| 1. |
- Ekwall, Eva, 1950-, et al.
(författare)
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Lived experiences of women with recurring ovarian cancer
- 2014
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Ingår i: European Journal of Oncology Nursing. - : Elsevier. - 1462-3889 .- 1532-2122. ; 18:1, s. 104-109
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Tidskriftsartikel (refereegranskat)abstract
- Background: Women with recurring ovarian cancer are living longer, due to advances in treatment options. They are now often outpatients, experiencing rapid encounters on treatment days. Whether this shift in care meets women’s needs has been scarcely explored scientifically.Purpose of the study: This study aimed to illuminate the phenomenon of living with recurring ovarian cancer as experienced by women in that condition.Methods and sample: A descriptive phenomenological method was used. Eight open-ended interviews with four women were performed approximately three and five years after the first recurrence of ovarian cancer. During these years the women had repeated clinically and radiologically verified recurrence requiring chemotherapy.Key results:The phenomenon of living with recurring ovarian cancer meant that the women felt forced to pay attention to the failing body in order to avoid a potential breakdown. The growing limitation of their intermittent strength meant that strength had to be captured and protected. Sharing their lives with others was difficult, due to the different living conditions. The women found no space to mediate their experiences, either in close relationships or with health care professionals. But, the circumstances they lived under also generated a gratitude for the unexpected extra time.Conclusions: The findings revealed that the four women were grateful to live a while longer, but needed to share their state of being. The findings are indeed directed to health care professionals, who need to provide a more patient-centred care to meet the women’s needs.
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| 2. |
- Ekwall, Eva, 1950-, et al.
(författare)
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The lived experience of life-prolonging treatment of recurring ovarian cancer
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- There has been an improvement in the effectiveness of chemotherapy agents to restrain recurring ovarian cancer, such that women live with the disease for longer than they used to. However, there is a knowledge gap concerning how patients define their world from a lifeworld perspective, when living with life-prolonging treatment. The aim of the study was to illuminate the phenomenon of living with life-prolonging treatment of recurring ovarian cancer. Four women were interviewed twice, once in 2003, three years after the first recurrence, and again in 2005. The method was based on Giorgi’s phenomenological method. A situated structure for each woman was followed by a transformation into a general structure for all women, which communicates the most invariant meaning of the phenomenon.The general structure showed the growing threat to the women’s existence and their perception that time was short, yet extendable. Awareness of life’s limitedness evoked gratitude for the possibility to postpone death. The body’s strength was increasingly fragile and jeopardized the restraining of the disease. The amount of strength available was unpredictable, which meant a break in the rhythm of everyday life. Strength had to be captured and cared for.The wish to share the meaning of the disease with others was expressed as unattainable. The women were unable to realize the desire to be seen as an example of someone living with ongoing treatments. In encounters with other people, the cancer-afflicted body stood out as a barrier to communication. Inability to share their experience was also manifested in the women’s encounters with caregivers, which were characterized by an objective attitude. The women met with a gradual compliance their caregivers’ inability to respond to them.
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| 3. |
- Ekwall, Eva, 1950-, et al.
(författare)
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Women's perceptions of interactions with the health care team during treatment of the first recurrence of ovarian cancer
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Most women suffering a recurrence of ovarian cancer return to the same department where their primary cancer was treated. The aim of this study was to explore what women with the first recurrence of ovarian cancer perceived as important in their interaction with the healthcare team. Interviews were conducted with 12 women at the end of a chemotherapy treatment. The interviews were subjected to qualitative content analysis. The findings stress the importance for the healthcare team to offer each woman the opportunity to obtain support to become familiar with the disease. This theme of becoming familiar with the disease was supported by the following sub-themes: being confirmed as a person, getting help in making sense of information regarding the disease and its treatment, having the opportunity to be involved and share responsibility, and feeling confident that medical expertise is good enough.Becoming familiar with the disease was expressed as a process of understanding and assimilating the whole new situation. Optimal support from healthcare professionals was facilitated by establishing trusting relationships. Being confirmed and treated as a unique person was seen as a prerequisite to achieving familiarity with the disease. The women needed help to make sense of the information available. They stressed the importance of being able to influence their encounters with healthcare professionals in accordance with their own perspectives. Also of importance was having the opportunity to share the responsibility for their care and lives. The findings suggest that patients’ need should be identified repeatedly throughout the illness trajectory.
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| 4. |
- Bohr Mordhorst, Louise, 1958-
(författare)
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Predictive and prognostic factors in cervical carcinomas treated with (chemo-) radiotherapy
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 5. |
- Bohr Mordhorst, Louise, 1958-, et al.
(författare)
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Prognostic impact of the expression of Hedgehog proteins in cervical carcinoma FIGO stages I-IV treated with radiotherapy or chemoradiotherapy
- 2014
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Ingår i: Gynecologic Oncology. - : Academic Press. - 0090-8258 .- 1095-6859. ; 135:2, s. 305-311
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 6. |
- Bohr Mordhorst, Louise, 1958-, et al.
(författare)
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Prognostic impact of the expression of Wnt-signaling proteins in cervical carcinoma FIGO stage I-IV treated with radiotherapy or chemoradiotherapy
- 2016
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Ingår i: Oncotarget. - Orchard Park, USA : Impact Journals LLC. - 1949-2553. ; 7:39, s. 63042-63053
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
- Ekwall, Ewa, 1950-, et al.
(författare)
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Important aspects of health care for women with gynecologic cancer
- 2003
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Ingår i: Oncology Nursing Forum. - Pittsburg : Oncology Nursing Society. - 0190-535X .- 1538-0688. ; 30:2, s. 313-319
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Tidskriftsartikel (refereegranskat)abstract
- Purpose/Objectives: To describe what women diagnosed with primary gynecologic cancer reported to be important during their interacion with the healthcare system. Design: Qualitative. Setting: A specialized gynecologic cancer care unit in central Sweden. Sample: 14 women diagnosed with primary gynecologic cancer were recruited. The women had been referred to the specialized care unit for radiation or cytostatic therapy. Methods: Tape-recorded interviews were transcnbed, coded, categoized, and analyzed. Main Research Variables: Primary diagnosed women with cancer and their experience with quality of care during diagnosis and treatment. Findings: Three partly overlapping categories (i.e., optima! care,good communication, and self-image and sexuality) were found to be of central importance in quality of health care. Participants stated that health care should be based on their own perceptions of the need for information and dialogue and how the disease and treatment would affect their health, self-image, and sexuality. Everyday conversations also were very important. Conclusions: Central importance in health care for the women included both rational and human aspects. The primary need of participants was available, competent, and coordinated. Implications for Nursing: Women with gynecologic cancer should be given individualized information and care to satisfy their individual needs and reinforce their self-image. Nurses have an important role in strengthening women´s feelings of hope and supporting them in maintaining as positive a self-image as possible. Information and everyday conversation are of great significance. Sexuality should be an integral part of holistic care; to this end, inclusion of each woman's sexual partner may be helpful when discussions concerning sexuality occur.
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| 8. |
- Ekwall, Eva, 1950-, et al.
(författare)
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Recurrence of ovarian cancer : living in limbo
- 2007
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Ingår i: Cancer Nursing. - Philadelphia : Lippincott Williams & Wilkins. - 0162-220X .- 1538-9804. ; 30:4, s. 270-277
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Tidskriftsartikel (refereegranskat)abstract
- Few studies have shed light on women's life situation after being informed of having recurrent ovanan cancer, The present study aimed to elucidate women's experiences of living with this knowledge. interviews were conducted with 12 women who were undergoing or had just completed chemotherapy, 5 to 10 months after learning or the recurrence. Data were collected and analyzed based on a life world perspective using a descriptive phenomenoiogical method. The women's experiences are described via 3 key constituents: being denied one's future while simultaneously hoping to be ble to delay the cancer's advancement, feeling alienated from both oneself and one's surroundings, and being responsible. The key constituents were integrated into the structure "living in limbo." The women lived on the threshoid to the unknown. They were preparing themselves both for a continued life and for death. "Living in limbo" can be described as a phase of a health-illness transition characterized by loneliness. The vulnerable position and existential struggle of these women should be focused upon in nursing. The sensitive dialogue is essential in these cases.
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| 9. |
- Farkas, Sanja A., 1983-, et al.
(författare)
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Epigenetic changes as prognostic predictors in endometrial carcinomas
- 2017
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Ingår i: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 12:1, s. 19-26
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Tidskriftsartikel (refereegranskat)abstract
- Endometrial carcinoma is one of the most frequent gynecological malignancies of the female. The diagnostic and prognostic markers for the high-risk subgroups with unfavorable prognosis are under intense debate worldwide, and, therefore, the aim of this study was to identify new potential DNA methylation markers for the high-risk groups. We used the Illumina Infinium HumanMethylation450 BeadChip to analyze the DNA methylation pattern and investigated its association with clinicopathological features important for defining the high-risk (FIGO-grade 3) and low-risk (FIGO-grade 1) groups of patients with endometrial cancer (n = 31 and n = 39, respectively). We identified specific DNA methylation signature in high-risk endometrial tumors, and potential molecular biomarker genes (TBX2, CHST11, and NID2) associated with unfavorable clinical predictive and prognostic factors.
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| 10. |
- Graflund, M., et al.
(författare)
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HPV-DNA, vascular space invasion, and their impact on the clinical outcome in early-stage cervical carcinomas
- 2014
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Ingår i: International Journal of Gynecological Cancer. - Malden, USA : Blackwell Publishing. - 1048-891X .- 1525-1438. ; 14:5, s. 896-902
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Tidskriftsartikel (refereegranskat)abstract
- The present study was designed to analyze the relationship of human papillomavirus (HPV)-DNA, microvessel density, and their impact on clinical outcome in early cervical carcinoma. HPV-DNA was evaluated in 171 cases of cervical carcinoma treated from 1965 to 1990. In 110 cases, the analyses could be performed. A polymerase chain reaction technique was used on paraffin-embedded specimens obtained before the start of therapy. HPV-DNA of any type was detected in 78% (86/110) of all evaluable tumors. HPV16 was the predominant type and was detected in 56% (62/110), HPV18 in 8% (9/110), and HPV35 in 21% (23/110). Patients with tumors containing HPV16 or HPV18 were significantly (P = 0.011) younger than patients with tumors not containing either of these two subtypes. Vascular space invasion and lymph node metastases were observed more frequently in tumors expressing HPV16 and HPV18 (P = 0.002, P = 0.047) than in tumors negative for these HPV strains. Tumors containing HPV16 and HPV18 were significantly (P = 0.012) larger and more frequently (P = 0.005) associated with higher FIGO stages. The cancer-specific survival rate was lower for patients with HPV16- and HPV18-positive tumors, but the difference was not statistically significant. The microvessel density was a non-significant prognostic factor. The overall 5-year survival rate of the complete series was 91%. It was concluded that HPV-DNA was a prognostic factor in early-stage cervical cancer and was associated with the age of the patient, vascular space invasion, lymph node metastases, tumor size, and FIGO stage.
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| 11. |
- Graflund, Marianne, et al.
(författare)
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Immunohistochemical expression of p53, bcl-2, and p21WAF1/CIP1 in early cervical carcinoma : Correlation with clinical outcome
- 2002
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Ingår i: International Journal of Gynecological Cancer. - Malden, USA : BMJ. - 1048-891X .- 1525-1438. ; 12:3, s. 290-298
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to assess the value of p53, bcl-2, and p21WAF1/CIP1 immunoreactivity as predictors of pelvic lymph node metastases (LNM), recurrences, and death due to the disease in early stage (FIGO I-II) cervical carcinomas. FIGO stage, type of histopathology, and tumor grade were also evaluated in this series of patients treated by radical hysterectomy (Wertheim-Meigs) between 1965 and 1990. A total of 172 patients were included. A tumor was regarded as positive when more than 30% of the neoplastic cells exhibited immunoreactivity. Positive immunostaining was found in 8.9% for p53, in 43.5% for bcl-2, and in 25.0% for p21WAF1/CIP1. None of them was able to predict LNM or clinical outcome. Presence of LNM, tumor recurrence, and death from disease were significantly associated with the FIGO stage (P = 0.014, P = 0.009, and P = 0.001, respectively). The 5-year cancer-specific survival rate was 91.6% and the overall survival rate was 90.5%. It was concluded that immunohistochemically detected p53, bcl-2, and p21WAF1/CIP1 appeared to be of no predictive value with regard to LNM, tumor recurrences, or long-term survival in early cervical carcinomas.
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| 12. |
- Graflund, Marianne, et al.
(författare)
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MIB-1, p53, bcl-2, and WAF-1 expression in pelvic lymph nodes and primary tumors in early stage cervical carcinomas : correlation with clinical outcome
- 2002
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Ingår i: International Journal of Oncology. - Athens, Greece : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 20:5, s. 1041-1047
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Tidskriftsartikel (refereegranskat)abstract
- A complete series of 40 cervical carcinomas with pelvic lymph node metastases were analysed immunohistochemically for prognostic markers. The aims of this study were to examine whether the detection of MIB-1, p53, bcl-2, and WAF-1 could be used as a prognostic marker for tumor recurrence and survival rate. During the period of observation (mean 222, range 72-360 months) 22 (55%) recurrences were encountered and 20 patients died of the disease. There were 35 squamous cell carcinomas (87.5%), 2 adenosquamous carcinomas (5.0%), and 3 pure adenocarcinomas (7.5%). One tumor (2.5%) was well differentiated, 12 tumors (30%) were moderately differentiated, and 27 tumors (67.5%) were poorly differentiated. The primary tumor grade (P=0.037) and radicality of the surgical margins (P=0.021) were significant prognostic factors with regard to tumor recurrence. The site and number of lymph nodes with metastases had no prognostic value. P53, bcl-2, and WAF-1 were not predictive factors for recurrences or the cancer-specific survival rate. The concordant expression of WAF-1 in the primary tumor and in lymph node metastases was lower than for p53 and bcl-2. The proliferative activity (MIB-1) seemed to be lower in tumor cells metastasized to the pelvic lymph nodes than in cells of the primary tumor. Expression of MIB-1 in lymph nodes was predictive of disease-free survival in both univariate and multivariate proportional hazard Cox analyses.
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| 13. |
- Graflund, M., et al.
(författare)
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Relation between HPV-DNA and expression of p53, bcl-2, p21WAF-1, MIB-1, HER-2/neu and DNA ploidy in early cervical carcinoma : correlation with clinical outcome
- 2004
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Ingår i: Oncology Reports. - Athens, Greece : Spandidos Publications. - 1021-335X .- 1791-2431. ; 12:1, s. 169-176
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of the present study was to analyze the relation between the expression of p53, bcl-2, p21WAF1, MIB-1, HER-2/neu, DNA ploidy and HPV16 or 18 infections with clinical parameters. HPV-DNA was evaluated in 171 early cervical carcinomas treated from 1965 to 1990 and detected by PCR (polymerase chain reaction) on paraffin specimens obtained before therapy was started. HPV-DNA of any type was detected in 78% (86/110) of all tumors, HPV16 was the predominant type and was seen in 56% (62/110), HPV18 in 8% (9/110) and HPV35 in 21% (23/110). Patients with HPV16 or 18 were significantly (P=0.011) younger than patients with tumors not containing these two HPV subtypes. Lymph node metastases were seen more frequently (P=0.047) in tumors expressing HPV16 or 18. Tumor size was associated with the HPV-type. The frequency of DNA aneuploidy was lower in high-risk HPV tumors than in tumors with other HPV subtypes (P=0.014). MIB-1 expression was highly significantly (P=0.00007) associated with presence of HPV16 or 18. The cancer-specific survival rate was lower for patients with HPV16 and 18 positive tumors, but the difference was not statistically significant. The overall 5-year survival rate of the complete series was 91%. In conclusion, the HPV DNA subtype was a prognostic factor in early stage cervical cancer and it was associated with age, positive lymph nodes, tumor size, DNA ploidy and the proliferation marker MIB-1.
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| 14. |
- Graflund, Marianne, et al.
(författare)
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The prognostic value of a histologic grading system, DNA profile, and MIB-1 expression in early stages of cervical squamous cell carcinomas
- 2002
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Ingår i: International Journal of Gynecological Cancer. - Malden, USA : Blackwell Publishing. - 1048-891X .- 1525-1438. ; 12:2, s. 149-157
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Tidskriftsartikel (refereegranskat)abstract
- This study evaluated the prognostic importance of a new grading system focusing on the invasive tumor front, DNA profile, and the proliferation marker MIB-1. A complete geographic series of 172 women treated with radical hysterectomy (Wertheim-Meigs) for FIGO stage I-II cervical carcinomas was the target population. The analyses were performed on 141 (82%) squamous cell carcinomas of the complete series. During the period of observation (mean 222 months), 17 recurrences (12.1%) were encountered. Prognostic factors for disease-free survival were lymph node status (P < 0.000001), radical surgical margins (P = 0.00004), and tumor size (P = 0.002). The complete score of the invasive front grading system (IFG), and the individual scores of two variables-pattern of invasion and host response-were all significantly (P = 0.002, P = 0.007, P = 0.0001) associated with pelvic lymph node metastases. Host response was the single most important factor in the IFG system, and it was superior to the complete score in predicting lymph node metastases. The total IFG score was also a significant (P = 0.003) prognostic factor for disease-free survival. DNA ploidy, S-phase fraction, and MIB-1 expression were nonsignificant factors in predicting pelvic lymph node metastases and disease-free survival of the patient. The IFG in the original or modified versions could predict low- and high-risk groups of tumors and therefore be of value in treatment planning for these patients.
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| 15. |
- Graflund, Marianne, et al.
(författare)
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The prognostic value of histopathologic grading parameters and microvessel density in patients with early squamous cell carcinoma of the uterine cervix
- 2002
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Ingår i: International Journal of Gynecological Cancer. - Malden, USA : Blackwell Publishing. - 1048-891X .- 1525-1438. ; 12:1, s. 32-41
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to investigate the prognostic importance of clinical and histopathologic factors, including malignancy grading systems (MGS), partial index (PI), invasive front grading (IFG), and microvessel density. A complete geographic series of 172 early stage (FIGO I-II) cervical carcinomas treated by Wertheim-Meigs surgery during the period 1965-1990 was studied. The patients were followed up for at least 10 years. Significant prognostic factors for disease-free survival were lymph node status (P < 0.0000001), radical surgical margins (P = 0.00003), and tumor size (P = 0.008). In a multivariate Cox analysis it was shown that lymph node status was the single most important prognostic factor with regard to disease-free survival. The total MGS and the PI scores were highly significantly (P = 0.0001) associated with pelvic lymph node metastases and disease-free survival rate in squamous cell carcinomas. The MGS and the PI systems were superior to the IFG system in predicting lymph node metastases. The total IFG score was also a statistically highly significant (P = 0.003) prognostic factor with regard to disease-free survival in both univariate and multivariate analyses. Microvessel density was a nonsignificant prognostic factor. There was a highly significant (P = 0.002) association between vascular space invasion of tumor cells and the presence of lymph node metastases. In conclusion, histopathologic malignancy grading systems provide valuable prognostic information in patients with early stage squamous cell carcinomas of the uterine cervix.
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| 16. |
- Hallak, Sorana, et al.
(författare)
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Prophylactic inguinal-femoral irradiation as an alternative to primary lymphadenectomy in treatment of vulvar carcinoma
- 2007
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Ingår i: International Journal of Oncology. - Athens, Greece : Lychnia. - 1019-6439 .- 1791-2423. ; 31:5, s. 1077-1085
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Tidskriftsartikel (refereegranskat)abstract
- In a complete geographic series of 294 cases of primary vulvar carcinomas prophylactic inguinal-femoral irradiation was used as a standard postoperative therapy. Inguinal lymph node dissection was performed in only 27 cases (9%) and was not part of the standard surgery. The histology was squamous cell carcinoma in 269 cases (92%). The primary surgery was total vulvectomy, partial vulvectomy, or local resection of the tumor. The main type of radiotherapy was adjuvant inguinal irradiation. Two separate, symmetrical and rectangular inguinal fields were irradiated with combined photon and electron beams. In the complete series 127 recurrences (43%) were recorded. Local (24%) and regional recurrences (19%) were most frequent. Type of surgery was not associated with the risk of tumor recurrence. The 5-year overall survival rate was 53% and the relapse-free survival (RFS) rate was 55%. Tumor grade was significantly (P=0.007) associated with the RFS. The inguinal RFS rate was 75% both for patients treated with adjuvant inguinal irradiation without lymphadenectomy and patients treated with primary lymph adenectomy +/- inguinal irradiation. Postoperative complications were recorded in 22%. Postoperative complications occurred most frequently in the subgroup undergoing inguinal lymphadenectomy. Chronic lymph edemas were the most serious late tissue reactions.
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| 17. |
- Isaksson, Helena, 1978-
(författare)
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Clinical studies of RNA as a prognostic and diagnostic marker for disease
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Technologies for RNA detection are evolving rapidly and gives an op-portunity for discovery of new markers for early detection of complex diseases. Today in clinical work we rely on signs and symptoms in com-bination with the measurement of protein levels for diagnosis. The quick turnaround time of mRNA synthesis may provide an earlier diagnostic signal than protein-based biomarkers assays, in acute dramatic condi-tions such as acute mesenteric ischemia (AMI), for early detection of cancer, as prognostic tool in cancer treatment and as an aid in difficult diagnosis of unknown origin.The main goals of this thesis was to apply a whole genome approach to study different complex diseases to evaluate the applicability of RNA as a diagnostic or prognostic marker for disease, preferably from an easily accessible source such as peripheral blood. This was investigated in an animal model with induced AMI, a cohort of ovarian cancer patients and in a single-patient study of a girl with a severe inflammatory syn-drome.Through this thesis we have gained insight into how gene expression is regulated in ischemic intestinal tissue.We found that a peripheral blood test can distinguish between ovarian cancer patients with or without residual tumour mass after surgery with the help of expression analysis of six genes. We also found that gene expressions of three genes can predict overall survival in peripheral whole blood from ovarian cancer patients. And that gene expression profiles indeed can significantly distinguish between two groups of high and low risk ovarian cancer. In the single-patient study, we tried but failed to device a successful treatment before it was too late. Neverthe-less, the things we learned and the case studies that were published may serve as a diagnostic tool for clinicians facing similar syndromes.
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| 18. |
- Isaksson, Helena S., 1978-, et al.
(författare)
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Whole genome expression profiling of blood cells in ovarian cancer patients : prognostic impact of the CYP1B1, MTSS1, NCALD, and NOP14 genes
- 2014
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Ingår i: Oncotarget. - : Impact press. - 1949-2553. ; 5:12, s. 4040-4049
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Tidskriftsartikel (refereegranskat)abstract
- Ovarian cancer patients with different tumor stages and cell differentiation might be distinguished from each other by gene expression profiles in whole blood cell mRNA by the Affymetrix Human Gene 1.0 ST Array. We also examined if there is any association with other clinical variables, response to therapy, and residual tumor burden after surgery. Patients were divided into two groups, one with poor prognosis, advanced stage and poorly differentiated tumors (n = 22), and one group with good prognosis, early stage and well-to medium differentiated tumors (n = 11). Six genes were found to be differentially expressed: the PDIA3, LYAR, NOP14, NCALD and MTSS1 genes were down-regulated and the CYP1B1 gene expression was up-regulated in the poor prognosis group, all with p value <0.05, adjusted for mass comparison. In survival analyses, CYP1B1, MTSS1, NCALD and NOP14 remained significantly different (p<0.05). Patient groups did not differ in any transcript related to acute phase or immune responses. This minimal gene expression signature of prognostic ovarian cancer-related genes opens up an avenue for more practicable monitoring of ovarian cancer patients by simple peripheral blood tests, which may evolve into a tool to guide selection of curative and postoperative supportive therapies.
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| 19. |
- Karlsson, Johannes, et al.
(författare)
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Differences in outcome for cervical cancer patients treated with or without brachytherapy
- 2017
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Ingår i: Brachytherapy. - Philadelphia, USA : Elsevier. - 1538-4721 .- 1873-1449. ; 16:1, s. 133-140
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To compare the clinical outcome of cervical cancer patients treated with primary radiotherapy with and without the addition of brachytherapy.Methods and Materials: In all, 220 patients with cervical cancer stage I-IV treated between 1993 and 2009 were included. Three or five 6.0 Gy fractions of brachytherapy were given in addition to the external beam radiotherapy to 134 patients, whereas 86 patients received external beam radiotherapy alone (EBRTA). In the EBRTA group, the patients received external boost instead of brachytherapy with a total dose to the tumor of 64-72 Gy.Results: The 5-year overall survival and cancer-specific survival rates of the complete series were 42.5% and 55.5%, respectively. The rates of primary complete remission, 5-year cancer-specific survival, and recurrence were 92.5%, 68.5%, and 31.3% for the brachytherapy group vs. 73.3%, 35.4%, and 37.2% for the EBRTA group. The survival (all types) of the patients receiving brachytherapy was significantly (p < 0.0001) better than for the patients treated with external boost, but the difference was most pronounced in FIGO stage II tumors. Higher FIGO stage, nonsquamous cell carcinoma histology, treatment with EBRTA, and lower total equal 2-Gy (EQD2) external dose were significantly associated with poorer survival, lower rate of remission, and higher recurrence rate in multivariate models.Conclusions: Primary tumor remission rate, recurrence rate, and all types of survival rates were improved in the brachytherapy group. Brachytherapy is important to achieve sufficient doses to the periphery and central part of the tumor and should always be considered in treatment of cervical carcinomas.
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| 20. |
- Lillsunde Larsson, Gabriella, 1971-, et al.
(författare)
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HPV16 viral characteristics in primary, recurrent and metastatic vulvar carcinoma
- 2018
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Ingår i: Papillomavirus research. - : Elsevier. - 2405-8521. ; 6, s. 63-69
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Tidskriftsartikel (refereegranskat)abstract
- Vulvar carcinoma is the fourth most common gynecological malignancy. Two separate carcinogenic pathways are suggested, where one is associated with the human papillomavirus (HPV) and HPV16 the most common genotype.The aim of this study was to evaluate HPV-markers in a set of primary tumors, metastases and recurrent lesions of vulvar squamous cell carcinomas (VSCC). Ten HPV16-positive VSCC with metastatic regional lymph nodes, distant lymphoid/hematogenous metastases or local recurrent lesions were investigated for HPV genotype, HPV16 variant, HPV16 viral load, HPV16 integration and HPV16 E2BS3 and 4 methylation.In all 10 analyzed case series, the same HPV genotype (HPV16), HPV16 variant and level of viral load were detected in all lesions within a patient case. Primary tumors with a high E2/E6 ratio were found to have fewer vulvar recurrences and/or metastases after diagnosis and treatment. Also, a significantly lower viral load was evident in regional lymph nodes compared to primary tumors.The data presented strengthens the evidence for a clonal HPV-induced pathway for vulvar carcinoma.
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| 21. |
- Lillsunde-Larsson, Gabriella, 1971-, et al.
(författare)
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Viral Load, Integration and Methylation of E2BS3 and 4 in Human Papilloma Virus (HPV) 16-Positive Vaginal and Vulvar Carcinomas
- 2014
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Ingår i: PLOS ONE. - : Public Library Science. - 1932-6203. ; 9:11
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate if viral load, integration and methylation of E2BS3 and 4 represent different ways of tumor transformation in vaginal and vulvar carcinoma and to elucidate its clinical impact.Methods: Fifty-seven samples, positive for HPV16, were selected for the study. Detection of viral load was made with realtime-PCR using copy numbers of E6 and integration was calculated from comparing E2 to E6-copies. Methylation of E2BS3 and 4 was analysed using bisulphite treatment of tumor DNA, followed by PCR and pyrosequencing.Results: Vaginal tumors were found to have a higher viral load (p=0.024) compared to vulvar tumors but a high copy number (> median value, 15 000) as well as high methylation (> 50%) was significantly (p=0.010 and p=0.045) associated with a worse cancer-specific survival rate in vulvar carcinoma, but not in vaginal carcinoma. Four groups could be defined for the complete series using a Cluster Two step analysis; (1) tumors holding episomal viral DNA, viral load below 150 000 copies not highly methylated (n=25, 46.3%); (2) tumors harboring episomal viral DNA and being highly methylated (>50%; n=6, 11.1%); (3) tumors with viral DNA fully integrated (n=11, 20.4%), and (4) tumors harboring episomal viral DNA and being medium-or unmethylated (< 50%) and having a high viral load (> total mean value 150 000; n=12, 22.2%). The completely integrated tumors were found to be distinct group, whilst some overlap between the groups with high methylation and high viral load was observed.Conclusion: HPV16-related integration, methylation in E2BS3 and 4 and viral load may represent different viral characteristics driving vaginal and vulvar carcinogenesis. HPV16-related parameters were found to be of clinical importance in the vulvar series only.
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| 22. |
- Mordhorst, Louise Bohr, et al.
(författare)
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Combined External and Intracavitary Irradiation in Treatment of Advanced Cervical Carcinomas Predictive Factors for Treatment Outcome and Early and Late Radiation Reactions
- 2014
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Ingår i: International Journal of Gynecological Cancer. - : Lippincott Williams & Wilkins. - 1048-891X .- 1525-1438. ; 24:7, s. 1268-1275
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The objective of this study was to find out predictive factors of tumor control as well as acute and late radiation reactions in treatment of advanced cervical carcinomas.Methods: In a series of 134 primary cervical carcinomas in International Federation of Gynecology and Obstetrics stages I to IV treated with combined external pelvic and intraluminal cervical-vaginal brachytherapy, predictive and prognostic factors were analyzed with regard to tumor control, recurrences, survival data, and adverse effects. Concomitant chemotherapy was given to 48 patients (35.8%). The external beam therapy was given with a 4-field technique (50-60 Gy) and brachytherapy was given with a high-dose rate (iridium-192) afterloading technique using a ring applicator set. A computed tomographically based 3-dimensional dose-planning system was used for the external beam therapy and for the brachytherapy planning. The mean age of the patients was 65 years. A total of 110 tumors were squamous cell carcinomas and 24 were adenocarcinomas or adenosquamous carcinomas. A total of 111 tumors were in International Federation of Gynecology and Obstetrics stages I to II; 23 tumors, in stages III to IV.Results: The primary control rate of the complete series was 92.5%. Tumor size, the brachytherapy dose, the combined external and brachytherapy dose, as well as the number of days of interruption (delay) of irradiation were all significant predictive factors for local tumor control. Forty recurrences (30%) were recorded. Early radiation reactions were recorded in 67% (mostly grade 1) and were associated with the widths of the anterior-posterior and lateral pelvic fields. Serious late radiations reactions (grade 3-4) were noted in 11%.Conclusions: The width of the lateral pelvic fields, left point A and B doses, dose to the rectal reference point, as well as asymmetry of the dose distribution were associated with late severe reactions. Prior abdominal and pelvic surgery was also a high-risk factor for late tissue reactions. Concomitant chemotherapy did not increase the risk for acute or late toxicity.
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| 23. |
- Qvick, Alvida, 1990-, et al.
(författare)
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Does p53 codon 72 polymorphism have a prognostic value in carcinoma of the vulva and vagina?
- 2017
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Ingår i: Medical Oncology. - Heidelberg, Germany : Springer. - 1357-0560 .- 1559-131X. ; 34:3
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Tidskriftsartikel (refereegranskat)abstract
- Human papilloma virus (HPV) is considered to be responsible for a large part of vaginal and vulvar carcinomas, and the p53 codon 72 polymorphism has been implicated in susceptibility to cancer induced by this virus, but with contradicting results. In this study, we have investigated the prognostic value of the codon 72 polymorphism by real-time PCR (qPCR) in two cohorts of vaginal (n = 66) and vulvar (n = 123) carcinomas. In vaginal carcinoma, arginine homozygous patients were significantly associated with a higher primary cure rate (p = 0.023) but also associated with a higher recurrence rate (p = 0.073), significant at distant locations (p = 0.009). No significant differences were found in overall survival rate (p = 0.499) or cancer-specific survival rate (p = 0.222). A higher frequency of arginine homozygosity was noted in HPV-positive tumors (p = 0.190) in comparison with HPV-negative tumors. In vulvar carcinoma, the genotype homozygous for arginine was significantly associated with a larger tumor size at diagnosis in the entire cohort (p = 0.015) and a lower cancer-specific survival rate (p = 0.024) compared with heterozygous (arginine/proline) in HPV-negative tumors. Our results indicate that the relation between HPV and the p53 codon 72 polymorphism is complex and the significance and mechanisms responsible for this relationship need to be further elucidated.
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| 24. |
- Ranhem, Cecilia, et al.
(författare)
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Expression of LRIG proteins as possible prognostic factors in primary vaginal carcinoma
- 2017
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 12:8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Primary vaginal carcinoma (PVC) is a rare malignancy. Established prognostic factors include tumour stage and age at diagnosis. The leucine-rich repeats and immunoglobuline-like domains (LRIG)-1 protein functions as a tumour suppressor, but less is known about the functions of LRIG2 and LRIG3. The present study aimed to evaluate the expression of LRIG proteins and analyse their possible associations with clinical characteristics and survival in a cohort of PVC patients.Methods: We used immunohistochemistry to investigate LRIG1, LRIG2, and LRIG3 expression in tumour samples from a consecutive cohort of 70 PVC patients. The association between LRIG protein expression and clinical characteristics and cancer-specific survival was investigated using univariate and multivariate analyses.Results: The majority of PVC patients (72%) had > 50% LRIG1-and LRIG2-positive cells, and no or low LRIG3-positive cells. HPV status was significantly correlated with LRIG1 expression (p = 0.0047). Having high LRIG1 expression was significantly correlated with superior cancer-specific survival in univariate and multivariate analyses. LRIG2 and LRIG3 expression did not significantly correlate with clinical characteristics or survival.Conclusion: LRIG1 expression might be of interest as a prognostic marker in PVC patients, whereas the role of LRIG2 and LRIG3 expression remains to be clarified.
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| 25. |
- Skírnisdóttir, Ingirídur, et al.
(författare)
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Adjuvant chemotherapy with carboplatin and taxane compared with single drug carboplatin in early stage epithelial ovarian carcinoma
- 2007
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Ingår i: Oncology Reports. - Athens, Greece : National Hellenic Research Foundation. - 1021-335X .- 1791-2431. ; 18:5, s. 1249-1256
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Tidskriftsartikel (refereegranskat)abstract
- The objective of the present study was to compare recurrence-free survival (RFS) in early stages (FIGO stages I-II) of epithelial ovarian cancer after adjuvant chemotherapy with carboplatin and a taxane (113 patients) and with carboplatin alone (27 patients). The distribution of clinical and pathological prognostic factors as well as type of primary surgery were comparable in the two groups. Recurrence rate was 21% and RFS was 79% in the series of patients treated with taxane-based chemotherapy and 19% and 81%, respectively, in the series of patients who received single drug carboplatin. Thus, no significant differences were recorded. The major toxicities in the present study were myelosuppression (46%) and neuro-toxicity (26%). Neurotoxicity was more frequently (P=0.007) recorded and of higher grade (P=0.011) for patients in the carboplatin-taxane series compared with patients in the carboplatin series. RFS for patients in FIGO-stage I was 85% and for patients in FIGOstage II only 47%. In a multivariate logistic regression analysis of predictive factors for tumor recurrence in the complete series (n=140) the FIGO stage was the only independent and significant (P=0.0006) predictive factor with an odds ratio of 6.4 (95% CI: 2.2-18.9) for stage II versus IA-C. Age, tumor grade and type of adjuvant chemotherapy (± taxane) were not significant predictive factors. In the present study, although based on a limited number of patients, we could not find any improvement in recurrence rate or recurrence-free survival for patients treated with a carboplatin-taxane combination regimen compared with patients treated with carboplatin monotherapy. The spectrum of side effects was also in favor of the monotherapy regimen. Further, larger randomized studies are needed to give a final and fully conclusive answer to this question.
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| 26. |
- Skírnisdóttir, Ingirídur, et al.
(författare)
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Prognostic factors for surgical outcome and survival in 447 women treated for advanced (FIGO-stages III-IV) epithelial ovarian carcinoma
- 2007
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Ingår i: International Journal of Oncology. - Athens, Greece : Lychnia. - 1019-6439 .- 1791-2423. ; 30:3, s. 727-734
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Tidskriftsartikel (refereegranskat)abstract
- The objectives of this population-based, retrospective study, was to find predictive factors for surgical outcome and long-term survival in 447 patients with epithelial ovarian cancer in FIGO-stages III-IV treated during 1975-1993. The median overall survival rate of this series was 18 months, the 5-year cancer-specific survival rate was 18%, and the 5-year overall survival rate, 16%. In a logistic regression analysis, type of surgeon was the strongest (P=0.006) predictive factor for surgical outcome after the age of the patient. The optimal debulking rate was 36% for gynecologic oncologists, 29% for general gynecologists, 24% for combined gynecologist and obstetrician with the third level of specialization, and 4% for general surgeons. Optimal debulking (no visible tumor or residual tumor <2 cm) was achieved in 26% of the cases. Predictive factors of the outcome of cyto-reduction were FIGO-stage (P=0.007), histological subtype (P=0.016), and tumor grade (P=0.046) in univariate analyses. In a Cox multivariate analysis the most important prognostic factor for overall survival was the amount of residual cancer (P=0.000001) before age, grade and stage. Therefore, to achieve optimal surgical outcome and optimal overall survival rate the primary surgery of advanced ovarian cancer should be performed by gynecologic oncologists or by gynecologists specially trained in gynecologic cancer surgery.
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| 27. |
- Skirnisdottir, Ingiridur, 1951-, et al.
(författare)
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Prognostic impact of body mass index and effect of overweight and obesity on surgical and adjuvant treatment in early-stage epithelial ovarian cancer
- 2008
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Ingår i: International Journal of Gynecological Cancer. - Oxford : BMJ. - 1048-891X .- 1525-1438. ; 18:2, s. 345-351
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Tidskriftsartikel (refereegranskat)abstract
- The present study was performed to find out if the body mass index (BMI) was associated with clinical and pathologic features (age, histology, tumor grade, and substages) and prognosis in early stages (FIGO I-II) of epithelial ovarian cancer. Further aims of the study were to evaluate if overweight or obesity affected the feasibility of optimal surgery and postoperative adjuvant therapy. A total of 635 patients were included in this study. Four percent of the patients were underweight (BMI < 18.5), 53% were of ideal body weight (BMI 18.5-25), 31% were overweight (BMI 25-30), and 12% were obese (BMI > 30). Overweight and obese patients were significantly (P = 0.006) older than underweight and ideal body weight patients. Tumor grade and histologic type distributions were not different across the BMI strata. FIGO stage (P = 0.011) and presence of ascites (P = 0.007) at primary surgery were associated with the BMI status. A history of cardiovascular disease was significantly (P = 0.006) more common in overweight and obese patients. Survival analyses in the four BMI subgroups did not show any significant differences with regard to recurrence-free survival. The 5-year recurrence-free survival of the complete series was 72%. Overweight and obese patients did not have worse survival than normal weight and underweight patients. Perioperative or postoperative morbidity and adjuvant oncologic treatment were not affected by the BMI. In a multivariate Cox analysis, FIGO substage and tumor grade, but not BMI, were independent and significant prognostic factors with regard to all types of survival rates.
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| 28. |
- Skírnisdóttir, Ingirídur, et al.
(författare)
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Survival and prognostic factors in early-stage epithelial ovarian carcinoma treated with taxane-based adjuvant chemotherapy
- 2007
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Ingår i: International Journal of Gynecological Cancer. - Cambridge, Mass. : Blackwell. - 1048-891X .- 1525-1438. ; 17:6, s. 1231-1237
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Tidskriftsartikel (refereegranskat)abstract
- The present study was undertaken with the question about the outcome (recurrence-free survival, [RFS]) after adjuvant chemotherapy with taxane and carboplatin in the early stages of epithelial ovarian cancer after primary surgery. Treatment-related toxicity was also evaluated. A total of 113 patients were included in this study. The 5-year RFS rate for all 113 patients treated with adjuvant chemotherapy including taxane and carboplatin after primary surgery was 79%. The 5-year RFS rate for 85 patients in FIGO stage I was 85% and for 18 patients in FIGO stage II, it was 44%. For clear-cell carcinomas, the RFS was 87%. In univariate analysis, recurrent disease was associated with both FIGO stage and tumor grade, but in multivariate logistic regression analysis of prognostic factors for tumor recurrences, only FIGO stage (stage I versus stage II) was a significant and independent prognostic factor. However, an odds ratio (OR) of 1.9 for tumor grade (grade 3 versus grades 1–2) demonstrated two times increased risk for recurrence in a patient with a grade 3 tumor compared with grade 1–2 tumors. Furthermore, an OR of 0.39 for lymph node sampling versus no sampling meant 61% reduced risk for recurrence for a patient who had undergone lymph node sampling at surgical staging laparotomy. The major toxicities in the present study were myelosuppression (46%) and neurotoxicity (34%). Despite the use of prophylaxis, severe paclitaxel-related hypersensitivity occurred in three patients (3%).
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| 29. |
- Sorbe, Bengt, 1947-, et al.
(författare)
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Natural history of recurrences in endometrial carcinoma
- 2014
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Ingår i: Oncology Letters. - : Spandidos Publications. - 1792-1074 .- 1792-1082. ; 8:4, s. 1800-1806
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to evaluate the natural history of endometrial cancer recurrences with regard to predictive and prognostic factors. Between 1990 and 1999, 100 patients were treated for recurrences of endometrial carcinoma (all FIGO stages). Overall, 90 tumors were of endometrioid type. A total of 82 patients were treated with surgery, 41 patients received adjuvant external irradiation and 91 patients received vaginal brachytherapy. The median time to recurrence (TTR) was 32 months. The recurrences were treated using a combination of high-dose-rate brachytherapy and external pelvic irradiation in 35 cases. In addition, 44 patients were treated with chemotherapy and 21 patients received other types of therapy. The complete remission rate was 29% and the overall response rate was 44%. Among patients treated with radiotherapy, the response rate was 88% and, for those treated with chemotherapy, the rate was 33%. The local control of vaginal recurrences treated with combined radiotherapy was 93%. In 45 patients (45%) a second recurrence was identified and a third recurrence occurred in 12 patients. The overall five-year survival rate was 44%. Age, FIGO grade, nuclear grade, TTR and response to treatment were found to be independent and significant prognostic factors for overall survival rate. Locoregional recurrences were associated with a generalized extra-pelvic disease in 63% of the cases.
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| 30. |
- Sorbe, Bengt, 1947-, et al.
(författare)
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Prophylactic pelvic irradiation as part of primary therapy in uterine sarcomas
- 2008
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Ingår i: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 32:5, s. 1111-1117
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Tidskriftsartikel (refereegranskat)abstract
- In a complete geographic series of 155 cases of primary uterine sarcomas, prophylactic pelvic irradiation was used as standard postoperative therapy in the majority of the cases. Vaginal brachytherapy was also added as a boost. The histology was leiomyosarcoma in 62 cases (40%), carcinosarcoma in 60 (39%), endometrial stromal sarcoma in 25 (16%), and other types in 8 cases (5%). The primary surgery was extended hysterectomy in 11 cases (7%), simple hysterectomy in 110 (71%), and supravaginal hysterectomy in 12 (8%). In 22 cases (14%) no major surgery was possible. In the complete series, 62 recurrences (40%) were recorded. Local (9%), regional (9%), and distant recurrences (28%) were the most frequent. The type of surgery was associated with the risk of tumor recurrence. Extended surgery reduced the risk of local and regional recurrences. The 5-year overall survival rate was 42% and the recurrence-free survival (RFS) was 37%. The number of mitoses was significantly (P=0.007) associated with survival. The locoregional RFS rate was 75% for patients treated with adjuvant irradiation and 83% for patients treated with primary surgery alone. Serious late tissue reactions from the bladder and intestine occurred in 7% of the irradiated cases. The locoregional tumor control rate was high in this series of patients, but no significant difference was found between patients treated with surgery alone and surgery plus postoperative pelvic irradiation. This was true for all histological subtypes of the uterine sarcomas. However, this was not a randomized study and selection bias cannot be ruled out
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