be a target for treatments.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-361500 (URN)10.1016/j.tranon.2018.05.012 (DOI)000438977600023 ()29982101 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2018-09-28 Created: 2018-09-28 Last updated: 2018-09-28Bibliographically approved
Glimelius, B., Melin, B., Enblad, G., Alafuzoff, I., Beskow, A. H., Ahlström, H., . . . Sjöblom, T. (2018). U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.. Acta Oncologica, 57(2), 187-194
Open this publication in new window or tab >>U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.
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2018 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 2, p. 187-194Article in journal (Refereed) Published
Abstract [en]

Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.

Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.

Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.

Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.

National Category
Cancer and Oncology Urology and Nephrology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-325565 (URN)10.1080/0284186X.2017.1337926 (DOI)000423473200003 ()28631533 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2017-06-26 Created: 2017-06-26 Last updated: 2020-01-08Bibliographically approved
Padhan, N., Yan, J., Boge, A., Scrivener, E., Birgisson, H., Zieba, A., . . . Landegren, U. (2017). Highly sensitive and specific protein detection via combined capillary isoelectric focusing and proximity ligation. Scientific Reports, 7, Article ID 1490.
Open this publication in new window or tab >>Highly sensitive and specific protein detection via combined capillary isoelectric focusing and proximity ligation
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 1490Article in journal (Refereed) Published
Abstract [en]

Detection and quantification of proteins and their post-translational modifications are crucial to decipher functions of complex protein networks in cell biology and medicine. Capillary isoelectric focusing together with antibody-based detection can resolve and identify proteins and their isoforms with modest sample input. However, insufficient sensitivity prevents detection of proteins present at low concentrations and antibody cross-reactivity results in unspecific detection that cannot be distinguished from bona fide protein isoforms. By using DNA-conjugated antibodies enhanced signals can be obtained via rolling circle amplification (RCA). Both sensitivity and specificity can be greatly improved in assays dependent on target recognition by pairs of antibodies using in situ proximity ligation assays (PLA). Here we applied these DNA-assisted RCA techniques in capillary isoelectric focusing to resolve endogenous signaling transducers and isoforms along vascular endothelial growth factor (VEGF) signaling pathways at concentrations too low to be detected in standard assays. We also demonstrate background rejection and enhanced specificity when protein detection depended on binding by pairs of antibodies using in situ PLA, compared to assays where each antibody preparation was used on its own.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-323033 (URN)10.1038/s41598-017-01516-7 (DOI)000400554200002 ()28473697 (PubMedID)
Funder
EU, European Research Council, 294409EU, FP7, Seventh Framework Programme, 241481Swedish Research CouncilSwedish Cancer Society
Available from: 2017-06-02 Created: 2017-06-02 Last updated: 2017-06-02Bibliographically approved
Enblad, M., Birgisson, H., Ekbom, A., Sandin, F. & Graf, W. (2017). Increased incidence of bowel cancer after non-surgical treatment of appendicitis. European Journal of Surgical Oncology, 43(11), 2067-2075
Open this publication in new window or tab >>Increased incidence of bowel cancer after non-surgical treatment of appendicitis
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2017 (English)In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 43, no 11, p. 2067-2075Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: There is an ongoing debate on the use of antibiotics instead of appendectomy for treating appendicitis but diagnostic difficulties and longstanding inflammation might lead to increased incidence of bowel cancer in these patients. The aim of this population-based study was to investigate the incidence of bowel cancer after non-surgical treatment of appendicitis.

PATIENTS AND METHODS: Patients diagnosed with appendicitis but lacking the surgical procedure code for appendix removal were retrieved from the Swedish National Inpatient Register 1987-2013. The cohort was matched with the Swedish Cancer Registry and the standardised incidence ratios (SIR) with 95% confidence interval (95% CI) for appendiceal, colorectal and small bowel cancers were calculated.

RESULTS: Of 13 595 patients with non-surgical treatment of appendicitis, 352 (2.6%) were diagnosed with appendiceal, colorectal or small bowel cancer (SIR 4.1, 95% CI 3.7-4.6). The largest incidence increase was found for appendiceal (SIR 35, 95% CI 26-46) and right-sided colon cancer (SIR 7.5, 95% CI 6.6-8.6). SIR was still elevated when excluding patients with less than 12 months since appendicitis and the incidence of right-sided colon cancer was elevated five years after appendicitis (SIR 3.5, 95% CI 2.1-5.4). An increased incidence of bowel cancer was found after appendicitis with abscess (SIR 4.6, 95% CI 4.0-5.2), and without abscess (SIR 3.5, 95% CI 2.9-4.1).

CONCLUSION: Patients with non-surgical treatment of appendicitis have an increased short and long-term incidence of bowel cancer. This should be considered in the discussion about optimal management of patients with appendicitis.

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
Appendiceal cancer, Appendicitis, Colorectal cancer, Non-surgical treatment
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-333277 (URN)10.1016/j.ejso.2017.08.016 (DOI)000418107200012 ()28942236 (PubMedID)
Available from: 2017-11-09 Created: 2017-11-09 Last updated: 2018-03-09Bibliographically approved
Martling, A., Smedby, K. E., Birgisson, H., Olsson, H., Granath, F., Ekbom, A. & Glimelius, B. (2017). Risk of second primary cancer in patients treated with radiotherapy for rectal cancer. British Journal of Surgery, 104(3), 278-287
Open this publication in new window or tab >>Risk of second primary cancer in patients treated with radiotherapy for rectal cancer
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2017 (English)In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 104, no 3, p. 278-287Article in journal (Refereed) Published
Abstract [en]

Background: Many patients with rectal cancer receive radiotherapy (RT) to reduce the risk of local recurrence. Radiation may give rise to adverse effects, including second primary cancers. In view of the divergent results of previous studies, the present study evaluated the risk of second primary cancer following RT in all randomized RT rectal cancer trials conducted in Sweden and in the Swedish ColoRectal Cancer Registry (SCRCR).

Methods: Patients included in five randomized trials and the SCRCR were linked to the Swedish Cancer Registry. Cox regression models estimated the hazard ratio (HR) of second primary cancer among patients who received RT compared with those who did not.

Results: A total of 13 457 patients were included in this study; 7024 (52.2 per cent) received RT and 6433 (47.8 per cent) had surgery alone. Overall, no increased risk of second primary cancer was observed with RT (HR 1.03; 95 per cent c. i. 0.92 to 1.15), independently of follow-up time and location within or outside of the irradiated volume. In the randomized trials, with longer follow-up (maximum 31 years), a slight increase was observed outside of (HR 1.33, 1.01 to 1.74) but not within (HR 1.11, 0.73 to 1.67) the irradiated volume. Irradiated men had a lower risk of prostate cancer than those treated with surgery alone (HR 068, 0.51 to 091).

Conclusion: Overall, there was no increased risk of second primary cancer following RT for rectal cancer within or outside of the irradiated volume up to 20 years of follow-up. Men with rectal cancer who received RT had a reduced risk of prostate cancer.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-317594 (URN)10.1002/bjs.10327 (DOI)000393597100014 ()27802358 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer Society
Available from: 2017-03-24 Created: 2017-03-24 Last updated: 2017-11-29Bibliographically approved
Ghanipour, L., Darmanis, S., Landegren, U., Glimelius, B., Påhlman, L. & Birgisson, H. (2016). Detection of prognostic biomarkers with solid-phase proximity ligation assay in patients with colorectal cancer. Translational Oncology, 9(3), 251-255
Open this publication in new window or tab >>Detection of prognostic biomarkers with solid-phase proximity ligation assay in patients with colorectal cancer
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2016 (English)In: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 9, no 3, p. 251-255Article in journal (Refereed) Published
Abstract [en]

Background: In the search for prognostic biomarkers a significant amount of precious biobanked blood samples is needed if conventional analyses are used. Solid-phase proximity ligation assay (SP-PLA) is an analytic method with the ability to analyse many proteins at the same time in small amounts of plasma. The aim of this study was to explore the potential use of  SP-PLA in patients with colorectal cancer (CRC).

Material and methods: Plasma from patients with stage I-IV CRC, with (n=31) and without (n=29) disease dissemination at diagnosis or later, was analysed with SP-PLA using 35 antibodies targeting an equal number of proteins in 5 ml plasma. Carcinoembryonic antigen (CEA), analysed earlier on this cohort, was used as a reference.

Results: A total of 21 of the 35 proteins were detectable with SP-PLA. Patients in stage II-III with disseminated disease had lower plasma concentrations of HCC-4 (p=0.025). Low plasma levels of TIMP-1 were seen in patients with disseminated disease stage II (p=0.003). The level of CEA was higher in patients with disease dissemination compared to those without (p=0.007).

Conclusion: SP-PLA has the ability to analyse many tumour markers simultaneously in a small amount of blood. However, none of the markers selected for the present SP-PLA analyses gave better prognostic information compared with CEA. 

Keywords
colorectal cancer, biomarkers, SP-PLA, recurrence, prognosis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-224696 (URN)10.1016/j.tranon.2016.04.001 (DOI)000378028300014 ()27267845 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 294409; 259796
Available from: 2014-05-19 Created: 2014-05-19 Last updated: 2017-12-05Bibliographically approved
Enblad, M., Birgisson, H., Wanders, A., Sköldberg, F., Ghanipour, L. & Graf, W. (2016). Importance of Absent Neoplastic Epithelium in Patients Treated With Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy. Annals of Surgical Oncology, 23(4), 1149-1156
Open this publication in new window or tab >>Importance of Absent Neoplastic Epithelium in Patients Treated With Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy
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2016 (English)In: Annals of Surgical Oncology, ISSN 1068-9265, E-ISSN 1534-4681, Vol. 23, no 4, p. 1149-1156Article in journal (Refereed) Published
Abstract [en]

The importance of absent neoplastic epithelium in specimens from cytoreductive surgery (CRS) is unknown. This study aimed to investigate the prevalence and prognostic value of histopathology without neoplastic epithelium in patients treated with CRS and hyperthermic intraperitoneal chemotherapy (HIPEC). Data were extracted from medical records and histopathology reports for patients treated with initial CRS and HIPEC at Uppsala University Hospital, Sweden, between 2004 and 2012. Patients with inoperable disease and patients undergoing palliative non-CRS surgery were excluded from the study. Patients lacking neoplastic epithelium in surgical specimens from CRS, with or without mucin, were classified as "neoplastic epithelium absent" (NEA), and patients with neoplastic epithelium were classified as "neoplastic epithelium present" (NEP). The study observed NEA in 78 of 353 patients (22 %). Mucin was found in 28 of the patients with NEA. For low-grade appendiceal mucinous neoplasms and adenomas, the 5-year overall survival rate was 100 % for NEA and 84 % for NEP, and the 5-year recurrence-free survival rate was 100 % for NEA and 59 % for NEP. For appendiceal/colorectal adenocarcinomas (including tumors of the small intestine), the 5-year overall survival rate was 61 % for NEA and 38 % for NEP, and the 5-year recurrence-free survival rate was 60 % for NEA and 14 % for NEP. Carcinoembryonic antigen level, peritoneal cancer index, and completeness of the cytoreduction score were lower in patients with NEA. A substantial proportion of patients undergoing CRS and HIPEC have NEA. These patients have a favorable prognosis and a decreased risk of recurrence. Differences in patient selection can affect the proportion of NEA and hence explain differences in survival rates between reported series.

National Category
Cancer and Oncology Surgery
Identifiers
urn:nbn:se:uu:diva-282455 (URN)10.1245/s10434-015-4989-y (DOI)000371333200015 ()26577120 (PubMedID)
Available from: 2016-04-05 Created: 2016-04-05 Last updated: 2018-03-09Bibliographically approved
Larsson, A. H., Lehn, S., Wangefjord, S., Karnevi, E., Kuteeva, E., Sundström, M., . . . Jirström, K. (2016). Significant association and synergistic adverse prognostic effect of podocalyxin-like protein and epidermal growth factor receptor expression in colorectal cancer. Journal of Translational Medicine, 14, Article ID 128.
Open this publication in new window or tab >>Significant association and synergistic adverse prognostic effect of podocalyxin-like protein and epidermal growth factor receptor expression in colorectal cancer
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2016 (English)In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 14, article id 128Article in journal (Refereed) Published
Abstract [en]

Background: Podocalyxin-like 1 (PODXL) is an anti-adhesive transmembrane protein that has been demonstrated to be an independent factor of poor prognosis in colorectal cancer (CRC). The gene encoding PODXL is located to chromosome 7, which also harbours the gene for the epidermal growth factor receptor (EGFR). The aim of this study was to examine the associations between PODXL and EGFR expression in CRC in vitro and in vivo.

Methods: EGFR expression was analysed in tumours from three independent patient cohorts; cohort 1 (n = 533), cohort 2 (n = 259) and cohort 3 (n = 310), previously analysed for immunohistochemical PODXL expression and KRAS and BRAF mutations (cohort 1 and 3). Levels of EGFR and PODXL were determined by western blot in six different CRC cell lines.

Results: High expression of PODXL was significantly associated with high EGFR expression (p < 0.001) in all three cohorts, and with BRAF mutation (p < 0.001) in cohort 1 and 3. High EGFR expression correlated with BRAF mutation (p < 0.001) in cohort 1. High EGFR expression was associated with adverse clinicopathological factors and independently predicted a reduced 5-year overall survival (OS) in cohort 1 (HR 1.77; 95 % CI 1.27-2.46), cohort 2 (HR 1.58; 95 % CI 1.05-2.38) and cohort 3 (HR 1.83; 95 % CI 1.19-2.81). The highest risk of death within 5 years was observed in patients with tumours displaying high expression of both EGFR and PODXL in cohort 1 and 3 (HR 1.97; 95 % CI 1.18-3.28 and HR 3.56; 95 % CI 1.75-7.22, respectively). Western blot analysis showed a uniform expression of PODXL and EGFR in all six examined CRC cell lines.

Conclusions: The results from this study demonstrate that high expression of EGFR is an independent factor of poor prognosis in CRC. Moreover, strong links have been uncovered between expression of the recently proposed biomarker candidate PODXL with EGFR expression in CRC in vivo and in vitro, and with BRAF mutation in vivo. High expression of both PODXL and EGFR may also have a synergistic adverse effect on survival. These findings suggest a potential functional link in CRC between PODXL, EGFR and BRAF, all originating from chromosome 7, which may be highly relevant in the clinical setting and therefore merit future in-depth study.

Keywords
Podocalyxin-like, EGFR, BRAF, Colorectal cancer, Prognosis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-297267 (URN)10.1186/s12967-016-0882-0 (DOI)000375475400002 ()27160084 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Cancer SocietyGunnar Nilsson Cancer Foundation
Available from: 2016-06-23 Created: 2016-06-22 Last updated: 2017-11-28Bibliographically approved
Lomnytska, M., Stalberg, K., Birgisson, H., Silins, I. & Graf, W. (2015). Complications Related To Surgery For Ovarian Cancer With Intestinal Involvement. International Journal of Gynecological Cancer, 25(9), 492-492
Open this publication in new window or tab >>Complications Related To Surgery For Ovarian Cancer With Intestinal Involvement
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2015 (English)In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 25, no 9, p. 492-492Article in journal, Meeting abstract (Other academic) Published
National Category
Cancer and Oncology Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-299992 (URN)000377145701104 ()
Available from: 2016-08-01 Created: 2016-08-01 Last updated: 2017-11-28Bibliographically approved
Birgisson, H., Edlund, K., Wallin, U., Påhlman, L., Kultima, H. G., Mayrhofer, M., . . . Sundström, M. (2015). Microsatellite instability and mutations in BRAF and KRAS are significant predictors of disseminated disease in colon cancer. BMC Cancer, 15, Article ID 125.
Open this publication in new window or tab >>Microsatellite instability and mutations in BRAF and KRAS are significant predictors of disseminated disease in colon cancer
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2015 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 15, article id 125Article in journal (Refereed) Published
Abstract [en]

Background: Molecular alterations are well studied in colon cancer, however there is still need for an improved understanding of their prognostic impact. This study aims to characterize colon cancer with regard to KRAS, BRAF, and PIK3CA mutations, microsatellite instability (MSI), and average DNA copy number, in connection with tumour dissemination and recurrence in patients with colon cancer. Methods: Disease stage II-IV colon cancer patients (n = 121) were selected. KRAS, BRAF, and PIK3CA mutation status was assessed by pyrosequencing and MSI was determined by analysis of mononucleotide repeat markers. Genome-wide average DNA copy number and allelic imbalance was evaluated by SNP array analysis. Results: Patients with mutated KRAS were more likely to experience disease dissemination (OR 2.75; 95% CI 1.28-6.04), whereas the opposite was observed for patients with BRAF mutation (OR 0.34; 95% 0.14-0.81) or MSI (OR 0.24; 95% 0.09-0.64). Also in the subset of patients with stage II-III disease, both MSI (OR 0.29; 95% 0.10-0.86) and BRAF mutation (OR 0.32; 95% 0.16-0.91) were related to lower risk of distant recurrence. However, average DNA copy number and PIK3CA mutations were not associated with disease dissemination. Conclusions: The present study revealed that tumour dissemination is less likely to occur in colon cancer patients with MSI and BRAF mutation, whereas the presence of a KRAS mutation increases the likelihood of disseminated disease.

Keywords
Colon cancer, MSI, BRAF, KRAS, PIK3CA, DNA copy number, Prognosis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-251424 (URN)10.1186/s12885-015-1144-x (DOI)000351047900001 ()
Available from: 2015-04-23 Created: 2015-04-17 Last updated: 2018-02-01Bibliographically approved
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