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  • 1.
    Graflund, M.
    et al.
    Department of Gynecological Oncology, Örebro University Hospital, Örebro, Sweden.
    Sorbe, Bengt
    Department of Gynecological Oncology, Örebro University Hospital, Örebro, Sweden.
    Sigurdardóttir, S.
    Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    HPV-DNA, vascular space invasion, and their impact on the clinical outcome in early-stage cervical carcinomas2014In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 14, no 5, p. 896-902Article in journal (Refereed)
    Abstract [en]

    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.

  • 2.
    Graflund, Marianne
    et al.
    Departments of Gynecological Oncology, Örebro University Hospital, Örebro, Sweden.
    Sorbe, Bengt
    Departments of Gynecological Oncology, Örebro University Hospital, Örebro, Sweden.
    Bryne, M.
    Department of Pathology, Institute of Cancer Research, Norwegian Radium Hospital, Oslo, Norway.
    Karlsson, Mats G.
    Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    The prognostic value of a histologic grading system, DNA profile, and MIB-1 expression in early stages of cervical squamous cell carcinomas2002In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 12, no 2, p. 149-157Article in journal (Refereed)
    Abstract [en]

    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.

  • 3.
    Graflund, Marianne
    et al.
    Department of Gynecological Oncology, Örebro University Hospital, Örebro, Sweden .
    Sorbe, Bengt
    Department of Gynecological Oncology, Örebro University Hospital, Örebro, Sweden.
    Hussein, A.
    Department of Pathology, Medical Center Hospital, Örebro, Sweden.
    Bryne, M.
    Department of Pathology, Institute of Cancer Research, the Norwegian Radium Hospital, Oslo, Norway.
    Karlsson, Mats G.
    Department of Pathology, Medical Center Hospital, Örebro, Sweden.
    The prognostic value of histopathologic grading parameters and microvessel density in patients with early squamous cell carcinoma of the uterine cervix2002In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 12, no 1, p. 32-41Article in journal (Refereed)
    Abstract [en]

    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.

  • 4.
    Graflund, Marianne
    et al.
    Department of Gynecological Oncology, Örebro University Hospital, Örebro, Sweden.
    Sorbe, Bengt
    Department of Gynecological Oncology, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G
    Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Immunohistochemical expression of p53, bcl-2, and p21(WAF1/CIP1) in early cervical carcinoma: correlation with clinical outcome2002In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 12, no 3, p. 290-298Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to assess the value of p53, bcl-2, and p21(WAF1/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 p21(WAF1/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 p21(WAF1/CIP1) appeared to be of no predictive value with regard to LNM, tumor recurrences, or long-term survival in early cervical carcinomas.

  • 5.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden.
    Andersson, Sören
    Örebro University Hospital, Örebro, Sweden.
    Elgh, Fredrik
    Umeå University Hospital, Umeå, Sweden.
    Sorbe, Bengt
    Örebro University, School of Health and Medical Sciences. Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro University Hospital, Örebro, Sweden.
    Human Papillomavirus (HPV) and HPV 16-Variant Distribution in Vulvar Squamous Cell Carcinoma in Sweden2012In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 22, no 8, p. 1413-1419Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate the human papillomavirus (HPV) and HPV type 16-variant distribution in a series of vulvar squamous cell carcinomas (VSCC) and to evaluate the impact of HPV and HPV 16-variant on prognosis.

    Methods: A series of 133 patients who had a diagnosis of VSCC (1983-2008) was selected for the study. Detection of 11 high-risk HPV types (16, 18, 31, 33, 39, 45, 51, 52, 56, 58, and 59) and 2 low-risk HPV types (6 and 11) was performed with real-time polymerase chain reaction. Samples positive for HPV 16 were further analyzed for variant determination of 7 positions in the E6 gene with polymerase chain reaction and pyrosequencing.

    Results: Forty (30.8%) of 130 tumors were found to be HPV positive. Human papillomavirus type 16 was found in 31 cases, HPV 18 was found in 2 cases, HPV 33 was found in 5 cases, and HPV 56 and HPV 59 were found in one case each. All but one tumor harboring HPV 16 were of European linage, and the 3 most common variants were E-p (n = 13), E-G350 (n = 7), and E-G131 (n = 5). HPV positivity was associated with the basaloid tumor type and occurred in significantly younger patients. Overall and recurrence-free survival rates were better in HPV-positive cases, but after correction for age and tumor size, HPV status was no longer an independent and significant prognostic factor. The survival rates of the various HPV 16 variants were not significantly different, but there was a trend of worse outcome for the E-G131-variant group.

    Conclusions: Human papillomavirus positivity of 30.8% is similar to other reports on VSCC. To our knowledge, this first variant determination of HPV 16 in vulvar carcinoma in a Swedish cohort indicated that the variant E-G131 may have an increased oncogenic potential in patients with VSCC.

  • 6.
    Mordhorst, Louise Bohr
    et al.
    Department of Oncology, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Leif
    Department of Radiation Physics, Örebro University Hospital, Örebro, Sweden.
    Bärmark, Berit
    Department of Oncology, Örebro University Hospital, Örebro, Sweden.
    Sorbe, Bengt
    Örebro University Hospital. Department of Oncology, Örebro University Hospital, Örebro, Sweden.
    Combined External and Intracavitary Irradiation in Treatment of Advanced Cervical Carcinomas Predictive Factors for Treatment Outcome and Early and Late Radiation Reactions2014In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 24, no 7, p. 1268-1275Article in journal (Refereed)
    Abstract [en]

    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.

  • 7. Skirnisdottir, Ingiridur
    et al.
    Sorbe, Bengt
    Örebro University, School of Health and Medical Sciences.
    Prognostic impact of body mass index and effect of overweight and obesity on surgical and adjuvant treatment in early-stage epithelial ovarian cancer2008In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 18, no 2, p. 345-351Article in journal (Refereed)
    Abstract [en]

    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.

  • 8. Skirnisdottir, Ingiridur
    et al.
    Sorbe, Bengt
    Örebro University, School of Health and Medical Sciences.
    Survival and prognostic factors in early-stage epithelial ovarian carcinoma treated with taxane-based adjuvant chemotherapy2007In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 17, no 6, p. 1231-1237Article in journal (Refereed)
    Abstract [en]

    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%).

  • 9.
    Sorbe, Bengt
    et al.
    Örebro University, School of Health and Medical Sciences.
    Andersson, H
    Boman, K
    Rosenberg, P
    Kalling, M
    Treatment of primary advanced and recurrent endometrial carcinoma with a combination of carboplatin and paclitaxel-long-term follow-up2008In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 18, no 4, p. 803-808Article in journal (Refereed)
    Abstract [en]

    There is no generally accepted standard chemotherapy in treatment of advanced and recurrent endometrial carcinoma. Cisplatin and doxorubicin with or without cyclophosphamide are widely used. Response rates have improved with combination chemotherapy compared with single-agent therapy. A platinum analog seems to be an important part of the chemotherapy regimen. Since few patients are cured from their disease and since the duration of response is short, further improvement of this therapy is warranted. During the past years, the taxanes (paclitaxel) are being added to prior evaluated regimens and not only improved response rates are reported but also increased toxicity is observed. In a prospective, phase II, multicenter study, carboplatin (area under the curve = 5) and paclitaxel (175 mg/m(2)) were evaluated in treatment of primary advanced and recurrent endometrial carcinoma. In total, 66 patients were recruited during the years 2000-2004. Eighteen primary advanced tumors and 48 recurrences were treated. All histologic types and tumor grades were allowed. The median follow-up was 57 months (range 37-69 months). The overall response rate was 67% (95% CI 55-78). The complete response rate was 29% and the partial response rate 38%. Primary advanced and recurrent tumors as well as endometrioid and nonendometrioid tumors showed similar response rates. The median response duration was 14 months. The 1- and 3-year survival rates were 82% and 33%, respectively. The main toxicities were hematologic and neurologic (sensory neuropathy). The response rates were encouraging, superior to prior platinum-containing regimens, but response duration and the long-term survival rate were still short. The neurologic toxicity was frequent and was a substantial problem in this series of patients. Further research is highly needed to improve the treatment of advanced and recurrent endometrial cancer.

  • 10.
    Sorbe, Bengt
    et al.
    Örebro University, School of Health and Medical Sciences.
    Nordström, Britta
    Mäenpää, Johanna
    Kuhelj, Janez
    Kuhelj, Dimitrij
    Okkan, Sait
    Delaloye, Jean-Francois
    Frankendal, B.
    Intravaginal brachytherapy in FIGO stage I low-risk endometrial cancer: a controlled randomized study2009In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 19, no 5, p. 873-878Article in journal (Refereed)
    Abstract [en]

    The purpose of the study was to compare postoperative vaginal irradiation with surgery alone in low-risk International Federation of Gynecology and Obstetrics (FIGO) stage IA-IB endometrial carcinoma. The study was a prospective, randomized trial of 645 evaluable low-risk endometrial carcinoma patients from 6 European gynecologic cancer centers. All tumors were in FIGO stage IA-IB, of endometrioid histological type, and FIGO grade 1-2. High-dose-rate afterloading equipments (iridium [Ir] 192 or cobalt [co] 60) were used at 5 centers, and low-dose-rate (LDR) afterloading equipment (cesium [Cs] 137) at 1 center. Perspex vaginal applicators or ovoids were normally used, and the dose was specified at 5 mm from the surface of the applicator. Three to 6 fractions (3.0-8.0 Gy) were given, and the overall treatment time was 4 to 15 days. A total of 319 patients were treated with surgery plus vaginal irradiation (treatment group), and 326 patients with surgery alone (control group).Twenty-six recurrences (4.0%) were recorded in the complete series. The locoregional recurrence rate was 2.6%, whereas distant metastases occurred in 1.4%. The rate of vaginal recurrences was 1.2% in the treatment group versus 3.1% in the control group. The difference was not statistically significant (P = 0.114). Side effects were few and mild (grade 1-2). Dysuria, frequency, and incontinence were slightly more common after vaginal irradiation (2.8% vs 0.6%, respectively). Late intestinal problems were few and similar in the 2 groups. The conclusions were that the impact of postoperative brachytherapy on even the locoregional recurrence rate seems to be limited in patients with low-risk endometrial carcinoma. The overall recurrence rate and survival were similar in the 2 groups.

  • 11.
    Wegman [Palmebäck-Wegman], Pia
    et al.
    Örebro University, School of Health and Medical Sciences.
    Ahlin, Cecilia
    Sorbe, Bengt
    Genetic alterations in the K-ras gene influence the prognosis in patients with cervical cancer treated by radiotherapy2011In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 21, no 1, p. 86-91Article in journal (Refereed)
    Abstract [en]

    Introduction: A high incidence of K-Ras mutations has been identified in a variety of human cancers, especially in codon 12, 13, and 61. Nevertheless, the presence of K-Ras mutations in cervical cancer remains controversial. The aim of this study was to investigate possible mutations in exon 1 and 2 of the K-Ras gene and to assess whether K-Ras mutation status had prognostic and predictive significance and were linked to clinicopathological parameters. Methods: Genomic DNA from 107 patients with cervical cancer, treated with radio-chemotherapy, were examined for mutations in the coding exons 1 and 2, including exon/intron borders of the K-Ras gene using single-stranded conformation polymorphism and sequence analyses. Results: K-Ras mutations were detected in 11 patients (10%). Seven tumors showed a mutation in codon 59, 3 tumors in codon 38, and 1 tumor in codon 13. In 6 of the cases with a mutation in codon 59, an additional alteration located in codon 65 was found. Patients with K-Ras mutations had significantly worse recurrence-free survival (P = 0.03), and an association between K-Ras status and distant metastases was also seen (P = 0.04). Conclusions: The present data indicate that K-Ras mutations are relatively uncommon in cervical cancer but associates with poorer prognosis, especially in the subset of squamous cell carcinomas. There is a need for new markers in cervical cancer to improve individual treatment, but whether K-Ras mutation status is a potential biomarker in this situation needs further investigations in larger tumor series and in more regions of the K-Ras gene.

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