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Despite the common perception that the human papilloma virus (HPV) is a requirement for the development of cervical cancer (CC), a considerable number of CCs test HPV negative. Presently, many countries are shifting to HPV primary CC screening, and it is of importance to increase the knowledge about the group of CCs that test HPV negative. The aim of this study was to reinvestigate a proportion of cervical tumors with a primary negative or invalid test result. Reinvestigation with repeated genotyping (targeting L1) was followed by analysis with an alternative target method (targeting E6/E7) on existing or additional tumor material. Consistently negative tumors were histologically evaluated, and cases with low or lacking tumor cell content, consistent invalid test results, or with suspicion of other than cervical origin were excluded. HPV-negative cases were thereafter subjected to immunohistochemistry (Cytokeratin 5, pan cytokeratin, protein 63, P16, and P53). The HPV-negative proportion could after reinvestigation be reduced by one-half (14%-7%). Additional positive samples were often detected in late polymerase chain reaction cycles, with an alternative (E6/E7) or the same (L1) target, or with a method using shorter amplicon lengths. Confirmed HPV negativity was significantly associated with worse prognosis, high patient age, longer storage time, and adenocarcinoma histology. Some of the HPV-negative cases showed strong/diffuse p16 immunoreactivity, indicating some remaining false-negative cases. False HPV negativity in this cohort was mainly linked to methodological limitations in the analysis of stored CC material. The small proportion of presumably true HPV-negative adenocarcinomas is not a reason for hesitation in revision to CC screening with primary HPV testing.

Purpose External pelvic chemoradiotherapy and image-guided adaptive brachytherapy (IGABT) were studied in advanced cervical carcinomas. Treatment modalities were defined and related to outcomes and side effects. Material and methods From a single cancer center, 138 patients with advanced cervical cancer were recruited. All patients were treated with external radiotherapy and IGABT. A dosimetric study was performed and related to treatment outcome and side effects. Toxicity of the organs at risk was evaluated by the CTCAE-grading system. Results The median follow-up was 44 months. More than 60% of the tumors were FIGO stage IIB-IIIB and 82% were squamous cell carcinomas. Largest tumor size (width) was in mean 41 mm and 27% had lymph node spread. The mean total external dose was 51 Gy, and the mean total dose to the high-risk clinical target volume (HRCTV) was 88 Gy. In 130 patients (94%), weekly cisplatin was given in 4-6 cycles. The median number of brachytherapy fractions was four, and in 86 patients, interstitial needles were applied. The primary local control was 97% and 94% after four local recurrences. The overall pelvic control was 89%. The overall recurrence rate was 25% and distant metastases rate was 22%. The overall 5-year survival rate was 65% and cancer-specific survival rate was 69%. Prognostic factors were FIGO stage and total brachytherapy dose (D90) to HRCTV. Late serious toxicity of the bladder and intestine were rare, occurring in only 3% of patients. Conclusions The local and pelvic control rates were excellent in this series. The IGABT was an important part of the treatment schedule and could probably not be replaced by increasing the external pelvic dose. Adenocarcinomas seemed to benefit from the addition of interstitial needles. Late serious toxicity was rare.

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 Keywords: Vulvar carcinoma, Human papillomavirus, Recurrences, Metastases, Integration, Viral load

Primary vaginal cancer (PVC) is a rare gynaecological malignancy, which, at present, lacks appropriate biomarkers for prognosis. The proteins dyskerin and WD repeat containing antisense to TP53 (WRAP53β), both of which exert their functions in the telomerase holoenzyme complex, have been shown to be upregulated in different cancer types. These proteins have also been proposed as prognostic markers in some types of cancer. The aim of the present study was to examine the expression patterns of dyskerin and WRAP53β in patients with PVC. Moreover, as part of a search for effective biomarkers to evaluate prognosis in PVC, the expression of these two proteins and their potential association with clinical variables and survival were also evaluated. The expression of dyskerin and WRAP53β was assessed in PVC tumour samples from 68 patients using immunohistochemistry. The majority of tumour samples showed low and moderate expression levels of dyskerin. Upregulation of dyskerin in tumour samples was significantly associated with a shorter survival time and a poorer cancer-specific survival rate. WRAP53β was also expressed in most of the cells but was not significantly associated with clinical variables or survival. This study demonstrates that upregulation of dyskerin is significantly associated with poor prognosis. Thus, dyskerin may serve as a promising prognostic marker and a potential putative therapeutic target in PVC.

Cervical cancer (CC) is one of the most common cancers in women and virtually all cases of CC are a result of a persistent infection of human papillomavirus (HPV). For disease detected in early stages there is curing treatment but when diagnosed late with recurring disease and metastasis there are limited possibilities. Here we evaluate HPV impact on treatment resistance and metastatic disease progression. Prevalence and distribution of HPV genotypes and HPV16 variants in a Swedish CC patient cohort (n=209) was evaluated, as well as HPV influence on patient prognosis. Tumor samples suitable for analysis (n=204) were genotyped using two different real-time PCR methods. HPV16 variant analysis was made using pyrosequencing. Results showed that HPV prevalence in the total series was 93%. Of the HPV-positive samples, 13% contained multiple infections, typically with two high-risk HPV together. Primary cure rate for the complete series was 95%. Recurrence rate of the complete series was 28% and distant recurrences were most frequent (20%). Patients with tumors containing multiple HPV-strains and particularly HPV genotypes belonging to the alpha 7 and 9 species together had a significantly higher rate of distant tumor recurrences and worse cancer-specific survival rate.

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.

Background/aim To investigate the overall survival rate, quality indicators and treatment outcome in FIGO stage IIIB-IVB epithelial ovarian cancer at a University Hospital in Sweden between 2006 and 2015. Materials and methods A cohort of 110 patients was followed-up for 3-12 years after cancer diagnosis. Three main groups (primary surgery, neoadjuvant chemotherapy, palliative treatment), and six subgroups were defined according to treatment modality. Results The mean age was 65 years. Patients were observed for a mean of 50 months. The total resection frequency was 83%. Significant differences in overall survival at 5 years were observed between the groups varying from 60% to 12%. Conclusion Patient age, tumor stage and complete tumor removal at surgery were significant, independent prognostic factors of overall survival. Complication rate was a significant adverse prognostic factor in univariate analysis. Data discrepancy was observed between public quality reports and locally obtained data.

The present study investigated the predictive and prognostic impact of DNA ploidy together with other well-known prognostic factors in a series of non-endometrioid, high-risk endometrial carcinomas. From a complete consecutive series of 4,543 endometrial carcinomas of International Federation of Gynecology and Obstetrics (FIGO) stages I–IV, 94 serous carcinomas, 48 clear cell carcinomas and 231 carcinosarcomas were selected as a non-endometrioid, high-risk group for further studies regarding prognosis. The impact of DNA ploidy, as assessed by flow cytometry, was of particular focus. The age of the patients, FIGO stage, depth of myometrial infiltration and tumor expression of p53 were also included in the analyses (univariate and multivariate). In the complete series of cases, the recurrence rate was 37%, and the 5-year overall survival rate was 39% with no difference between the three histological subtypes. The primary cure rate (78%) was also similar for all tumor types studied. DNA ploidy was a significant predictive factor (on univariate analysis) for primary tumor cure rate, and a prognostic factor for survival rate (on univariate and multivariate analyses). The predictive and prognostic impact of DNA ploidy was higher in carcinosarcomas than in serous and clear cell carcinomas. In the majority of multivariate analyses, FIGO stage and depth of myometrial infiltration were the most important predictive (tumor recurrence) and prognostic (survival rate) factors. DNA ploidy status is a less important predictive and prognostic factor in non-endometrioid, high-risk endometrial carcinomas than in the common endometrioid carcinomas, in which FIGO and nuclear grade also are highly significant and important factors.

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 GLI1. 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.

ObjectiveThe 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.MethodsIn 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.ResultsThe 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%.ConclusionsThe 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.

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.

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

Computer-controlled scalp cooling to prevent alopecia is currently available for patients undergoing chemo-therapy. Previous studies have suggested that the temperature should be

The purpose of this study was to compare the toxicity profiles of docetaxel administered on a weekly schedule and the standard three-week schedule in the treatment of advanced primary ovarian carcinoma. Eligible patients were treated with intravenous docetaxel (30 mg/m2) on days 1, 8 and 15, and carboplatin (AUC 5) on day 1 or with docetaxel (75 mg/m2) and carboplatin (AUC 5) on day 1; Q21 days for 6 cycles. This study was a pooled study of two primary phase II studies. A total of 108 patients received the weekly schedule and 59 patients received the three-week schedule. All patients were evaluated for toxicity. The overall response rate was 79% and the biochemical response 93% for the weekly schedule. The median overall survival rate was 35.3 months. Neutropenia was significantly more common (ANOVA; p

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

Background. Carcinosarcomas are a highly malignant type of endometrial carcinomas where extra uterine spread and recurrences are frequent. There is no consensus regarding the best treatment of this group of malignancies. Material and methods. In a complete geographic series of 322 cases of primary uterine carcinosarcomas prophylactic pelvic irradiation and/or chemotherapy was used as postoperative treatment in the majority of the cases. Vaginal brachytherapy was also added as a boost. The primary surgery was extended hysterectomy in 23 cases (10%), and simple hysterectomy in 220 cases (90%). In 46 cases (14%) no major surgery was possible. Results. In the complete series 123 recurrences (38%) were recorded. Locoregional recurrences (11%) and distant recurrences (28%) were most frequent. Type and extent of surgery was not associated with the risk of tumor recurrence. Extended surgery did not reduce the risk of local and regional recurrences. In the complete series, the fi ve-year overall survival rate was 30% and the recurrence-free survival (RFS) rate was 27%. The fi ve-year pelvic disease control was 82% in stage I, 68% in stage II, and 76% for more advanced stages. The fi ve-year locoregional RFS rate was 63% for patients treated with surgery alone, 68% after addition of adjuvant chemotherapy, 86% after adjuvant radiotherapy, and 95% after combined chemotherapy and radiotherapy. Conclusion. Radiotherapy seems to be the most important constituent of the adjuvant therapy. Serious late tissue reactions, requiring surgery, from the bladder and intestine occurred in 2.5% of the irradiated cases. The death of three patients could be related to radiotherapy and of four patients due to the cytotoxic treatment. This population-based series may serve as a baseline for improvements by, e.g. standard care programs and referral to a few specialist centers for this rare and serious disease.

ObjectiveTo 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.MethodsA 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 theE6gene with polymerase chain reaction and pyrosequencing.ResultsForty (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.ConclusionsHuman 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.

BackgroundA combination of vaginal brachytherapy and external beam radiotherapy was compared with brachytherapy alone in medium-risk endometrial carcinomas. Quality-of-life analysis is an important part of a randomized study to find out the optimal adjuvant treatment for this group of patients.ObjectiveTo evaluate the value of adjuvant external beam pelvic radiotherapy in adjunct to vaginal brachytherapy in medium-risk endometrial carcinoma. Quality-of-life evaluation is the main topic of this report.MethodsA consecutive series of 527 evaluable patients were included in this randomized trial. Median follow-up for patients alive was 62 months. The primary study end points were locoregional recurrences and overall survival. Secondary end points were recurrence-free survival, toxicity, and quality-of-life. European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-OV28 modules were used to evaluate global health status, functional scales, and symptom scales.ResultsFive-year locoregional relapse rates were 1.5% after external beam (ERT) plus vaginal irradiation (VBT) and 5% after vaginal irradiation alone (P = 0.013), and 5-year overall survival (OS) rates were 89% and 90%, respectively. External beam radiotherapy was associated with a higher rate of adverse effects from the intestine and the bladder, and quality-of-life parameters deteriorated at the end of radiotherapy but recovered to normal levels within a few months. There was a significant difference in favor of VBT alone with regard to adverse effects of the bowel and urinary tract, and quality-of-life.ConclusionsDespite a significant locoregional control benefit with combined radiotherapy, no survival improvement was recorded; but increased late toxicity from the intestine and the bladder. External beam irradiation decreased global health status during and after treatment, and 3 functional scale items (physical, role, and social). Six of 11 symptom items showed a pattern favoring vaginal brachytherapy alone.

ObjectivesThe purpose of this study was to assess the response rate, toxicity, progression-free survival, and overall survival in a series of patients with advanced-stage ovarian carcinoma treated with a first-line weekly docetaxel and 3 weekly carboplatin regimen.MethodsAll eligible patients were treated with intravenous docetaxel (30 mg/m2) on days 1, 8, and 15, and carboplatin (area under the curve, 5) on day 1; every 21 days for at least 6 cycles.ResultsOne hundred six patients received at least one cycle of primary chemotherapy (median, 6.0; range, 1–9), and they were evaluable for toxicity assessment. Eighty-five patients had evaluable (measurable) disease and received at least 3 courses of chemotherapy and were evaluable for clinical response rate. The overall response rate was 78.8% (95% confidence interval, 70.1%–87.5%), and the biochemical response 92.8% (95% confidence interval, 87.2%–98.4%). The median progression-free survival was 12.0 months and the median overall survival was 35.3 months. Thirty-six patients (34.0%) experienced grades 3 and 4 neutropenia, which resulted in the removal of 3 patients. Six patients (5.7%) experienced grades 3 or 4 thrombocytopenia. No patients experienced grade 3 to grade 4 sensory neuropathy. Epiphora, nail changes, and fatigue were frequently recorded nonhematologic adverse effects.ConclusionsThe tolerable hematologic toxicity (no need for colony-stimulating factors) and the low rate of neurotoxicity (only grades 1–2) and response rates in line with the standard 3-week paclitaxel-carboplatin regimen for advanced primary ovarian carcinoma after suboptimal cytoreductive surgery make this regimen an interesting alternative in selected patients.

The aim of this study was to explore what women with recurrent ovarian cancer perceived as important in their communication with the health care team.Interviews were conducted with 12 women at the end of chemotherapy treatment at a department of gynecological oncology in central Sweden. The interviews were subjected to qualitative content analysis.The findings stress the importance for the health care team to offer each woman the opportunity for support in becoming familiar with the disease. This theme of becoming familiar with the disease is underpinned by four sub-themes: being acknowledged as a unique person, getting help to make sense of information regarding the disease and its treatment, having the opportunity to be involved and to share responsibility, and feeling confident that medical expertise was adequate. Becoming familiar with the disease was expressed as a process of understanding and assimilating the whole new situation. To achieve familiarity, the women needed help from the health care team to make sense of the information they received. They stressed the importance of being able to influence encounters with health professionals, in accordance with their own perspectives. Being acknowledged as a unique person was a prerequisite to achieve familiarity. Also important to the women was having the opportunity to share responsibility for their care and lives with someone from the health care team.Helping women with recurrence of ovarian cancer attain a sense of familiarity with the disease should be an important priority for health care providers.

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 radiochemotherapy, 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.

To compare two different fractionation schedules for postoperative vaginal high-dose-rate (HDR) irradiation in endometrial carcinomas.In a complete geographic series of 290 low-risk endometrial carcinomas, the efficacy and side effects of two different fractionation schedules for postoperative vaginal irradiation were evaluated. The patients were treated during the years 1989-2003. The tumors were in International Federation of Gynecology and Obstetrics Stages IA-IB and Grades 1-2. The HDR MicroSelectron afterloading equipment (iridium-192) was used. Perspex vaginal applicators with diameters of 20-30 mm were used, and the dose was specified at 5 mm from the surface of the applicator. Six fractions were given, and the overall treatment time was 8 days. The size of the dose per fraction was randomly set to 2.5 Gy (total dose of 15.0 Gy) or 5.0 Gy (total dose of 30.0 Gy). One hundred forty-four patients were treated with the 2.5-Gy fraction and 146 patients with the 5.0-Gy fraction.The overall locoregional recurrence rate of the complete series was 1.4% and the rate of vaginal recurrences 0.7%. There was no difference between the two randomized groups. The vaginal shortening measured by colpometry was not significant (p = 0.159) in the 2.5-Gy group (mean, 0.3 cm) but was highly significant (p0.000001) in the 5.0-Gy group (mean 2.1 cm) after 5 years. Mucosal atrophy and bleedings were significantly more frequent in the 5.0-Gy group. Symptoms noted in the 2.5-Gy group were not different from what could be expected in a normal group of postmenopausal women.The fractionation schedule recommended for postoperative vaginal irradiation in low-risk endometrial carcinoma is six fractions of 2.5 Gy when the HDR technique is used.

In a large study on 1220 patients with ovarian carcinoma in FIGO stages I–IV, the prognostic importance of the time factor for start of postoperative chemotherapy was studied together with other important factors for long-term survival. The patient series was a total geographic material of ovarian carcinoma patients treated during the years 1975–1993. All patients were followed up for 10 years or until death. The 5-year cancer-specific survival rate of the complete series was 50%. Significant and independent prognostic factors with regard to long-term cancer-specific survival were FIGO stage, histology, tumor grade, and completeness of the primary surgery. Special attention was paid to the prognostic importance of the time interval between primary surgery and the first course of chemotherapy. Patient groups with intervals shorter or longer than the median value were compared. In early-stage disease, no significant difference was noted. In advanced and bulky disease, an interval longer than the median value seemed to be beneficial compared with a shorter interval. However, after correction for other prognostic factors, the interval was not a significant factor (P = 0.647) with regard to the cancer-specific survival rate. Therefore, the time factor should not be an important argument for how to best organize the gynecologic oncology service.

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.

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for ovarian cancer is based on data from six randomized trials. Moreover, data from one prospective study and three retrospective studies were used. In total, 10 scientific articles are included, involving 1 282 patients. The results were compared with those of a similar overview from 1996 including 15042 patients. The conclusions reached can be summarized in the following points: There is no scientific documentation supporting adjuvant radiotherapy for early-stage, low-risk patients. No studies have been reported where adjuvant radiotherapy has been compared with no adjuvant therapy in early-stage, high-risk patients. Adjuvant radiotherapy, either whole abdominal irradiation or intraperitoneal p32, has been compared with adjuvant chemotherapy in early-stage, high-risk patients. There is no scientific evidence to show that there is a difference in efficacy. There is some evidence to suggest that adjuvant radiotherapy after radical surgery leads to an increase in disease-free survival rate for patients with advanced-stage ovarian cancer. There is little documentation on long-term side effects (second malignancy) after adjuvant radiotherapy and no conclusions can be drawn.

In a prospective randomized trial, consolidation treatment with radiotherapy or chemotherapy was compared with no treatment in a series of 172 patients with epithelial ovarian carcinoma, FIGO stage III, with complete surgical remission after primary cytoreductive surgery and induction chemotherapy. In the subgroup with complete pathological remission, progression-free survival (PFS) was significantly (P = 0.032) better in the radiotherapy group (56%) than in the chemotherapy group (36%) and the untreated control group (35%). The number of recurrences was lowest in the radiotherapy group. The overall relapse rate was reduced by 33% and the pelvic recurrences by 43% by consolidation radiotherapy. On the other hand, treatment-related side effects were more frequent in the radiotherapy group.

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.

Skirnisdóttir I, Seidal T, Gerdin E, Sorbe B. The prognostic importance of p53, bcl-2, and bax in early stage epithelial ovarian carcinoma treated with adjuvant chemotherapy.Epithelial ovarian cancer is one of the major causes of death among women. The increasing knowledge about molecular events involved in the early stages of ovarian tumorigenesis may provide the basis for management in the future. In a series of 109 patients with epithelial carcinomas in FIGO stages IA-IIC, a number of clinicopathologic prognostic factors (age, FIGO stage, histopathologic type, and tumor grade) were studied in relation to the biologic factors p53, bcl-2, and bax, which are important regulators of apoptosis. Immunohistochemical techniques were used. All the patients received adjuvant chemotherapy after the primary surgery. Univariate analysis showed that expression of p53 was significantly associated with tumor grade (P = 0.014), probability of persistent disease (P = 0.016), and cancer-specific survival rate (P = 0.007). Positive bcl-2 staining was associated with endometrioid tumor subtype (P = 0.029) and a favorable tumor grade distribution (P = 0.034), but not with the survival status. The combined p53-bcl-2 expression was related to histopathologic subtype (P = 0.032), tumor grade (P = 0.011), persistent disease (P = 0.014), and risk of dying due to the disease (P = 0.039). The bax status was not a prognostic factor, but the combined p53-bax expression showed an association with FIGO stage (P = 0.014), tumor grade (P = 0.034), persistent disease (P = 0.006), and risk of dying due to the disease (P = 0.039). The combined bcl-2-bax expression was related to histopathologic subtype (P = 0.045) and tumor grade (P = 0.022). In a multivariate Cox analysis, tumor grade (P = 0.014), and p53 status (P = 0.020) were independent and significant prognostic factors with regard to the cancer-specific survival rate.

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 ( 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.

Epithelial ovarian cancer is a heterogeneous disease and many biologic and molecular factors are important for its development and progression, including growth rate, metastatic potential, chemo- and radiosensitivity, and prognosis. Even in the early stages (FIGO I–II), many questions persist about the biologic behavior, optimal treatment, and prognosis. In a series of 106 patients with epithelial ovarian cancers in FIGO stages IA-IIC, a number of known prognostic factors (age, FIGO stage, histopathologic type, and tumor grade) were studied in relation to two important growth factor receptors for oncogenesis (HER-2/neu and EGFR). Immunohistochemical techniques were used. All patients received adjuvant radiotherapy 4–6 weeks after the primary surgery. In a univariate analysis, the expression of the HER-2/neu receptor was not associated with any of the clinicopathologic factors studied or survival status. Positive EGFR staining was associated with poor survival in a univariate analysis. Co-expression of HER-2/neu and EGFR was most frequently seen in serous tumors and positive staining for HER-2/neu alone was associated with mucinous tumors. Both endometrioid and clear cell tumors belonged to the largest subgroup with concomitant negativity for both HER-2/neu and EGFR. In a multivariate Cox analysis, the tumor grade and EGFR status of the tumors were independent and significant prognostic factors. A therapeutic strategy for epithelial ovarian cancer might be to decrease EGFR expression by gene therapy in combination with adjuvant radiotherapy or chemotherapy.

BACKGROUND: Owing to the wide spread perception of a possible benefit from paclitaxel in the second-line situation the Nordic Gynecologic Oncology Group (NGOG) conducted two prospective phase II studies of paclitaxel single agent treatment (175 mg/m2, three-hour i.v. infusion with standard pre-medication every third week) in patients with relapsing or progressing epithelial ovarian cancer following platinum.PATIENTS AND METHODS: Between 1992-1994 138 patients in total were enrolled of whom 136 received paclitaxel and were included in the toxicity and survival analysis, while 112 were evaluable for response.RESULTS: The overall response rate (CR + PR) was 28% with 16 patients achieving a CR (14%). The estimated median (range) time to progression was 4.1 (0.7-60.7) months. The projected four-year overall survival was 7%, with a median (range) of 9.6 (0.3-60.7) months. A multivariate logistic regression analysis showed that platinum resistance, and WHO performance status at baseline, independently correlated with survival at all three time points (median survival time 9.6, 18, and 24 months). Patients with platinum sensitive tumors and WHO performance status 0 had a median survival of 25.6 months compared to 7.0 months for the rest of the patients (P < or = 0.0001). No serious toxicity was registered.CONCLUSION: Paclitaxel could safely be administered in an outpatient setting using this schedule. Patients with platinum sensitive tumors and a good performance status were most likely to survive. However, these patients are also most likely to respond to re-treatment with a platinum compound. With reference to the reasonably good tumor control and limited toxicity observed in this study, we conclude that paclitaxel single agent therapy is a viable option in the salvage situation, which in some patients can give long-lasting responses. However, although responses can be induced in a significant number of patients, the survival figures remain poor. (Less)

BACKGROUND: Chemotherapy-induced emesis is one of the most disturbing side effects of cancer therapy. Control of acute emesis has improved substantially during recent years, but control of delayed emesis and nausea remains a challenging problem. The role of 5-HT3 receptor antagonists in the treatment of delayed emesis is disputed.METHODS: Tropisetron, a highly specific 5-HT3 receptor antagonist, was compared (as an adjunct to dexamethasone) with placebo in a randomized, double blind, multicenter trial for the prevention of delayed emesis during platinum-containing chemotherapy. Three hundred chemotherapy-naive women with gynecologic malignancies were included. The cisplatin dose was in the range of 50-100 mg/m2.RESULTS: Acute emesis was prevented completely in 87% of patients and acute nausea in 77% of patients in the complete series. During the complete delayed period (Days 2-6), total control of emesis was achieved in 77% of the dexamethasone and tropisetron-treated patients and in 72% of the patients receiving dexamethasone and placebo (P = 0.2473). During the same period nausea was controlled completely in 42% of the dexamethasone and tropisetron group and in 41% of the dexamethasone and placebo group. On Day 3, complete protection from nausea was achieved in 65% of patients receiving tropisetron and in 51% of patients receiving placebo (P = 0.0304). Constipation occurred more frequently in the tropisetron group.CONCLUSIONS: Tropisetron added to dexamethasone improved control of delayed nausea on Day 3 compared with placebo. No significant differences were recorded regarding control of delayed emesis. (Less)

The aim of the present study was to evaluate a consecutive series of ovarian carcinosarcomas with regard to prognosis, treatment and prognostic factors.A consecutive series of 81 ovarian carcinosarcomas from two well-defined geographic regions were studied with regard to survival, type of primary and adjuvant therapy and prognostic factors. All patients but one underwent primary surgery and some patients also received adjuvant chemotherapy (platinum-based) alone or in combination with radiotherapy. Univariate and multivariate Cox proportional regression analysis was used. Survival was analyzed by the Kaplan-Meier technique and differences were assessed by the log-rank test.The mean age of the patients was 73 years. Fifty-one patients received adjuvant chemotherapy and nine patients pelvic irradiation. The 5-year overall survival rate was 10%. Adjuvant therapy (any type) and six completed cycles of chemotherapy were highly significant factors with regard to improved overall survival rate. The only significant tumor-associated prognostic factor was the International Federation of Gynecology and Obstetrics (FIGO) grade of the tumor. FIGO stage, site of metastatic spread, tumor size, histology, DNA ploidy, and tumor necrosis were non-significant factors. Therapy was rather well-tolerated and 29 patients (57%) completed at least six cycles of adjuvant chemotherapy.Adjuvant and completed chemotherapy according to the treatment plan were the most important prognostic factors. FIGO grade (grade 3 vs. 1-2) of the epithelial component of the tumor was also a significant prognostic factor in multivariate Cox analysis.

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.

Emesis is a serious and poorly tolerated side-effect of cancer chemotherapy. Highly emetogenic agents (e.g., cisplatin, dacarbazine) and combination chemotherapy have been used frequently since the end of the 1970s. The introductions of high-dose metoclopramide and corticosteroid-containing antiemetic cocktails at the beginning of the 1980s were important improvements. The discovery of the 5-HT3 receptors and the synthesis of their antagonists (e.g., ondansetron, granisetron, tropisetron) in the mid 1980s signified a great breakthrough in antiemetic research and therapy. Acute nausea and vomiting are well controlled by these new drugs in 80 — 90% of cases; combination with a corticosteroid further improves their efficacy. However, the value of 5-HT3 receptor antagonists in the prevention of delayed emesis following highly emetogenic chemotherapy remains controversial. Further studies are needed to settle this question definitively. A number of new 5-HT3 antagonists are in Phase I-Ill development; however,...

In a controlled prospective randomized study the regimen doxorubicin (A) 40 mg/m2 + melphalan (M) 0.4 mg/kg was compared with A + M + cisplatin (C) 50 mg/m2 given every four weeks in advanced ovarian cancer, FIGO stage III or IV and with serous or anaplastic histology. From 1981 to 1983, 300 patients entered the study and 295 patients were evaluable for response, toxicity and long-term survival. All patients were followed for at least 10 years. The majority of patients had large residual tumours >2 cm. Patients treated with MAC had a higher response rate compared with patients treated with MA (76% vs. 50%, p < 0.01) and treatment with MAC resulted in significantly more pathological complete responders than MA. There was a significant difference in median duration of response (19 months vs. 13 months, p < 0.006) and in median survival time (26 months vs. 19 months, p = 0.05). After 5- and 10 years a significant difference in progression-free and overall survival was found. The independent prognostic factors in this study were residual tumour after primary surgery, treatment with MAC, tumour grade, ascites, and stage. Objective and subjective side effects were significantly worse with MAC, although tolerable. In conclusion, this study shows that incorporating C into MA improves the duration of progression-free survival and overall survival in women with incompletely resected Stage III or Stage IV ovarian epithelial cancer. A 5- and 10-year survival of 25% and 18%, respectively, is impressive.

The aim of the present study was to evaluate the efficacy and safety of high-dose-rate brachytherapy alone or in combination with external pelvic irradiation in treatment of vaginal recurrences in endometrial carcinomas. Predictive and prognostic factors were also evaluated.Between 1990 and 2005, forty patients were consecutively treated for vaginal recurrences with or without extravaginal tumoral spread from endometrial carcinoma of International Federation of Gynecology and Obstetrics (FIGO) stages IA-IIIA. Thirty-five patients were treated primarily with surgery and five patients with primary radiotherapy. Six patients were treated with adjuvant external beam irradiation and seven patients with vaginal brachytherapy upfront. The medium time from diagnosis to recurrence was 17 months. The recurrences were treated with a combination of high-dose-rate brachytherapy (mean 25.8 Gy) and external beam pelvic irradiation (mean 46.7 Gy) in 24 cases (60%) and with external therapy-alone or brachytherapy-alone in 12 cases.The local control of vaginal recurrences treated with a combination of external beam therapy and brachytherapy was 92%. The local control rate was lower for external beam therapy-alone. In eleven patients (28%), a second recurrence occurred (five vaginal and six distant metastases). The overall 5-year survival rate was 50%. Age, FIGO grade and time from diagnosis to recurrence were the only independent and significant prognostic factors. Upfront external beam therapy was associated with a worse overall survival rate. Site of recurrence was significant only in univariate analysis. Late gastrointestinal toxicity (grade 3-4) was recorded in 11% of irradiated patients.Combined high-dose-rate brachytherapy and external beam therapy was an effective treatment for vaginal recurrences. Age, FIGO grade, and time-to-recurrence were significant and independent prognostic factors. Upfront radiotherapy was an unfavorable prognostic factor in univariate analysis.

The objectives of this study are to investigate the human papilloma virus (HPV) distribution in vaginal cancer and to evaluate HPV-genotype as well as HPV16-variant impact on prognosis.Sixty-nine patients diagnosed with primary vaginal carcinoma (1975-2002) were included in the study. Detection of twelve high-risk HPV (hr HPV) and two low-risk HPV (lr HPV) was performed with realtime-PCR. Samples positive for HPV-16 were analyzed for variants in the E6-gene with PCR and pyrosequencing.53.6% (37/69) of the tumors were found to be HPV-positive, mostly for HPV-16 (N=26). Other HPV-types were HPV-18 (N=2), HPV-31 (N=2), HPV-33 (N=2), HPV-45 (N=1), HPV-52 (N=2), HPV-56 (N=1) and HPV-58 (N=1). Only European subtypes of HPV-16 were represented and the two most common HPV-16-variants were E-p (N=13) and E-G350 (N=11). Patients with HPV-positive tumors (N=37) had a significantly (log-rank test=3.341; p=0.0008) superior 5-year overall survival rate as well as cancer-specific survival rate and progression-free survival rate (p=0.0002; p=0.0004), compared with patients with HPV-negative tumors (N=32). Interestingly, patients with HPV-16-positive tumors had a superior overall survival compared with patients with tumors containing other HPV-genotypes. In a Cox proportional multivariate analysis age, tumor size, and HPV-status were independent and significant prognostic factors with regard to overall survival rate.HPV-status is of prognostic importance in vaginal carcinoma and varies with viral genotype. In this era of HPV-vaccination, genotypes other than those included in the vaccination program could still lead to vaginal carcinoma with unfavorable prognosis.

To evaluate the efficacy and safety of Navoban (tropisetron) three different Nordic multicentre trials were conducted during the period 1988-92. In all, 1050 patients were recruited from 15 centres. In the first study, Navoban monotherapy was compared with a high-dose metoclopramide cocktail. In the second, Navoban +/- dexamethasone was evaluated for those patients not fully protected by Navoban alone. In the third trial, Navoban was evaluated for various chemotherapy regimens, for long-term efficacy, and for various risk groups of patients. Spontaneous intercycle variations were also evaluated. Navoban was found to be as effective as the antiemetic cocktail but with a more favourable spectrum of side effects and a simpler schedule of administration. Navoban was more effective during the acute than the delayed phase. Addition of dexamethasone significantly improved prevention of both acute and delayed emesis. Long term efficacy seemed to be stable up to 10 cycles of chemotherapy. Patients treated with noncisplatin regimens showed significantly higher protection rates than patients treated with cisplatin. Various cancer diagnoses and cytostatic agents were also evaluated. Gender and age were important risk factors. Navoban was found to be an efficacious antiemetic agent, especially regarding acute nausea and vomiting. Addition of a corticosteroid significantly improved the effect during highly emetogenic chemotherapy. The role of Navoban for delayed emesis must be evaluated in future trials. The two most common side effects were headache and constipation. Overall, Navoban was well tolerated and patient compliance with the drug was high.

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

Background. The aim was to evaluate predictive and prognostic factors in a large consecutive series of endometrial carcinomas and to discuss pre- and postoperative risk groups based on these factors. Material and Methods. In a consecutive series of 4,543 endometrial carcinomas predictive and prognostic factors were analyzed with regard to recurrence rate and survival. The patients were treated with primary surgery and adjuvant radiotherapy. Two preoperative and three postoperative risk groups were defined. DNA ploidy was included in the definitions. Eight predictive or prognostic factors were used in multivariate analyses. Results. The overall recurrence rate of the complete series was 11.4%. Median time to relapse was 19.7 months. In a multivariate logistic regression analysis, FIGO grade, myometrial infiltration, and DNA ploidy were independent and statistically predictive factors with regard to recurrence rate. The 5-year overall survival rate was 73%. Tumor stage was the single most important factor with FIGO grade on the second place. DNA ploidy was also a significant prognostic factor. In the preoperative risk group definitions three factors were used: histology, FIGO grade, and DNA ploidy. Conclusions. DNA ploidy was an important and significant predictive and prognostic factor and should be used both in preoperative and postoperative risk group definitions.

An open, noncomparative, Nordic multicenter study was carried out during 1991-1992 to evaluate the 5-HT3 receptor antagonist tropisetron (Navoban) as an antiemetic agent for various types of cancer chemotherapy. A total of 630 patients were recruited from 15 centers in Sweden, Denmark, and Finland. Gynecological cancers (60%), breast cancer (15%), and lung cancer (10%) were the main diagnoses. Prior experience of chemotherapy was documented in 338 patients (54%). In 260 patients (41%), cisplatin was part of the cytostatic regimen. Carboplatin (23%), doxorubicin (27%), and epidoxorubicin (24%) were also frequently included. In all, 23 cytostatic agents were used in various combinations. The mean number of courses studied was 4.6 (range 1-19). Altogether, 394 of 619 evaluable patients (64%) were completely protected from acute nausea and vomiting during the first course of chemotherapy. Delayed nausea and vomiting were completely prevented in 45%-73% (days 2-6) in the complete series. Treatment efficacy remained stable (60%-79%) during ten consecutive courses of chemotherapy. With noncisplatin regimens, complete protection from acute nausea and vomiting was achieved in 72% compared with 52% for cisplatin regimens (P < 0.0001). Patients without prior experience of chemotherapy had higher control rates of acute nausea and vomiting (72%) compared to patients treated before (57%) during the first course, but not later on. There were no differences in delayed nausea and vomiting.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND: Chemotherapy-induced emesis is one of the most disturbing side effects in cancer therapy. Thus, antiemetic treatment is a mandatory adjunct in emetogenic chemotherapy.METHODS: Tropisetron (Navoban, Sandoz Pharma Ltd., Basel, Switzerland), a new 5-HT3 receptor antagonist, was compared in a randomized multicenter trial with a high-dose metoclopramide-dexamethasone cocktail for the prevention of nausea and emesis during cisplatin-containing chemotherapy. Two hundred fifty-nine chemotherapy-naive patients were included and followed during two consecutive courses. The main cancer types were gynecologic tumors, followed by lung cancer, head and neck cancer, and bladder cancer. The cisplatin dose usually was in the range of 50-89 mg/m2. The efficacy and quality of life assessments and the safety recordings were done during the first 6 days of both courses of chemotherapy.RESULTS: Acute vomiting was prevented in 63-64% of patients by both antiemetic regimens. The total rate of control of vomiting increased from 63% on day 1 to 93% on day 6 in the group receiving tropisetron. Acute nausea was prevented in 40% of the patients with tropisetron monotherapy and in 61% of patients receiving the antiemetic cocktail. With regard to delayed nausea, there were no significant differences between the two antiemetic regimens. Mild headache and constipation were more frequently associated with tropisetron, and extra-pyramidal side effects and sedation were associated with the antiemetic cocktail.CONCLUSIONS: Tropisetron was easier to administer and better tolerated than the cocktail, and it seems to be a highly efficacious and safe new antiemetic drug. (Less)

Significant improvements in the treatment results of ovarian cancer have been achieved during the last decades, but further improvements require additional methods identifying signs of the disease and its biological behavior, preferably by a simple blood test. We hypothesized that peripheral blood leukocytes may express genes that carry such clinical information. Therefore, we studied the relative gene expressions of 168 cancer- and metastasis-specific genes in blood samples from ovarian cancer patients with different prognoses after primary cytoreductive surgery. Total RNA was extracted from whole blood and the relative gene expression profile of 168 genes were analyzed using real-time qPCR assays. Two groups of patients were analyzed; one group with residual tumor mass after primary surgery, and one group where the tumor was macroscopically radically resected, resulting in no visible tumor mass left behind. The group with the remaining tumor mass after surgery showed significantly different gene expression profiles compared to the group with no remaining tumor mass. Differences were noted for the metastasis associated 1 family, member 2 gene (MTA2), the TNF, α-catenin, interleukin 1β, the KiSS-1 metastasis suppressor and the matrix metallo-proteinase 10 genes. All genes were downregulated with a fold-change between 1.15 to 1.57; there were no upregulated genes. Thus, a signature of genes involved in metastasis, invasion and inflammation was found to be significantly downregulated in native unstimulated blood leukocytes from ovarian cancer patients with a poor prognosis. Preoperatively it may serve as a guide to the biology of the tumor and postoperatively in the optimization of adjuvant treatment of ovarian cancer patients.

The purpose of this study was to assess the response rate, toxicity, progression-free survival (PFS) and overall survival (OS) in a series of advanced stage ovarian carcinoma patients treated with a first-line weekly docetaxel and three weekly carboplatin regimens. All eligible patients were treated with intravenous docetaxel (30 mg/m2) on Days 1, 8 and 15, and carboplatin (area under the curve, 5) on Day 1; Q21 days for at least 6 cycles. Neurological tests, questionnaires, and the EORTC QLQ-C30 and OV28 were used for quality-of-life assessments. One hundred and six patients received at least one cycle of primary chemotherapy (median 6.0; range, 1-9) and they were evaluable for toxicity assessment. Eighty-five patients had evaluable disease and received at least 3 courses of chemotherapy and were evaluable for clinical response rate. The overall response rate was 78.8% (95% CI 70.1-87.5%) and the biochemical response was 92.8% (95% CI 87.2-98.4%). The median PFS was 12.0 months and the median OS was 35.3 months. Thirty-six patients (34.0%) experienced grades 3 and 4 neutropenia, which resulted in the removal of 3 patients. Six patients (5.7%) experienced grades 3 or 4 thrombocytopenia. No patients experienced grade 3-4 sensory neuropathy. Epiphora, nail changes and fatigue were frequently recorded non-hematological side effects. The tolerable hematological toxicity (no need for colony-stimulating factors) and the low rate of severe neurotoxicity (only grade 1-2) and response rates in line with the standard 3-week paclitaxel-carboplatin regimen for advanced primary ovarian carcinoma after suboptimal cytoreductive surgery make this regimen an interesting alternative in selected patients.

Hypermethylation of the O 6 -MGMT, p14 ARF , p16 INK4a , RASSF1A and APC1A genes are unfavourable prognostic markers in colorectal cancer (CRC). We hypothesized that they could be related to prognosis also in cervical cancer. Methylation was studied in DNA extracts from surgical specimens of cancer tissue by novel pyrosequencing methods. In 109 patients (90 squamous cell carcinomas, 19 adenocarcinomas), we found that hypermeth- ylation of the APC1A gene promoter occurred in 8.3% of patients, and of p16 INK4a in 1.8%. APC1A hypermethylation was significantly related to more advanced FIGO stage of the tumor (P=0.013), larger tumor diameter (P=0.049) and distant recurrence-free survival (P=0.0007), but not with locoregional recurrence rate, age, HPV status, DNA ploidy, tumor grade or malignancy grading score. We conclude that methylation of the APC1A promoter in cervical cancer, as diagnosed by pyrosequencing, is significantly related to major biological characteristics of the tumor, and may be a new predictor of poor prognosis in cervical cancer.

In a retrospective analysis of a complete geographic series of cervical carcinomas treated by Wertheim-Meigs radical surgery, a number of important prognostic factors were evaluated and long-term survival data are presented. In all, 367 women with FIGO stage I-II tumors were included. The main histopathologic types were squamous cell carcinoma in 84% and adenocarcinoma in 12%. The mean age of the patients was 42.5 (range 19-68) years. In 125 women (34%), adjuvant radiotherapy was administered pre- or postoperatively. The median period of follow-up was 12 (range 2-27) years. In 88% of the specimens surgery (93% in stage I and 66% in stage II) was classified as radical with regard to the excision margins. This was an important and highly significant prognostic factor. If the margins were wide and free of tumor, the 10-year survival rate was 93%, but if margins were infiltrated by the tumor, the survival rate was 14%. Pelvic lymph node involvement was recorded in 52 cases (14%). The frequency of lymph node spread was associated with tumor stage (IA O%, IB 14%, IIA 32%). The probability of survival of the complete series was 93% at 5 years and 84% at 10 years. In cases of lymph node involvement, the 10-year survival rate was 57%. The preoperative tumor stage had a highly significant influence on long-term tumor-specific survival. Tumor grade was also a significant prognostic factor, but not the histologic type (squamous, adenosquamous, or adenocarcinoma). Age and parity were also insignificant prognostic factors. The tumor recurred in 59 cases (16%). The mean time to relapse was 28 months. The 10-year survival was 29% for this group of patients. Peroperative complications were recorded in 50 patients (14%). Excessive bleeding (11%) and urinary tract injuries (3%) were most frequent. Postoperatively, 101 patients (28%) had some kind of complication associated with the surgical procedure. Surgical complications were more frequent among women over 50 years of age. Bladder dysfunction (11%) and obstruction of the ureter (8%) were recorded most frequently. In 19 cases (5.2%), urinary tract or intestinal fistulas were diagnosed during the period of follow-up. With increasing experience of the surgeons and fewer stage II tumors, the frequency of fistulas associated with the surgical procedure decreased to 2.4% during the latter part (1975-90) of the period. Adjunctive postoperative radiotherapy increased the risk of late complications. In 8 cases (6.4%), serious complications associated with the combination of surgery and radiotherapy were reported.

Introduction:The objective of the study was to evaluate the prognostic effect of p53, p27, and C-MYC on clinicopathological features, recurrent disease, and disease-free survival (DFS) of 131 patients with ovarian cancer in International Federation of Gynecology and Obstetrics (FIGO) stages I-II.Methods:The technique of tissue microarray and immunohistochemistry was used for detection of positivity/overexpression of the biological markers p53, p27, and C-MYC.Results:In the complete series, the 5-year and overall survival rates were 68% and 71%, respectively. Positive staining for p53, p27, and C-MYC was detected in 25%, 57%, and 76% of cases, respectively. Positivity of p53, p27, concomitant p53-p27, C-MYC, and C-MYC-p27 status were associated with tumor grade. Positivity of p27 and concomitant p53-p27 were related to serous tumors. In survival analysis, DFS was related to p53, combined p53-p27, and combined p53-C-MYC status. Significant predictive factors for tumor recurrences were the FIGO stage (odds ratio [OR] = 9.8), status of node sampling (OR = 0.2), and p53 status (OR = 3.7) in a logistic regression analysis. In a multivariate Cox regression analysis, FIGO stage (hazard ratio [HR] = 4.3) and p53 status (HR = 3.0) were significant prognostic factors for DFS. In a separate Cox regression analysis, FIGO stage (HR = 2.0) and concomitant p53-p27-C-MYC status (HR = 0.3) were independent prognostic factors for DFS. It was possible to identify a subgroup, constituting 30% of the patients, who had excellent survival with tumors of concomitant p53 negativity, p27 positivity, and C-MYC positivity apart from the clinicopathological factors. Patients in this subgroup were longtime survivors with DFS of 92% at 5 and 9 years.Conclusions:The results of this study strongly suggest that patients with p53-positive tumors (alone/or combined with p27 and/or C-MYC) had significantly worse survival (DFS) compared with patients with p53-negative tumors. Patients with p53-positive tumors continued to have recurrences after the 5-year follow-up and die in disease.

DNA methylation status in the CpG sites of promoter regions in cancer-related genes, such as PTCH, has traditionally been investigated using either dye-terminator sequencing or methylation-specific PCR. We aimed to study the PTCH gene promoter methylation in gynecological cancers, with a method that gives a quantitative measure of the methylation status of the promoter region of the studied gene, and for this purpose, we designed novel Pyrosequencing-based assays. Bisulfite-treated genomic DNA (bsDNA) was amplified by standard PCR and applied to novel Pyrosequencing® assays, in order to measure the methylated fraction (%) at each CpG site of the PTCH gene promoter. We analyzed 22 squamous cell cervical cancer tissue specimens (11 with good and 11 with poor outcomes after radiotherapy) and 5 ovarian cancer tissue specimens matched with 5 normal ovarian tissue specimens. Six optimized PCR protocols which generated 8 Pyrosequencing assays covering 63 CpG sites in the promoter regions 1 and 2 as well as the previously unanalyzed promoter region 3 in the PTCH gene were developed. The 27 tumor tissue specimens and 5 normal tissues did not show any methylation within any of the 63 CpG sites. Our data suggest that methylation of the PTCH promoter is not a high-prevalence feature of squamous cell cervical cancer or ovarian cancer, but Pyrosequencing assays are a good method for studying promoter methylation.

To evaluate the value of adjuvant external beam pelvic radiotherapy as adjunct to vaginal brachytherapy (VBT) in medium-risk endometrial carcinoma, with regard to locoregional tumor control, recurrences, survival, and toxicity.Consecutive series of 527 evaluable patients were included in this randomized trial. Median follow-up for patients alive was 62 months. The primary study endpoints were locoregional recurrences and overall survival. Secondary endpoints were recurrence-free survival, recurrence-free interval, cancer-specific survival, and toxicity.Five-year locoregional relapse rates were 1.5% after external beam radiotherapy (EBRT) plus VBT and 5% after vaginal irradiation alone (p = 0.013), and 5-year overall survival rates were 89% and 90%, respectively (p = 0.548). Endometrial cancer-related death rates were 3.8% after EBRT plus VBT and 6.8% after VBT (p = 0.118). Pelvic recurrences (exclusively vaginal recurrence) were reduced by 93% by the addition of EBRT to VBT. Deep myometrial infiltration was a significant prognostic factor in this medium-risk group of endometrioid carcinomas but not International Federation of Gynecology and Obstetrics grade or DNA ploidy. Combined radiotherapy was well tolerated, with serious (Grade 3) late side effects of less than 2%. However, there was a significant difference in favor of VBT alone.Despite a significant locoregional control benefit with combined radiotherapy, no survival improvement was recorded, but increased late toxicity was noted in the intestine, bladder, and vagina. Combined RT should probably be reserved for high-risk cases with two or more high-risk factors. VBT alone should be the adjuvant treatment option for purely medium-risk cases.