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Predictive and prognostic factors in cervical carcinomas treated with (chemo-) radiotherapy
Örebro University, School of Medical Sciences.
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A series of 131 women with cervical carcinoma FIGO stage I-IV were treated with external radiotherapy and intracavitary brachytherapy. In 47 patients (36%) concomitant chemotherapy was given. One hundred and twenty-one tumors (92%) achieved complete remission. Addition of chemotherapy increased primary cure rate to 98%. Tumor stage, tumor size, and histology were significant predictive factors for primary cure. Treatment related factors were: brachytherapy dose and interruption of irradiation.

Thirty-nine recurrences (30%) were recorded. Tumor stage, histology, and concomitant chemotherapy were significant predictive factors.

The 5-year cancer-specific survival rate of the complete series was 65%. Tumor size was a strong prognostic factor in multivariate analysis.

Serum samples from 44 patients were analyzed. Ten candidate biomarker proteins with regard to tumor recurrences were identified.

Five Hedgehog proteins were analyzed with immunohistochemistry. Residual tumor, local and distant recurrences and survival rate were associated with PTCH, SMO and GLI2. In the Wnt-β-catenin study intense staining of the membranes and nuclear staining > 5% were of significant predictive and prognostic value. Intense nuclear APC staining was associated with recurrences and cancer-specific survival rate.

Conclusion: Histology, tumor size and brachytherapy dose were important clinical predictive and prognostic factors. Multiprotein analysis identified ten biomarker proteins associated with tumor recurrences. Three proteins (PTCH, SMO, and GLI2) in the Hedgehog pathway were of predictive and prognostic value. In the Wnt-β-catenin pathway intensity of β-catenin membrane staining and accumulation in the nuclei as well as nuclear APC-expression were of predictive and prognostic value.

Place, publisher, year, edition, pages
Örebro: Örebro University , 2017. , 61 p.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 159
Keyword [en]
cervical carcinoma, radio-chemotherapy, biomarkers, predictive factors, prognostic factors, multiprotein analysis, Hedgehog pathway, Wnt/β-catenin pathway
National Category
Surgery
Research subject
Surgery
Identifiers
URN: urn:nbn:se:oru:diva-56127ISBN: 978-91-7529-185-7 (print)OAI: oai:DiVA.org:oru-56127DiVA: diva2:1078761
Public defence
2017-04-21, Örebro universitet, Campus USÖ, hörsal C1, Södra Grev Rosengatan 32, Örebro, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2017-03-06 Created: 2017-03-06 Last updated: 2017-04-19Bibliographically approved
List of papers
1. Combined external and intracavitary irradiation in treatment of advanced cervical carcinomas: predictive factors for local tumor control and early recurrences.
Open this publication in new window or tab >>Combined external and intracavitary irradiation in treatment of advanced cervical carcinomas: predictive factors for local tumor control and early recurrences.
2010 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 36, no 2, 371-8 p.Article in journal (Refereed) Published
Abstract [en]

In a series of 131 primary cervical carcinomas in FIGO stages I-IV suitable for combined external pelvic and intraluminal cervical-vaginal brachytherapy predictive and prognostic factors were analyzed with regard to locoregional tumor control, recurrences and survival data. Patients with prior surgery or patients treated with external beam therapy alone were excluded from this series. Concomitant chemotherapy was given to 47 patients (36%). The external beam therapy was given with a four-field technique (50-60 Gy) and brachytherapy with high dose-rate (Ir-192) using a ring applicator set. The dose (18-30 Gy) was specified according to the rules in ICRU 38 (a minimum dose to the surface of the target volume). Three or five fractions were given once a week in parallel with external beam irradiation. A CT-based 3-D dose-planning system (TMS) was used for the external beam therapy and for the brachytherapy planning (PLATO). The mean age of the patients was 65 years. One hundred and seven tumors were squamous cell carcinomas (82%) and 24 adenocarcinomas or adenosquamous carcinomas. One hundred and eight tumors were in FIGO stages I-II and 23 tumors in stages III-IV. The mean tumor diameter was 44 mm. Most tumors (92%) were moderately well or poorly differentiated. The primary cure rate of the complete series was 92% and 98% after chemoradiotherapy. Squamous cell carcinomas had complete remission in 96% and adenocarcinomas in 81% (Pearson Chi-square; P=0.00002). Tumor size was also highly significantly associated with local tumor control. The brachytherapy dose, the combined external and brachytherapy dose and the number of days of interruption (delay) of external irradiation were all significant predictive factors of local tumor control. In the complete series 39 recurrences (30%) were recorded. A lower FIGO stage, chemoradiotherapy, squamous cell histology, diploid DNA-profile, a higher brachytherapy dose, more brachytherapy fractions and a higher total combined irradiation dose were favorable factors with regard to the risk of tumor recurrences. The overall survival rate was 50% and the cancer-specific survival rate 65%. Tumor size was the strongest individual prognostic factor in multivariate analysis. Chemoradiotherapy therapy versus radiotherapy alone and squamous cell carcinomas versus adenocarcinomas were associated with improved survival rates. Early radiation reactions were recorded in 58% (mostly grade 1) and serious late radiation reactions (grade 3-4) in 11%.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-56897 (URN)10.3892/ijo_00000509 (DOI)000273861900010 ()20043071 (PubMedID)2-s2.0-75449089521 (Scopus ID)
Available from: 2017-03-29 Created: 2017-03-29 Last updated: 2017-03-29Bibliographically approved
2. A study of serum biomarkers associated with relapse of cervical cancer
Open this publication in new window or tab >>A study of serum biomarkers associated with relapse of cervical cancer
2012 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 32, no 11, 4913-22 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND/AIM: To discover candidate protein biomarkers in the serum of patients with cervical cancer that differentiate between patients with relapse from those who are tumor-free after primary treatment with (platinum-based chemo-) radiation.

PATIENTS AND METHODS: Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) with cation exchange (CM10) and hydrophobic/reverse-phase (H50) was used to examine 44 serum samples from patients with advanced cervical cancer, primarily treated with (platinum-based chemo-) radiation.

RESULTS: Ten candidate biomarkers were identified in the serum of 34 patients. Six candidate markers were elevated in patients with no relapse and four were elevated in patients with relapse [p=0.007-0.11; area under the curve (AUC)=0.70-0.75]. Masses of candidate biomarkers ranged from 2,022 to 116,165 Da.

CONCLUSION: Patients with relapse from primary advanced cervical cancer exhibit different serum protein expression profiles from those with no relapse.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-56898 (URN)000311524500037 ()23155260 (PubMedID)2-s2.0-84872659639 (Scopus ID)
Available from: 2017-03-29 Created: 2017-03-29 Last updated: 2017-03-29Bibliographically approved
3. Prognostic impact of the expression of Hedgehog proteins in cervical carcinoma FIGO stages I-IV treated with radiotherapy or chemoradiotherapy
Open this publication in new window or tab >>Prognostic impact of the expression of Hedgehog proteins in cervical carcinoma FIGO stages I-IV treated with radiotherapy or chemoradiotherapy
2014 (English)In: Gynecologic Oncology, ISSN 0090-8258, E-ISSN 1095-6859, Vol. 135, no 2, 305-311 p.Article in journal (Refereed) Published
Abstract [en]

Objective: Hedgehog signaling proteins were assessed in patients with cervical carcinoma receiving chemoradiation. Associations between five Hedgehog proteins and prognosis were studied.

Methods: In all, 131 cases of cervical carcinomas (FIGO stages I-IV) were immunohistochemically (IHC) analyzed for Patched (PTCH), Smoothened (SMO), and GLI1, GLI2 and GLI3 protein expression. Associations between Hedgehog protein expressions, clinicopathological factors, and clinical outcome data were examined.

Results: Positive IHC staining for the five Hedgehog proteins was recorded in 8% to 37% of the tumor cells. The highest frequency was noted for SMO and the lowest for all. There was a significant association between low SMO- and GLI2-expression and KRAS-mutation. Tumors with overexpressed SMO had a higher frequency of residual tumor or local recurrences than tumors with low SMO expression. Patients with tumors expressing PTCH in more than 75% of the cells had significantly (P = 0.023) better recurrence-free survival than patients with tumors with low expression. The opposite situation was true for SMO. For GLI2, there was a statistically significant difference with regard to overall (P = 0.004) and distant (P = 0.015) relapse rate for groups with expression of GLI2 in the range of 5-25% compared to higher rates.

Conclusions: A predictive and prognostic value was found for PTCH, SMO, and GLI2 with regard to residual carcinoma, local recurrences, and for GLI2 distant relapses. The Hedgehog signaling pathway also seems to play an important role in cervical carcinogenesis together with HPV16-infection and KRAS-mutation.

Place, publisher, year, edition, pages
Academic Press, 2014
Keyword
Cervical carcinoma, Hedgehog proteins, Prognosis
National Category
Cancer and Oncology Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:oru:diva-56331 (URN)10.1016/j.ygyno.2014.08.026 (DOI)000345605200023 ()25158038 (PubMedID)2-s2.0-84914169236 (Scopus ID)
Note

Funding Agencies:

Research Foundation at the Department of Oncology

Research Funds of the University Hospital, Örebro

Foundation for Research in Gynecological Cancer, Örebro, Sweden 

Available from: 2017-03-14 Created: 2017-03-14 Last updated: 2017-03-29Bibliographically approved
4. Prognostic impact of the expression of Wnt-signaling proteins in cervical carcinoma FIGO stage I-IV treated with radiotherapy or chemoradiotherapy
Open this publication in new window or tab >>Prognostic impact of the expression of Wnt-signaling proteins in cervical carcinoma FIGO stage I-IV treated with radiotherapy or chemoradiotherapy
2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 39, 63042-63053 p.Article in journal (Refereed) Published
Abstract [en]

Wnt signaling proteins were assessed in patients with primary cervical carcinomas who received chemoradiation. The associations between three Wnt signaling proteins and prognosis were assessed. Specimens from 122 patients with cervical carcinomas (FIGO stage I-IV) were immunohistochemically (IHC) analyzed for β-catenin, APC and axin protein expression. Associations between these Wnt-protein expressions, clinicopathological factors, and clinical outcome data were examined.Positive IHC staining for the β-catenin protein (cell-membranes, cytoplasm and nuclei) was recorded in 88%, 58% and 5%, respectively. There was a strong association between β-catenin staining of the cell-membranes and prediction of recurrences and prognosis (p = 0. 002). Tumors with > 5% of nuclear β-catenin staining were associated with inferior cancer-specific survival (p = 0.048) compared with no staining. The overall recurrence rate was significantly higher in the group with increased nuclear staining (67%) compared with the group with no staining (33%). Nuclear APC staining of high intensity was associated with a significantly worse cancer-specific survival and increased overall recurrence rate compared to tumors with weak staining. Distant recurrences were recorded in 29% of cases with intense staining and in 14% of cases with low staining.The Wnt signaling pathway seems to be of importance in the process of cervical oncogenesis. A predictive and prognostic value was found for β-catenin, where strong cell-membrane staining was favorable, and > 5% positive nuclear staining was associated with poorer cancer-specific survival and overall recurrence rate. Nuclear APC staining intensity was also associated with a less favorable prognosis.

Keyword
APC, Wnt signaling pathway, cervical carcinoma, β-catenin
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-56900 (URN)10.18632/oncotarget.11642 (DOI)27577083 (PubMedID)2-s2.0-84994045434 (Scopus ID)
Available from: 2017-03-29 Created: 2017-03-29 Last updated: 2017-03-29Bibliographically approved

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