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The first Swedish National Guidelines for Ovarian Cancer (NGOC) were published in 2012. We aimed to evaluate surgical outcomes and survival in patients with stage IIIC-IV disease, before and after the NGOC implementation.Women with primary epithelial ovarian cancer, FIGO stage IIIC-IV, registered in the Swedish Quality Registry for Gynecologic Cancer 2008-2011 and 2013-2016 were included. Surgical outcomes were analyzed, including frequency of complete cytoreduction (R0). Relative survival (RS) and excess mortality rate ratios (EMRRs) were computed as measures of survival. Univariable and multivariable regression (Poisson) were calculated.In total, 3728 women were identified, 1746 before and 1982 after NGOC. After adjusting for age and stage, survival was improved 2013-2016 vs. 2008-2011 (EMRR 0.89; 95%CI:0.82-0.96, p 0.05). For women undergoing primary debulking surgery (PDS), R0 frequency (28.9% vs. 53.3%; p 0.001) and 5-year RS (29.6% (95%CI:26.8-32.8) vs. 37.4% (95%CI:33.6-41.7)) were increased, but fewer patients (58% vs. 44%, p 0.001) underwent PDS after NGOC implementation. Median survival for the PDS cohort increased from 35 months (95%CI,32.8-39.2) to 43 months (95%CI,40.9-46.4). In the neoadjuvant chemotherapy (NACT) + interval debulking surgery (IDS) cohort, R0 increased (36.8% to 50.1%, p 0.001), but not 5-year RS (17.5% vs. 20.7%, ns). Compared to PDS, the EMRR was 1.32 (95%CI,1.19-1.47, p 0.001) for NACT+IDS and 3.00 (95%CI,2.66-3.38, p 0.001) for chemotherapy alone. In multivariable analyses, PDS, R0, age ≤ 70 years, and stage IIIC were found to be independent factors for improved RS.Implementation of the first National Guidelines for Ovarian Cancer improved relative survival in advanced ovarian cancer.

Vulvar cancer affects mainly elderly women and with an ageing population the incidence has increased. We explored the primary treatment patterns and relative survival of patients with vulvar squamous cell carcinoma (VSCC) by stage and age-group.A population-based nationwide study on women diagnosed with VSCC between 2012 and 2016 and registered in the Swedish Quality Registry for Gynecologic Cancer (SQRGC). Main outcome was 5-year relative survival (RS) estimated by the Pohar Perme method. The relative risk of excess mortality (EMRR) between different groups was analyzed by Poisson regression. The age-standardized relative survival (AS-RS) was estimated for the total cohort.Median follow-up time was 41 months. The study population included 657 women; 33% were ≥ 80 years old. FIGO stage I was most common (55%). Primary surgery was performed in 96% stage I, 65% stage II, 80% stage III and 28% stage IV. In women ≥80 years, exploration of the groins and chemoradiotherapy was less often performed. They also received lower mean doses of radiation than younger women. The 5-year AS-RS was 74%. 5-year RS was 84% for stage I, 60% for stage II, 54% for stage III and 35% for stage IV. The EMRR for women ≥80 years compared with women60 years was 4.3 (p 0.001); 4.9 (p 0.001) for stages I-II and 3.5(p = 0.007) for stage III.In general, primary treatment of patients with vulvar squamous cell carcinoma in Sweden adhered to guidelines. Areas of improvement include treatment for stage II and for the very old.

Introduction Minimally invasive methods to reduce menorrhagia were introduced in the 1980s and 1990s. Transcervical endometrial resection (TCRE) and endometrial ablation (EA) are two of the most frequently used methods. As none of them can guarantee a complete removal of the endometrium, there are concerns that the remaining endometrium may develop to endometrial cancer (EC) later in life. The primary aim was to analyze the long-term incidence of EC after TCRE and EA in a nationwide population. The secondary aim was to assess the two treatment modalities separately. Material and Methods The Swedish National Patient Registry and National Quality Registry for Gynecological Surgery were used for identification of women who had TCRE or EA performed between 1997-2017. The cohort was followed from the first TCRE or EA until hysterectomy, diagnosis of EC, or death. Follow-up data were retrieved from the National Cancer Registry and the National Death Registry. Expected incidence for EC in Swedish women was calculated using Swedish data retrieved from the NORDCAN project after having taken into account differences of age and follow-up time. Cumulative incidence of EC after TCRE and EA, was calculated. A standardized incidence ratio was calculated based on the expected and observed incidence, stratified by age and year of diagnosis. Results In total, 17 296 women (mean age 45.1 years) underwent TCRE (n = 8626) or EA (n = 8670). Excluded were 3121 who had a hysterectomy for benign causes during follow up. During a median follow-up time of 7.1 years (interquartile range 3.1-13.3 years) the numbers of EC were 25 (0.3%) after TCRE and 2 (0.02%) after EA, respectively. The observed incidence was significantly lower than expected (population-based estimate) after EA but not after TCRE, giving a standardized incidence ratio of 0.13 (95% confidence interval [CI] 0.03-0.53) after EA and 1.27 (95% CI 0.86-1.88) after TCRE. Median times to EC were 3.0 and 8.3 years after TCRE and EA, respectively. Conclusions There was a significant reduction of EC after EA, suggesting a protective effect, whereas endometrial resection showed an incidence within the expected rate.

Survival in cervical cancer has improved little over the last decades. We aimed to elucidate primary treatment patterns and survival.Population-based study of patients included in the Swedish Quality Registry for Gynecologic Cancer diagnosed 2011-2015. Main outcome was 5-year relative survival (RS). Age-standardised RS (AS-RS) was estimated for the total cohort and for the pooled study population of squamous, adenosquamous-, adenocarcinoma.Median follow-up time was 4.6 years. The study population consisted of 2141 patients; 97% of the 2212 patients in the total cohort and the 5-year AS-RS was 71% and 70%, respectively. RS stage IB1: surgery alone 95% vs. 72% for definitive chemoradiotherapy (CT-RT) (p 0.001). In stage IIA1 74% had CT-RT, and 47% of operated patients received adjuvant (CT)-RT. RS stage IB2: surgically treated 81% (69% received adjuvant (CT)-RT) vs. 76% for (CT)-RT (p = 0.73). RS stage IIB: 77% for CT-RT + brachytherapy (BT), 37% for RT + BT (p = 0.045) and 27% for RT-BT (p 0.001). Stages III-IVA;40% received CT-RT + BT, RS 45% vs. 18% for RT-BT (RR 4.1, p 0.001). RS stage IVB 7%.Primary treatment of cervical cancer in Sweden adhered to evidence-based standard of care. Areas of improvement include optimising treatment for stages III-IVA, and avoiding combining surgery and radiotherapy.

Introduction Deep myometrial invasion (>= 50%) is a prognostic factor for lymph node metastases and decreased survival in endometrial cancer. There is no consensus regarding which pre/intraoperative diagnostic method should be preferred. Our aim was to explore the pattern of diagnostic methods for myometrial invasion assessment in Sweden and to evaluate differences among magnetic resonance imaging (MRI), transvaginal sonography, frozen section, and gross examination in clinical practice. Material and methods This is a nationwide historical cohort study; women with endometrial cancer with data on assessment of myometrial invasion and FIGO stage I-III registered in the Swedish Quality Registry for Gynecologic Cancer (SQRGC) between 2017 and 2019 were eligible. Data on age, histology, FIGO stage, method, and results of myometrial invasion assessment, pathology results, and hospital level were collected from the SQRGC. The final assessment by the pathologist was considered the reference standard. Results In the study population of 1401 women, 32% (n = 448) had myometrial invasion of 50% of more. The methods reported for myometrial invasion assessment were transvaginal sonography in 59%, MRI in 28%, gross examination in 8% and frozen section in 5% of cases. Only minor differences were found for age and FIGO stage when comparing methods applied for myometrial invasion assessment. The sensitivity, specificity, and accuracy to find myometrial invasion of 50% or more with transvaginal sonography were 65.6%, 80.3%, and 75.8%, for MRI they were 76.9%, 71.9%, and 73.8%, for gross examination they were 71.9%, 93.6%, and 87.3%, and for frozen section they were 90.0%, 92.7%, and 92.0%, respectively. Conclusions In Sweden, the assessment of deep myometrial invasion is most often performed with transvaginal sonography, but the sensitivity is lower than for the other diagnostic methods. In clinical practice, the accuracy is moderate for transvaginal sonography and MRI. Funding Agencies|Swedish Cancer SocietySwedish Cancer Society

Introduction: Epithelial Ovarian Cancer, tubal- and peritoneal cancer (EOC) is still the major cause of death in gynecological cancer. The outcome of primary surgery is an important prognostic factor. The primary aim of this study was to study the utility of HE4 and CA125 in monitoring the response of chemotherapy during treatment and in predicting prognosis and recurrence during follow-up. We have also evaluated the role of HE4 as a predictor of the result of surgical intervention. Methods: Seventy-eight patients scheduled for chemotherapy were monitored with serum HE4 and CA125 during treatment and follow-up. In 39 patients samples for tumor markers were also obtained prior to surgical intervention. Results: Both HE4 and CA125 decreased in response to treatment. PFS and OS were strongly dependent on HE4 levels prior to start of chemotherapy with significantly prolonged PFS and OS when HE4 levels were under upper reference limit of 82 pmol/L (P=0.018 resp. P

Background: The aim of this study was to validate a translated Swedish version of the lymphoedema-specific quality of life questionnaire (LYMQOL) in a cohort of Swedish cancer patients with secondary lymphoedema of the limbs after cancer treatment. Material and methods: We recruited 102 patients with lymphoedema of the arms or legs after cancer treatment who were visiting lymphoedema therapists at the departments of oncology at the university hospitals in Linköping and Umeå. The LYMQOL questionnaires were translated forward and backward from English to Swedish. Content and face validity were evaluated. The construct validity was assessed by comparing the LYMQOL with the Short Form Health Survey (SF-36) and the perceived degree of lymphoedema of the limbs, respectively. Reliability was determined through test-retest. The internal consistency was assessed by determining Cronbach’s alpha and by factor analysis. Results: The content and face validity assessments showed that LYMQOL was an easy, clear and not too long questionnaire to use for patients with lymphoedema. Construct validity was high in both versions when compared with the SF-36. The association between the degrees of perceived lymphoedema and the LYMQOL was only significant in the domains Function and Body Image in the arm version, whereas all domains in the leg version were significant. The reliability was good for the arm version (intra-class-correlation coefficients 0.53–0.87) and very good for the leg version (intra-class-correlation coefficients 0.78–0.90). The internal consistency was acceptable to excellent, with Cronbach’s alpha values between 0.79–0.93 (arm-version) and 0.87–0.94 (leg-version). The factor analysis confirmed the usefulness of the four domains in the LYMQOL versions. Conclusions: This study confirmed the validity of the Swedish version of LYMQOL and demonstrated that LYMQOL may be a simple and useful tool for use in clinical practice and scientific contexts for evaluating QoL in patients with lymphoedema of the limbs. Funding Agencies|Swedish Cancer SocietySwedish Cancer Society [CAN 2013/620]; Linkoping University; County Council of Ostergotland

Introduction Our primary objective was to test the hypothesis that human epididymal protein 4 (HE4) and risk of ovarian malignancy index outperform the CA 125 and risk of malignancy index tests in categorizing a pelvic mass into high or low risk of malignancy in a Swedish population. Furthermore, cut-off values needed to be defined for HE4 and ROMA in premenopausal and postmenopausal women prior to their introduction to clinical practice. A third objective was to investigate the correlation between HE4 levels in serum and urine. Material and methods Women with a pelvic mass scheduled for surgery were recruited from nine hospitals in south-east Sweden. Preoperative blood samples were taken for analyzing CA125 and HE4 as well as urine samples for analyzing HE4. Results We enrolled a total of 901 women, of whom 784 were evaluable. In the premenopausal and postmenopausal groups, no significant differences were found for sensitivity, positive and negative predictive value, either for RMI vs ROMA or for CA125 vs HE4 using a fixed specificity of 75%. Cut-off values indicating malignancy were established for HE4 and ROMA in premenopausal and postmenopausal women. We found no correlation between HE4 concentration in serum and urine. Conclusions We could not confirm that ROMA had diagnostic superiority over RMI in categorizing women with a pelvic mass into low-risk or high-risk groups for malignancy in a Swedish population. We have defined cut-off values for HE4 and ROMA. The lack of correlation between serum and urine HE4 obviates the introduction of urine HE4 analysis in clinical diagnostics.

Introduction/Background Ovarian cancer is the leading cause of death due to gynecological cancers, the majority are diagnosed in advanced stages. The first Swedish national guidelines for ovarian cancer, implemented in 2012, recommended centralization to tertiary centres and primary debulking surgery (PDS) to no macroscopic residual disease (R0) as gold standard. Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) was recommended according to predefined criteria. The aim of this study was to evaluate overall survival (OS) before and after the implementation of the national guidelines. Methodology Women diagnosed with epithelial ovarian/fallopian tube cancers FIGO stages III-IV and registered in the population-based nationwide Swedish Quality Registry for Gynecologic Cancer (SQRGC) between 2008–2016 were eligible excluding those diagnosed in 2012. Comparisons of OS before and after the implementation, 2008–2011vs 2013–2016, were performed in the cohorts of PDS, NACT+IDS and the total cohort. Overall survival (OS) was assessed by the Kaplan-Meier method and log rank test. The validity of SQRGC has previously been reported.1 Results In total, 3196 women were included in the study (n=1577 before and n=1619 after the implemented guidelines). PDS was performed in 937 (59%) women before and in 1038 (64%) women after the guidelines were introduced. During the same time periods the proportion of complete cytoreduction to R0 increased from 33% to 58%. In the PDS cohort, 5-year OS rate increased significantly from 29% (95% CI: 26–32%) to 40% (95% CI: 36–44%). In the NACT+IDS cohort, no significant difference in OS was observed. In the total cohort, 5-year OS increased significantly from 25% (95% CI: 23–28%) before to 34% (95% CI: 31–37%) after the introduction of national guidelines. Conclusion Centralization and implementation of the first Swedish national guidelines significantly improved 5-year overall survival in the total cohort of stages III-IV epithelial ovarian cancer. Disclosure Nothing to disclose.

Introduction / Background Vulvar cancer is a rare disease where treatment guidelines are mostly based on results from retrospective studies with small, heterogeneous materials. There are no data published from the Swedish population. Methodology A population-based nationwide study on all women treated for vulvar carcinoma included in the Swedish Quality Registry for Gynecologic Cancer (SQRGC) between 2012–2016. Relative survival (RS) was estimated using the Ederer II method. Simple and multivariable analyses were estimated by Poisson regression models. Results 657 women with squamous cell carcinoma were included in the study. The distribution by FIGO stage for stage IA, IB, II, III, IVA and IVB were18%, 37%, 12%, 19%, 5% and 3% respectively. The distribution by age at diagnosis for age groups 20–59, 60–69, 70–79 and 80–100 years were 20%, 20%, 27%, 33% respectively. 528 patients (80%) had primary surgery, 377 (57%) had surgery alone, 149 (23%) had adjuvant treatment (7% chemoradiation and 16% radiotherapy alone) and 110 (17%) received primary (chemo)radiation (6% chemoradiation and 11% radiotherapy alone). In 84% the treatment intention was curative, but only in 63% in the oldest age group (80–100). The overall 5-year RS was 75% and by stage (I, II, III and IV) it was 90%, 73%, 66% and 50% respectively. The 5-year RS per age groups (20–59, 60–69, 70–79 and 80–100 years) was 90%, 88%, 81% and 61% respectively. In the multivariate analysis there was a significant negative correlation between RS and FIGO stage (p Conclusion This is the first nation-wide populationbased study reporting on treatment patterns and relative survival in vulvar carcinoma in Sweden with data from SQRGC. The elderly patients more frequently received treatment with palliative intention and had significantly worse relative survival compared to younger patients. Disclosure Nothing to disclose.

Introduction/Background The aim of this study was to evaluate the impact of lymphovascular space invasion (LVSI) on the risk of lymph node metastases and survival in endometrioid endometrial adenocarcinoma. Methodology This is a retrospective cohort study based on prospectively recorded data. Patients with endometrioid adenocarcinoma registered in the Swedish Quality Registry for Gynecologic Cancer 2010–2017 with FIGO stages I-III and verified nodal status were identified (n=1587). LVSI together with DNA ploidy, FIGO grade, myometrial invasion and age, were included in multivariable regression analyses with lymph node metastases as the dependent variable. Associations between the risk factors and overall and relative survival were included in multivariable models. Estimates of risk ratios (RR), hazard ratios (HR), excess mortality rate ratios (EMR), and 95% confidence intervals (95% CI) were calculated. Results The presence of LVSI presented the strongest association with lymph node metastases (RR=5.46, CI 3.69–8.07, p Conclusion This large nationwide study identified LVSI as the strongest independent risk factor for lymph node metastases and decreased survival in patients with endometrioid adenocarcinomas. Moreover, decreased overall survival was also seen in patients with LVSI-positive tumors and negative lymph nodes, indicating that hematogenous dissemination might also be important. Disclosure Nothing to disclose.

Introduction/Background Development of lymphoedema after treatment of endometrial cancer (EC), is still an unexplored area. The aim of this study was to determine the incidence and clinical presentation of lymphoedema of the legs after surgery for EC including pelvic and para-aortic lymphadenectomy one year postoperatively. Methodology An observational multicentre study conducted in 14 centres in Sweden recruited 262 women. 130 women with high-risk early-stage EC underwent surgery including pelvic and para-aortic lymphadenectomy and 132 with low-risk EC had surgery without lymphadenectomy. Systematic leg circumference measurements enabling calculation of leg volumes were performed on four occasions; preoperatively, 4–6 weeks, 6 months, and 1 year postoperatively. Clinical evaluation of lymphoedema by a lymph therapist was conducted on the same occasion. A 10% increase in volume from baseline was categorised as lymphoedema. Results The incidence of lymphoedema increased from 1.8% at the 4–6 weeks assessment to 15% one year postoperatively when lymphadenectomy had been performed. The corresponding figures in the non-lymphadenectomy group were 1.7% to 9.3%. There was no significant difference in incidence on any occasion between the lymphadenectomy and non-lymphadenectomy group (table 1). In women with more than 10% increase in leg volume, 60.7% was objectively clinically graded as normal by lymph therapists. The distribution of the occurrence of lymphoedema differed significantly between those who had less than 10% increase in leg volume and those who had ≥ 10% (table 2). Conclusion The incidence of lymphoedema in legs caused by lymphadenectomy after surgery for EC seemed to be low when assessed by leg volume measurements. Clinically grading of lymphoedema seemed to be underestimated by lymph therapists especially in those who had ≥ 10% increase in leg volume. This raise concerns about the methods of determining and reporting lymphoedema. Disclosure Nothing to disclose.

Background: The International Federation of Gynecology and Obstetrics (FIGO) ovarian cancer staging system includes no sub-stage for lymph nodes (LN) as only distant disease manifestation. We explore the prognostic implication of LN as only stage IV classifier in serous ovarian cancer. Method: This is a nation-wide, population-based study on 551 women with serous stage IV cancers diagnosed between 2009–2014. We compare overall survival (OS) in women with LN as only distant metastatic site to those with pleural metastases only and to patients with other/multiple stage IV manifestations. Cox regression models were used for uni- and multivariable estimations. Results: Of 551stage IV cases, distant metastatic site was registered in 433. Median OS for women with LN (n = 51) was 41.4 months, compared to 25.2 and 26.8 months for patients with pleural (n = 195) or other/multiple (n = 187) distant metastases (p = .0007). The corresponding five-year survival rates were 32, 11 and 22%, respectively. Multivariable analyzes confirmed shorter survival for women with pleural (HR 2.99, p = .001) or other/multiple distant sites (HR 2.67, p = .007), as compared to LN cases. LN only patients lived 9.1 months longer after primary than after interval surgery, but this difference was not significant (p = .245). Conclusion: Women with stage IV serous ovarian cancer having lymph nodes as only distant metastatic site live longer than other stage IV patients. (Less)

The aim of the study was to determine survival outcome in patients with serous cancer in the ovary, fallopian tube, peritoneum and of undesignated origin.Nation-wide population-based study of women≥18years with histologically verified non-uterine serous cancer, included in the Swedish Quality Registry for primary cancer of the ovary, fallopian tube and peritoneum diagnosed 2009-2013. Relative survival (RS) was estimated using the Ederer II method. Simple and multivariable analyses were estimated by Poisson regression models.Of 5627 women identified, 1246 (22%) had borderline tumors and 4381 had malignant tumors. In total, 2359 women had serous cancer; 71% originated in the ovary (OC), 9% in the fallopian tube (FTC), 9% in the peritoneum (PPC) and 11% at an undesignated primary site (UPS). Estimated RS at 5-years was 37%; for FTC 54%, 40% for OC, 34% for PPC and 13% for UPS. In multivariable regression analyses restricted to women who had undergone primary or interval debulking surgery for OC, FTC and PPC, site of origin was not independently associated with survival. Significant associations with worse survival were found for advanced stages (RR 2.63, P0.001), moderate (RR 1.90, P0.047) and poor differentiation (RR 2.20, P0.009), neoadjuvant chemotherapy (RR1.33, P0.022), residual tumor (RR 2.65, P0.001) and platinum single (2.34, P0.001) compared to platinum combination chemotherapy.Survival was poorer for serous cancer at UPS than for ovarian, fallopian tube and peritoneal cancer. Serous cancer at UPS needs to be addressed when reporting and comparing survival rates of ovarian cancer.

Aim of the study: Endocrine treatment (ET) is an alternative as salvage therapy in epithelial ovarian cancer (EOC) but the usage in routine care is unknown. We evaluated the treatment patterns and outcome of patients receiving ET for EOC in the Southeast medical region in Sweden. Method: Patients were identified through the population-based Southeast Quality Registry for gynaecological cancer. Inclusion criteria were: age ≥18 years, histologically verified EOC diagnosed 2000–2013, ET for ≥4 weeks. Coverage compared with the Swedish National Cancer Registry was 100%. Data extracted from medical records was collected by means of a study-specific Case Report Form. Last date of follow-up was February 1st, 2018. All statistics were descriptive. Results: Altogether 248 (18%) of 1414 patients were treated with ET. Most (49%) had received only one, and 34% two previous lines of chemotherapy. Time from last chemotherapy to ET was 4 months, range 0–55months. The reason for initiating ET was tumor progression (66%), chemotherapy related toxicity (29%) and maintenance (4%). Tamoxifen was prescribed in 94% of cases. Best response was partial (< 5%) and stable disease (50%). No patient had a complete response. 194 (78%) patients received subsequent chemotherapy, of these 27% had 3–7 lines of chemotherapy. Duration of ET was a median 4 months (range 1–80 months). Median time from ET to subsequent chemotherapy was 5 months (range 0–79). The median overall survival was 45 months (range 9–173). Conclusion: In the Southeast region of Sweden, endocrine treatment for EOC was prescribed inconsistently and in various settings, usually initiated by a rising CA-125 level. Poorer documentation and irregular tumor response assessment were observed for endocrine treatment compared to chemotherapy.

Aim: The aim of this study is to evaluate the quality of data on endometrial (EC) and ovarian, fallopian tube, peritoneal, abdominal or pelvic cancers (OC) registered in the Swedish Quality Register of Gynecologic Cancer (SQRGC). Method: A random sample of 500 patients was identified in the SQRGC and their medical charts were reviewed for re-abstraction of 31 selected core variables by an independent validator. The data in the SQRGC and the re-abstracted data were compared. The data were collected from 25 hospitals evenly distributed throughout Sweden. The main outcomes were comparability, timeliness, completeness and validity. Coverage was compared with the National Cancer Register (NCR). Timeliness was defined as the speed of registration i.e. when patients were registered in the SQRGC relative to date of diagnosis. Internationally accepted coding systems for stage, grading and histologic type were used ensuring a high degree of comparability. Correlations were estimated using Pearson’s correlation coefficient and Cohen´s kappa coefficient. Results: The completeness was 95%. The timeliness was 88–91% within 12 months of diagnosis. The median degree of agreement between re-abstracted data and data in the SQRGC was 82.1%, with a median kappa value of 0.73 for ordinate variables and a median Pearson’s correlation coefficient of 0.96. The agreements for the type of surgery were 76% (95% CI 70–81%; kappa 0.49) and type of primary treatment 90% (95% CI 87–94%; kappa 0.85) in OC and in EC 88% (95% CI 84–93%; kappa 0.84). The agreements for the FIGO stage were in OC and EC 74% (95% CI 68–80%; kappa 0.69) and 87% (95% CI 82–91%; kappa 0.79), respectively. Conclusions: The data in the Swedish Quality Register for Gynecologic Cancer are of adequate quality in order to be used as a basis for research and to evaluate possible differences in treatment, lead times and treatment results.

The role of lymphadenectomy in the management of early endometrial cancer remains controversial. In the recent ESMO-ESGO-ESTRO guidelines, lymphadenectomy is recommended for patients with endometrioid adenocarcinoma Grade 3 with deep myometrial invasion, but complete agreement was not achieved. In Sweden, DNA aneuploidy has been included as a high-risk factor. The aim of our study was to evaluate the impact of tumor histology, FIGO grade, DNA ploidy and myometrial invasion (MI) on occurrence of lymph node metastasis (LNM) in patients with endometrial cancer. The study design is a retrospective cohort study based on prospectively recorded register data. Endometrial cancer patients registered in the Swedish Quality Registry for Gynecologic Cancer 2010-2015 with FIGO Stages I-III and verified nodal status were included. Data on DNA ploidy, histology, FIGO grade and MI were included in multivariable log-binomial regression analyses with LNM as dependent variable. 1,165 cases fulfilled the inclusion criteria. The multivariable analyses revealed increased risk of LNM in patients with tumors with MI ≥ 50% (risk ratio [RR] = 4.1; 95% confidence interval [CI] 3.0-5.6), nonendometrioid compared to endometrioid histology (RR 1.8; CI 1.4-2.4) and FIGO Grade 3 compared to Grade 1-2 tumors (RR 1.5; CI 1.1-2.0). No statistically significant association between DNA ploidy status and LNM was detected. This population-based, nation-wide study in women with endometrial cancer confirms a strong association between MI ≥ 50%, nonendometrioid histology and FIGO Grade 3, respectively, and LNM. DNA ploidy should not be included in the preoperative decision making of removing nodes or not.

Endometrial cancer is the most common gynecological cancer in developed countries and the observed rise in incidence is mainly caused by life style factors including obesity and diabetes. The management of the disease has undergone major changes in the past 5-10 years. Morphological and genetic studies constitute the basis for the new classification of the disease, and data emerging from the Cancer Genome Atlas suggest that genomic patterns differ within the two types of endometrial cancer. The prognosis seems to be related to occult lymphatic spread but the role of lymphadenectomy is heavily debated. Development of novel biomarkers, sentinel lymph node technique and refined radiological methods may reduce the need of comprehensive staging in the future. The results from the Cancer Genome Atlas suggest that women with endometrial cancer may benefit from »targeted therapies« in the evolving era of personalised medicine.

Coals with similar thermal maturity and from the same deposit normally show a considerable range in petroleum generation potential as measured by the Hydrogen Index (HI). This variation may partly be related to variations in plant input to the precursor mires and organic matter preservation. It is widely accepted that some Cenozoic coals and coaly sediments have the potential to generate oil, which is related to the coal's paraffinicity. Coal paraffinicity is not readily reflected in the bulk HI. In this paper, the relationships between measured HI and coal composition, coal kerogen paraffinicity and floral input have been investigated in detail for three sets of coals from Colombia/Venezuela, Indonesia, and Vietnam. The samples in each coal set are largely of iso-rank. The petroleum generation potential was determined by Rock–Eval pyrolysis. Reflected light microscopy was used to analyse the organic matter (maceral) composition and the thermal maturity was determined by vitrinite reflectance (VR) measurements. The botanical affinity of pollen and spores was analysed by palynology. Coal kerogen paraffinicity was determined by ruthenium tetroxide-catalysed oxidation (RTCO) followed by chain length analysis and quantification (mg/g TOC) of the liberated aliphatic chains. The coals are dominated by huminite, in particular detrohuminite. Only the Vietnamese coals are rich in microscopically visible liptinite. The pollen and spores suggest that the coals were derived principally fromcomplex angiospermmire vegetations, with subordinate proportions of ferns that generally grew in a subtropical to tropical climate.Measured HI values vary considerably, but for the majority of the coals the values lie between approximately 200 mg HC/g TOC and 300 mg HC/g TOC. Aliphatics yielding monocarboxylic acids dominate in the coal kerogen, whereas aliphatics yielding dicarboxylic acids are secondary. However, the dicarboxylic acids show that crosslinking long-chain aliphatics are present in the kerogen structure. All studied coals are paraffinicwith C19–35 aliphatic chains in the kerogen, and the aliphatics in the range C25–35 show that the coals may have the potential to generate waxy crude oil. The Indonesian coals are richest in long-chain aliphatics and are thus potentially most oil-prone. Multivariate statistical analysis shows that for the present three sample sets variations in HI are positively correlated to different combinations of the C10+ aliphatic chains in the kerogen and the amount of detrohuminite + liptodetrinite and liptinite. Furthermore, part of the HI can be attributed to hydrogen in compounds with less than 10 carbon atoms, which is the lowest alkyl detected by RTCO analysis, thus representing a potential for generation of gas and light liquid hydrocarbons. The measured HI is therefore not always a good indicator for humic coal's potential to source waxy oil. Vegetational influence (palynology) on the variation of HI cannot be shown within the investigated span of variance and for the present coals. However, it is likely that some of the range in measured HI values is caused by floral vairiations not revealed by the palynological analysis and to variations in the preservation of the organic matter. (Less)

P-glycoprotein (P-gp), encoded by the ABCB1 gene, confers multi-drug resistance to a variety of antineoplastic agents, for example, paclitaxel. Recently, the G1199T/A polymorphism in the ABCB1 gene was shown to be important for the function of P-gp as well as for the resistance to several chemotherapeutic agents in vitro. We analyzed the allelic distribution of the G1199T/A and other polymorphisms in exons 11 and 12 of the ABCB1 gene in ovarian cancer patients treated with paclitaxel and carboplatin in order to evaluate their predictive value in vivo. The SNPs C1236T, G1199T/A, and A1308G were determined using Pyrosequencing in 51 patients with advanced ovarian cancer and correlated to the progression free survival. The G1199T/A SNP was found to affect the progression free survival. Although only two heterozygous (G/A) patients were found their mean progression free survival was only 2 months as compared to 19 months for the wild-type patients. This is in accordance with the higher resistance for the 1199A genetic variant found in vitro. Genotyping of the ABCB1 gene may be important for determining the tumor resistance to paclitaxel and provide useful information for individualized therapy. This is a pre-peer-reviewed version of: Henrik Green, Peter Söderkvist, Per Rosenberg, Grörgy Horvath and Curt Peterson, ABCB1 G1199A Polymorphism and Ovarian Cancer Response to Paclitaxel, 2008, Journal of Pharmaceutical Sciences, (97), 6, 2045-2048. which is published in final form at: http://dx.doi.org/10.1002/jps.21169 Copyright: John Wiley and Sons, Ltd http://eu.wiley.com/WileyCDA/Brand/id-35.html

Detailed Fourier Transform Infrared Spectroscopy (FTIR), chemical oxidation and reduction, and multivariate regression analysis have been applied to gain insight into the relative proportions and types of oxygen functional groups in coals of varying rank and in alginite-rich organic matter in oil shales and marine shale. FTIR spectra of demineralised and non-demineralised coals with a vitrinite reflectance below ~ 0.4% R o revealed that the spectra are significantly different in the carbonyl region, probably due to the configuration of weak conjugated oxygen bonds into a more rigid form during demineralisation. In coals and lignin, the relative FTIR response from oxygen groups occurs in the order hydroxyl ≥ ether > ketone/ester > carboxyl > quinone, where ester groups are related to cutinite and sporinite. A pronounced decrease in oxygen content occurs from ~ 0.43–0.50% R o , but the oxygen groups show different evolutionary trends during initial thermal maturation: (i) carboxyl group absorption increases significantly up to lignite/subbituminous C rank, followed by a rapid decrease and disappearance at ∼ 0.45% R o , (ii) ketone (carbonyl) group absorption is prominent at maturities R o , but at higher maturities the response declines gradually, (iii) ether group absorption increases to a maximum at ∼ 0.45–0.50% R o , from where it decreases gradually, (iv) at atomic O/C ratios > 0.2 (approximately R o ) hydroxyl group (principally phenolic) absorption is highly variable, but at increasing thermal maturity significant dehydroxylation occurs. Elimination of oxygen groups in the coaly organic matter thus occurs in the order quinone, carboxyl, ketone/ester, hydroxyl and ether. Both ether and hydroxyl are still present at an O/C ratio of 0.05. Oxygen in the alginite-dominated kerogen of the shales is entirely bound as ether, carbonyl (mainly ester) and hydroxyl. The presence of ether agrees with the dominant role of ether bonds cross-linking long-chain n -alkanes in algaenan. Hydroxyl may be related to phenolic units in for example Botryococcus algae. The relative FTIR response from oxygen groups in kukersite is ether > carbonyl (ketone) > hydroxyl, which generally reflects the structural models proposed for kukersite. Oxygen groups in the coals can overall be correlated to the least-altered huminite macerals textinite, texto-ulminite, and densinite, or to the associated cutinite and sporinite, whereas the variation of the oxygen group composition in the studied shales seems to be controlled by thermal maturity. Hydrogen Index (HI) values of chemically oxidised and/or reduced coal samples do not provide an unequivocal answer to whether HI values of immature coals are underestimated. Incorporation of carboxyl groups into the original coal kerogen does not produce a more immature coal manifested by decreased HI values.

Purpose: P-glycoprotein, encoded by the mdr-1 gene, confers multidrug resistance to a variety of antineoplastic agents, e.g., paclitaxel. Recently, different polymorphisms in the mdr-1 gene have been identified and their consequences for the function of P-glycoprotein, as well as for the treatment response to P-glycoprotein substrates, are being clarified. We analyzed the allelic frequencies at polymorphic sites G2677T/A and C3435T in ovarian cancer patients with good or poor response to treatment with paclitaxel in combination with carboplatin in order to evaluate their predictive values. Experimental Design: Fifty-three patients were included in the study; 28 of them had been relapse-free for at least 1 year and 25 had progressive disease or relapsed within 12 months. A reference material consisting of 200 individuals was also analyzed. The genotypes of each single nucleotide polymorphism (SNP) were determined using Pyrosequencing. Results: The G2677T/A SNP was found to significantly correlate with treatment outcome. The probability of responding to paclitaxel treatment was higher in homozygously mutated patients (T/T or T/A; Fisher's exact test; P < 0.05). The frequency of the T or A alleles was also higher in the group of patients who had a good response (P < 0.05). There was also a dose-dependent influence of the number of mutated alleles on the response to paclitaxel treatment (Χ2 test for linear-by-linear association; P = 0.03). However, the C3435T SNP was not found to correlate to treatment outcome. Conclusions: The mdr-1 polymorphism G2677T/A in exon 21 correlates with the paclitaxel response in ovarian cancer and may be important for the function of P-glycoprotein and resistance to paclitaxel and provide useful information for individualized therapy. Original Publication:Henrik Green, Peter Söderkvist, Per Rosenberg, György Horvath and Curt Peterson, mdr-1 single nucleotide polymorphisms in ovarian cancer tissue – G2677T/A correlates with response to paclitaxel chemotherapy, 2006, Clinical Cancer Research, (12), 3 pt 1, 854-859.http://dx.doi.org/10.1158/1078-0432.CCR-05-0950Copyright: American Association for Cancer Research, Inc.http://www.aacr.org/

The spatial variability in the mineralisation rate of linuron [N-(3,4-dichlorophenyl)-N'-methoxy-N'-methylurea] was studied within a previously treated Danish agricultural field by sampling soils from eleven different plots randomly distributed across an area of 20 x 20 m. The soils were characterised with respect to different abiotic and biotic properties including moisture content, organic matter content, pH, nutrient content, bacterial biomass, potential for mineralisation of MCPA [(4-chloro-2-methylphenoxy)acetic acid] and linuron. Five soils had a potential for mineralisation of linuron, with 5-15% of the added [ring-U-14C]linuron metabolised to 14CO2 within 60 days at 10 degrees C, while no extensive mineralisation of linuron was observed in the six remaining soils within this period. A TLC analysis of the methanol-extractable residues showed no development of 14C-labelled metabolites from linuron in any of the samples. Multivariate analysis was conducted to elucidate relationships between the intrinsic properties of single soil samples and initial rate of linuron mineralisation. The analysis indicated that important soil parameters in determining the spatial heterogeneity included the C(total)/N(total) ratio, pH and the water-extractable potassium contents, with the first of these highly negatively correlated and the last two highly positively correlated to the initial linuron mineralisation rate. This study shows that enhanced biodegradation of linuron may develop with successive field treatments, but that considerable in-field spatial heterogeneity in the degradation rate still exists. Combined with a parallel enrichment study focused on the underlying microbial processes, the present results suggest that intrinsic soil properties affect the linuron-metabolising bacterial population and thereby determine the spatial variability in the linuron mineralisation activity.

The current work investigates the performance of petroleum coke (PC) as a blended fuel under pulverized-fuel combustion conditions. Three full-scale combustion experiments were carried out: a pure Carboniferous, high volatile bituminous coal and two blends of this coal with different proportions of PC. The samples studied included feed fuels and blends, fly ashes, chars taken at different positions of the combustion chamber, and chars prepared in a drop tube reactor to test the performance of the individual fuels. The addition of PC led to a substantial increase in the unburned carbon of the fly ashes. The petrographic analysis of the granulometric fractions of the fuels revealed that this increase cannot be attributed to an enrichment in coke of the coarser fractions, as reported in the literature. On the contrary, the finer fraction contained slightly more coke than the raw blend. The petrographic analysis of the chars collected with the suction probe and the fly ashes showed that the two blended fuels...

In Denmark the supply of drinking water is based almost solely on groundwater. During the past few decades Danish groundwater monitoring has encountered numerous instances of pollution with pesticides and their metabolites (GEUS 2003a). As a result, some hundreds of abstraction wells out of about 8000 in general water supply have been closed. With this background, there is a particular concern for reducing the leaching of pesticides into the groundwater. In the present study an approach for identification of areas potentially prone to pesticide leaching is described. The potential risk of leaching of pesticides from agricultural areas into groundwater is minimised through a procedure of approval; however, some leaching still occurs (GEUS 2003b). The Danish counties are therefore obliged to identify areas where there is a particular risk of pesticide leaching, and where restrictions in use of pesticides may be introduced to reduce the risk (Miljøstyrelsen 2000). The Geological Survey of Denmark and Greenland (GEUS) and the Danish Institute of Agricultural Sciences (DJF) have carried out a project, focusing on sandy agricultural areas, that attempts to establish the necessary background knowledge for identifying areas particularly prone to pesticide leaching. The project aims to distinguish vulnerable and less vulnerable areas, both locally and nationwide, in a cost-effective way.

An increasing number of herbicides are found in our groundwater environments. This underlines the need for examining the effects of herbicide exposure on the indigenous groundwater microbial communities, as microbial degradation is the major process responsible for the complete removal of most contaminants. We examined the effect of in situ exposure to realistic low concentrations of herbicides on the microbial diversity and community structure of sub-surface sediments from a shallow aquifer near Vejen (Denmark). Three different community analyses were performed: colony morphology typing, sole-carbon source utilisation in Biolog EcoPlates, and denaturing gradient gel electrophoresis. Cluster analysis demonstrated that the microbial communities of those aquifer sediments that acclimated to the herbicide exposure also had similar community structure. This observation was concurrent for all three community analyses. In contrast, no significant effect was found on the bacterial diversity, except for the culturable fraction where a significantly increased richness and Shannon index was found in the herbicide acclimated sediments. The results of this study show that in situ exposure of sub-surface aquifers to realistic low concentrations of herbicides may alter the overall structure of a natural bacterial community, although significant effects on the genetic diversity and carbon substrate usage cannot be detected. The observed impact was probably due to indirect effects. In future investigations, the inclusion of methods that specifically detect relevant microbial sub-populations and functional genes is therefore recommended.

TPS5611 Background: Endometrial cancer (EC) patients with advanced and recurrent disease relapse despite treatment with combination chemotherapy and have a short progression-free survival (PFS). With the emerging clinical data on anti-angiogenic agents and with promising results of nintedanib in ovarian cancer, it is apparent to explore its role in EC. Nintedanib is a potent, orally available triple receptor tyrosine kinase inhibitor targeting VEGFR 1-3, PDGFR α/β, and FGFR 1-3. This placebo-controlled, multicenter, two-arm, phase 2 trial compares nintedanib versus placebo as concomitant and maintenance therapy in combination with chemotherapy in patients with advanced or recurrent EC. Methods: The primary objective of this trial is to evaluate efficacy of nintedanib against placebo in combination with chemotherapy, defined by PFS. Key eligibility criteria include: histologically confirmed EC, stage 3C 2 or 4 A & B or relapsed after adjuvant therapy for stage 1-3 disease; prior surgery; adjuvant chemotherapy; radiation therapy; hormonal therapy are permitted; measurable/non-measurable disease. 148 patients will be randomized 1:1 to receive nintedanib 200mg twice daily or placebo days 2-21 during chemotherapy (six cycles of Carboplatin (AUC5) and paclitaxel (175mg/m2) every 21 days) and continuously in maintenance phase. Nintedanib/placebo is continued until disease progression, unacceptable toxicity, or withdrawal. Secondary endpoints include PFS in sub-populations, PFS2, disease specific survival, time to first subsequent therapy, time to second subsequent therapy, overall survival, objective response, disease control rate, patient reported outcoms (assessed via EORTC QLQ-C30 and EORTC QLQ-EN24) and safety. Trial is enrolling patients. The following cooperative groups are participating: NSGO (DK, FIN, SWE, NOR), NOGGO (GER), BGOG (BEL), & GINECO (FRA). Clinical trial information: NCT02730416.

5534 Background: Current therapies for recurrent OC include chemotherapy (C) or bevacizumab (B) in combination with C followed by continuous B, which showed improved progression-free survival (PFS) compared with C followed by placebo (P) over 3.4 months (GOG-0213) or 4.0 months (OCEANS). Potential impact of B on effectiveness of subsequent therapies has not been described. Niraparib (N) is a highly selective PARP 1/2 inhibitor (PARPi). In preclinical studies, N concentrates in the tumor; N showed significantly longer PFS vs P in patients (pts) with recurrent OC following complete/partial response (CR/PR) to platinum based chemotherapy (Plat) in the randomized, controlled, double-blind phase 3 ENGOT-OV16/NOVA trial. We report the long term effect of treatment with N and its impact on subsequent therapy. Methods: Eligibility for NOVA included recurrent OC, fallopian tube or peritoneal cancer, no prior PARPi use, and completion of ≥2 prior courses of Plat, with a CR or PR following the most recent Plat. Pts were enrolled into g BRCAmut or non-g BRCAmut cohorts based on BRCA mutation test results and randomized 2:1 to receive N 300 mg qd or P until progression of disease or death (PD). Tumors were tested for homologous recombination deficiency (HRD). Estimated probability of PD in each cohort at 12, 18 and 24 months post randomization, representing ~18, 24 and 30 months post chemotherapy initiation, was determined; the difference between PFS2 and PFS (PFS2-PFS) was evaluated in all randomized pts. Results: 203 pts were randomized in the g BRCAmut cohort. Of 350 pts randomized in the non-g BRCAmut cohort, 162 had HRD+ and 134 HRD− tumors. Estimated probability (product-limit method) of PFS at 12, 18 and 24 months was greater in the niraparib arm than in the placebo arm in each cohort and subgroup at each time interval. Probabilities (95% CI) at 24 months for niraparib vs control were 0.42 (0.30, 0.55) vs 0.16 (0.07, 0.28) (gBRCAmut) and 0.27 (0.19, 0.35) vs 0.12 (0.06, 0.21) (non-gBRCAmut). PFS2-PFS was similar in the 2 treatment arms in the combined cohorts (HR 1.02, 95% CI 0.765, 1.349). Conclusions: Niraparib provided long term benefit in pts with recurrent OC irrespective of g BRCAmut or HRD status, and no decrement in the benefit of subsequent therapy was observed. Clinical trial information: NCT01847274.

TPS5605 Background: Olaparib (Lynparza) is an oral PARP inhibitor indicated in the EU for the maintenance treatment of patients (pts) with platinum-sensitive relapsed BRCA-mutated high grade serous ovarian cancer (HGSOC). Bevacizumab is an anti-VEGF monoclonal antibody indicated in the EU in first line or relapse for the treatment of OC in combination with specific chemotherapeutic agents. Bevacizumab treatment is associated with increasing hypoxia-induced homologous recombination repair deficiencies in tumor cells, and is hypothesized to increase ovarian tumor sensitivity to olaparib. Methods: PAOLA-1 (ENGOT-ov25) is a randomized, placebo-controlled trial evaluating the efficacy and safety of olaparib (tablet formulation) in pts with advanced HGSOC receiving bevacizumab maintenance therapy. Eligible pts are those in complete or partial response following first-line platinum chemotherapy plus bevacizumab, and for whom bevacizumab maintenance therapy is planned. Approximately 762 European and 24 Japanese pts will be randomized 2:1 to olaparib 300 mg twice daily or placebo for up to 24 months. All pts will receive standard maintenance care of bevacizumab (15 mg/kg every three weeks) for up to 15 months. Primary objective: PFS1 according to RECIST 1.1 Secondary objectives: PFS2, OS, Safety, PRO/QoL, TFST, TSST All pts will undergo tumor BRCA testing prior to randomization. Central BRCA testing (tumor) will be performed in five screening platforms in France. Tumor BRCA test results have to be available within two months of sample provision. PFS will be evaluated using a log-rank test stratified by response to first-line treatment and BRCA mutation status. Treatment effect hazard ratio of 0.7 is expected and final PFS1 analysis will be performed after 372 events. The first pt from eight ENGOT groups plus Japan (10 participating countries) was randomized in July 2015. As of 31 January 2017, 549 pts have been randomized. The median period between the provision of a tumor sample and returned BRCA test result is 40 days. Accrual is expected to be complete before July 2017. Clinical trial information: NCT02477644.

Malignant ascites is a common phenomenon in cancer patients. It poses a great challenge to the clinician, because of limited treatment options and strong impairment of the quality of life of the often palliative patients. The SECIMAS study investigated the feasibility of a re-challenge with four catumaxomab intraperitoneal infusions in patients who had already received a first cycle of four infusions in the phase III CASIMAS study, which compared catumaxomab with and without prednisolone premedication. The primary endpoint was the proportion of patients who received at least three catumaxomab infusions. Secondary endpoints included a composite safety score (CSS) summarising the worst grades for the main catumaxomab-related adverse events (pyrexia, nausea, vomiting and abdominal pain), safety, efficacy and the occurrence of anti-drug antibodies (ADAs). Eight of nine screened patients received a second catumaxomab cycle. Compliance with a catumaxomab re-challenge was high: all eight patients (100%) received all four infusions. The median CSS was 3.0 versus 3.4 in CASIMAS. The tolerability profile of the second catumaxomab cycle was comparable to that of the first cycle. Median puncture-free survival (48 days) and overall survival (407 days) were longer than in CASIMAS (35 and 103 days, respectively), although median time to next puncture was shorter (60 vs. 97 days). Of six patients sampled, all were ADA positive at screening and remained ADA positive until the end of the study. The presence of ADAs did not affect catumaxomab's safety or efficacy. The CSS and tolerability profile for catumaxomab in SECIMAS were comparable to those in CASIMAS. The majority of patients benefitted from a second cycle of catumaxomab. A re-challenge seems to be feasible and safe for selected patients with recurrent malignant ascites due to carcinoma after a first cycle of catumaxomab.

Background: We evaluated the efficacy and safety of the aromatase inhibitor exemestane in patients with advanced, persistent or recurrent endometrial carcinoma.Methods: We performed an open-label one-arm, two-stage, phase II study of 25 mg of oral exemestane in 51 patients with advanced (FIGO stage III-IV) or relapsed endometrioid endometrial cancer. Patients were stratified into subsets of estrogen receptor (ER) positive and ER negative patients.Results: Recruitment to the ER negative group was stopped prematurely after 12 patients due to slow accrual. In the ER positive patients, we observed an overall response rate of 10%, and a lack of progression after 6 months in 35% of the patients. No responses were registered in the ER negative patients, and all had progressive disease within 6 months. For the total group of patients, the median progression free survival (PFS) was 3.1 months (95% CI: 2.0-4.1). In the ER positive patients the median PFS was 3.8 months (95% CI: 0.7-6.9) and in the ER negative patients it was 2.6 months (95% CI: 2.1-3-1). In the ER positive patients the median overall survival (OS) time was 13.3 months (95% CI: 7.7-18.9), in the ER negative patients the corresponding numbers were 6.1 months (95% CI: 4.1-8.2). Treatment with exemestane was well tolerated.Conclusion: Treatment of estrogen positive advanced or recurrent endometrial cancer with exemestane, an aromatase inhibitor, resulted in a response rate of 10% and lack of progression after 6 months in 35% of the patients. Trial registration: Trial identification number (Clinical Trials.gov): NCT01965080.Nordic Society of Gynecological Oncology: NSGO-EC-0302.EudraCT number: 2004-001103-35.

This two-arm, randomised, multicentre, openlabel, phase IIIb study investigated the safety and efficacy of a 3-h catumaxomab infusion with/without prednisolone premedication to reduce catumaxomab-related adverse events. Patients with malignant ascites due to epithelial cancer received four 3-h intraperitoneal catumaxomab infusions with/without intravenous prednisolone (25 mg) premedication before each infusion. The primary safety endpoint was a composite safety score calculated from the incidence and intensity of the most frequent catumaxomab-related adverse events (pyrexia, nausea, vomiting and abdominal pain). Puncture-free survival (PuFS) was a coprimary endpoint. Time to next puncture (TTPu) and overall survival (OS) were secondary endpoints. Prednisolone premedication did not result in a significant reduction in the main catumaxomab-related adverse events. The mean composite safety score was comparable in both arms (catumaxomab plus prednisolone, 4.1; catumaxomab, 3.8; p = 0.383). Median PuFS (30 vs. 37 days) and TTPu (78 vs. 102 days) were shorter in the catumaxomab plus prednisolone arm than in the catumaxomab arm, but the differences were not statistically significant (p = 0.402 and 0.599, respectively). Median OS was longer in the catumaxomab plus prednisolone arm than in the catumaxomab arm (124 vs. 86 days), but the difference was not statistically significant (p = 0.186). The superiority of catumaxomab plus prednisolone versus catumaxomab alone could not be proven for the primary endpoint. Prednisolone did not result in a significant reduction in the main catumaxomab-related adverse events. The study confirms the safety and efficacy of catumaxomab administered as four 3-h intraperitoneal infusions for the treatment of malignant ascites. © Springer Science+Business Media 2014.

The outcrop of Oligocene age at Dong Ho, northern Vietnam, may constitute an immature analogue to offshore terrestrial source rocks in the greater Song Hong Basin. The outcrop includes an interval with two source rocks: (1) highly oil-prone carbonaceous mudstones containing kerogen types IIA and IIA/I, and with TOC contents from 6.48 to 16.89 wt%, and HI values from 472 to 690; and (2) oilprone humic coals (kerogen type III) with HI values from 200 to 242. The mudstones were deposited in oxygen-deficient lakes, which on occasion were subject to marine influence, and the coals accumulated in freshwater peat-forming mires. The coals have broad activation energy (Ea) distributions, while the mudstones have Ea distributions characterised by a pronounced principal Ea. During artificial maturation about 16‐17% of the organic carbon in the coals and 45‐50% of the organic carbon in the mudstones participated in petroleum formation. The two source rocks primary generate oil and secondary generate gas, however, the mudstones realised the majority of their potential over a more narrow temperature range than the coals. The excellent generative potential of the terrestrial source rocks at Dong Ho is encouraging for offshore exploration for reservoirs charged by Cenozoic rift-lake successions. q 2001 Elsevier Science Ltd. All rights reserved.

No significant change in either the morphotype composition or the macroporosity (pores>5 μm) in the 0–30 wt.% char burnout interval were revealed by reflected light microscopy or image analysis. Two high temperature char series from a Tertiary South American coal (C1) and a Permian Gondwana coal (C2) were therefore examined by scanning electron microscopy to provide information on the combustion process up to ∼60 wt.% char burnout. This study documents a significant mesopore (∼0.1–5 μm) development on the fused chars in the burnout interval studied. A method to quantify the size and amount of the mesopores is described and both the parameters increased with increasing char burnout. Above a char burnout of ∼30 wt.% an increase in macroporosity was detected and ascribed to coalescence of mesopores to form larger pores. Although the measurement of mesoporosity is restricted to fused chars, i.e. pores in fragments and the char morphotypes inertoid, fusinoid and solid could not be measured, the consideration of mesoporosity seems to be fundamental in understanding, evaluating and modelling combustion processes in the char burnout interval studied.

The sorption of seven pesticides in 10 Danish aquifer sediments has been studied. These sediments all have a total organic carbon (TOC) content below 1 g kg -1 , and include carbonate-bearing and carbonate-free Quatenary sand deposits and a Cretaceous chalk aquifer. Batch experiments were carried out with metamitron, atrazine, isoproturon, mecoprop, 2,4-D, bentazone, and metsulfuron-methyl at an initial pesticide concentration of 0.25 mg L -1 in ground water. Generally, the sorption decreases in the order: metamitron, atrazine, isoproturon, mecoprop, 2,4-D, metsulfuron-methyl. The bentazone sorption was found to be insignificant. For a specific pesticide the sorption covers a range of K d values (L kg -1 ) reflecting the different sediment characteristics. Multivariate regression analyses demonstrate that: (i) metamitron sorption is enhanced by increasing content of iron silicates; by contrast the oxalate extractable iron oxides have no influence on the metamitron sorption; (ii) sorption of atrazine, mecoprop, and 2,4-D depends primarily on pH; the sorption is high at low pH ( 7.4); (iii) metsulfuron-methyl only sorbs at pH below 5; and (iv) isoproturon sorption is primarily influenced by the specific surface area (SSA) and TOC. The present results illustrate the importance of choosing sediments of different geological origin in order to describe the influence of sediment properties on pesticide sorption.

New data from five wells in the Søgne Basin, Danish Central Graben of the North Sea - West Lulu-1, West Lulu-3, Lulu-1, Amalie-1 and Cleo-1 - together with previously released data from the West Lulu-2 well, show that the cumulative thickness of the Bryne Formation coal seams decreases towards the palaeo-shoreline from 5.05 m to 0.60 m, and that the seams have varying extents. Their overall organic petrographic and geochemical composition reflects the palaeoenvironmental conditions in the precursor mires, in particular the rate of rise in the water table, principally related to the relative rise in sea level, and the degree of marine influence. Laterally towards the palaeo-shoreline, all coal seams have increased proportions of C27 steranes and higher C35-homohopane indices suggesting stronger marine influence on the coastal reaches of the ancient mires. In each well it is also observed that coal seams formed during accelerated relative sea-level rise (T-seams) are characterised by higher contents of sterane C27 and higher C35-homohopane indices than seams formed during slower rates of base-level rise (R-seams). The most landward and freshwater-influenced parts of the seams have higher proportions of sterane C29 and the highest Pr/Ph ratios. The coals, with respect to thermal maturity, are well within the oil window, except in the Amalie-1 well where they are more mature. The largest average hydrogen indices and thermally extracted and generated bitumen yields are obtained from the T-seams. However, generally an increase in the hydrogen index is recorded in a seaward direction for all seams. Multivariate regression analysis demonstrates that collotelinite, telinite, the vitrinite maceral group, vitrinite-rich microlithotypes and the TOC content have a significant positive influence on the remaining generative potential represented by S2. Pyrolysis-gas chromatography reveals that during maturation the coals will generate from 72.4 to 82.0% oil-like components and only 18.0 to 27.6% gas. However, this does not necessarily imply that all of these oil-like components can be expelled to form a crude oil accumulation. Distribution of C27–29 regular steranes shows good correlation between extracts of Bryne Formation coals and oils/condensates present in Bryne Formation sandstones. The sum of evidence indicates that the coals in the Søgne Basin have generated and are still capable of generating liquid and gaseous petroleum, but with respect to petroleum generation potential, they are not as good as the documented oil-prone Middle Jurassic coals from North-East Greenland and Tertiary coals from Asia. Mudstones intercalated with the Bryne Formation coals have a similar or lower generative potential as the coals. In areas outside the Søgne Basin, the coastal plain deposits of the Central Graben Group contain predominantly terrestrial-derived kerogen type III or IIb. The thermal maturity of the organic matter ranges from close to or within the peak oil generation range in the oil window (Alma-1x, Anne-3a and M-8 well) to the late oil window (Elly-3 and Falk-1 wells) or close to the end of the oil window (Skjold Flank-1 well). Only a limited generative potential remains in Elly-3, but the kerogen may initially have possessed a good petroleum potential. In the Falk-1 well, a good generative capacity still remains. The kerogen in Skjold Flank-1 may possess the capability to generate condensate and gas, whereas the organic matter in the Alma-1x, Anne-3a and M-8 wells generally exhibits a poor petroleum generative potential.

The factors affecting the combustion rates of coals have been investigated using multivariate analysis. Coals from Australia, Colombia, Germany, UK and USA and their separated maceral group constituents were subjected to detailed optical and chemical characterisation followed by the measurement of combustion reactivity at low temperatures (up to 1323 K) using TGA, and at high temperatures (1300–1900 K) in an entrained flow reactor. The derived activation energies and pre-exponential factors were used in conjunction with eighty-six detailed chemical and petrographic parameters as the basis for statistical analysis. This demonstrated that the parameters which significantly influence the combustion rate could be used to divide the coals and maceral groups into two classes. One class containing predominantly the northern hemisphere coals with their corresponding maceral groups and the other containing the Australian and Colombian coals with their maceral groups. No significant relationships were found between the reactivity of the coals and the maceral groups within the coal, or between the same maceral group for all the coals. However the chemical composition of the organic matter content was found to be an important parameter in determining coal reactivity and such information could be used to supplement classical petrographical classification and proximate and ultimate analyses in order to predict the reactivity of a given coal. The effect of ash on the burning rate of the individual maceral components was also investigated and the implications for burnout in practical combustion systems discussed.

To evaluate the degree of intratumoral DNA ploidy heterogeneity in endometrial carcinoma, the authors examined curettage specimens from 30 patients with clinical stage I and II endometrial carcinoma. The curettage material was obtained before the onset of treatment. A representative sample from each tumour was chosen and a 50 microm section was cut. The paraffin block of tumor was then divided into 4 equal parts and a 50 microm section was cut from each part. All tumour samples were analysed separately by flow cytometry. DNA ploidy heterogeneity was noted in 5/29 cases (17%). In three cases DNA-aneuploid stem cell lines were found only among the 4-part sections and were not detected when the whole tumor section was analysed.

Background. A number of chemotherapeutic drugs are active in epithelial ovarian cancer (EOC) but so far choice of drugs for treatment is mostly empirically based. Testing of drug activity in tumour cells from patients might provide a rationale for a more individualised approach for drug selection. Material and methods. Sensitivity of EOC to chemotherapeutic drugs was analysed in 125 tumour samples from 112 patients using a short-term primary culture assay based on the concept of total cell kill. Sensitivity was related to tumour histology, treatment status and clinical tumour response. Results. For most EOC standard drugs serous high grade and clear cell EOC were the most sensitive subtypes and the mucinous tumours the most resistant subtype. Docetaxel, however, tended to show the opposite pattern. Samples from previously treated patients tended to be more resistant than those from treatment naïve patients. The activity of cisplatin correlated with that of other drugs with the exception of docetaxel. Tumour samples from two sites in the same patient at the same occasion showed similar cisplatin sensitivity in contrast to samples taken at different occasions. Samples from patients responding in the clinic to treatment were more sensitive to most drugs than samples from non-responding patients. At the individual patient level, drug sensitivity in vitro compared with clinical response showed sensitivities and specificities in the 83–100% and 55–83% ranges, respectively. Conclusions. Assessment of EOC tumour cell drug sensitivity in vitro provides clinically relevant and potentially useful information for the optimisation of drug treatment.

The morphology of chars sampled from various laboratory-scale reactors operating at temperatures from 800 to > 1400°C, together with chars collected directly in the flame zone in a full-scale pulverized fuel combustion experiment, was examined. A coal and coal blend dominated by vitrinite-rich microlithotypes together with four coals dominated by inertinite-rich microlithotypes were used to produce the combustion chars. Char samples produced at temperatures above ∼1300°C have a morphotype composition very similar to the composition of the full-scale char samples, whereas the morphotype compositions of those produced at ∼1150°C or lower are significantly different. Correlation between coal petrography and char morphology and determination of char reactivity should thus be attempted only using chars produced at temperatures comparable with those for the intended use of the coal. A clear distinction between the high-temperature char samples (burnout 50–60 wt% daf) emerges which is related mainly to the parent coal petrography and probably secondarily to the rank. Vitrite, clarite and vitrinertite V may be correlated with the porous tenuisphere and crassisphere morphotypes, whereas inertite, durite, vitrinertite I, duroclarite and clarodurite may be correlated with the crassinetwork-mixed-network-mixed morphotype group.

Background: During an international workshop held in September 1998, a group of specialists in the field of ovarian cancer reached consensus on a number of issues with implications for standard practice and for research of advanced epithelial ovarian cancer. Methods: Five groups of experts considered several issues which included: biologic factors, prognostic factors, surgery, initial chemotherapy, second-line treatment, the use of CA 125, investigational drugs, intra-peritoneal treatment and high-dose chemotherapy. The group attempted to arrive at answers to questions such as: Are there prognostic factors, which help to identify patients who will not do well with current therapy? What is the current best therapy for advanced ovarian carcinoma? What directions should research take in advanced ovarian cancer? These issues were discussed in a plenary meeting. Results: One of the major conclusions drawn by the consensus committee was that in previously untreated advanced ovarian cancer, cisplatin plus paclitaxel has been shown to be superior to previous standard therapy with cisplatin plus cyclophosphamide (level I evidence). However, for many patients, carboplatin plus paclitaxel is a reasonable alternative because of toxicity and convenience considerations. Most participants felt that the benefits in terms of toxicity for the paclitaxel-carboplatin are such that its widespread adoption at this stage is justified. Until mature survival data are available a minority of investigators would recommend continued use of cisplatin plus paclitaxel, specifically for those patients with advanced disease with the best prognostic characteristics. For future clinical research in this area, new end points for randomised clinical trials, together with a new Trials Network, are proposed.

Between January 1, 1988 and December 31, 1990, a new high-intensity treatment was delivered to 10 patients with clinical stage I uterine papillary serous carcinoma (UPSC) and 21 patients with clinical stage I, FIGO grade 3 endometrial adenocarcinoma. The treatment consisted of a radical hysterectomy and bilateral salpingo-oophorectomy with pelvic lymph node sampling, adjuvant external pelvic radiation, and four courses of cis -platinum/epirubicin. The clinical outcome was compared to that of a historical control group treated before 1998 with surgery and radiation. None of the high-intensity treated UPSC patients died or relapsed during a median observation time of 32 months. There was a significantly better survival in the high-intensity treated UPSC group compared to the controls. The UPSC patients diagnosed after January 1, 1988 showed a trend toward better survival compared to those diagnosed before this date, whether they had received high-intensity treatment or not. No significant difference in survival was observed in the non-UPSC group subjected or not to the high-intensity treatment.

Introduction: Endometrial cancer patients with high grade tumours, deep myometrial invasion or advanced stage disease have a poor prognosis. Randomised studies have demonstrated the prevention of loco-regional relapses with radiotherapy (RT) with no effect on overall survival (OS). The possible additive effect of chemotherapy (CT) remains unclear. Two randomised clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) were undertaken to clarify if sequential combination of chemotherapy and radiotherapy improves progression-free survival (PFS) in high-risk endometrial cancer. The two studies were pooled. Methods: Patients (n = 540; 534 evaluable) with operated endometrial cancer International Federation of Obstetrics and Gynaecology (FIGO) stage I-III with no residual tumour and prognostic factors implying high-risk were randomly allocated to adjuvant radiotherapy with or without sequential chemotherapy. Results: In the NSGO/EORTC study, the combined modality treatment was associated with 36% reduction in the risk for relapse or death (hazard ratio (HR) 0.64, 95% confidence interval (CI) 0.41-0.99; P = 0.04); two-sided tests were used. The result from the Gynaecologic Oncology group at the Mario Negri Institute (MaNGO)-study pointed in the same direction (HR 0.61), but was not significant. In the combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44-0.89; P = 0.009). Neither study showed significant differences in the overall survival. In the combined analysis, overall survival approached statistical significance (HR 0.69, CI 0.46-1.03; P = 0.07) and cancer-specific survival (CSS) was significant (HR 0.55, CI 0.35-0.88; P = 0.01). Conclusion: Addition of adjuvant chemotherapy to radiation improves progression-free survival in operated endometrial cancer patients with no residual tumour and a high-risk profile. A remaining question for future studies is if addition of radiotherapy to chemotherapy improves the results. © 2010 Elsevier Ltd. All rights reserved.

10 páginas, 7 figuras, 6 tablas.-- Trabajo presentado al ICCP-TSOP joint meeting 2008: International conference on coal and organic petrology.-- et al., This paper describes an assessment of char classification system by the Combustion Working Group in Commission III of the International Committee for Coal and Organic Petrology (ICCP). The work of the group culminated in the production of a char atlas after a final round robin exercise. This round robin involved 21 analysts and was an electronic exercise using digitally captured images of individual char particles, rather than actual char blocks. A software program featuring 170 char images was specifically designed to allow operators to identify each char based on a classification system with 9 individual char types; tenuisphere, crassisphere, tenuinetwork, crassinetwork, mixed porous, mixed dense, fusinoid, solid and mineroid. The program electronically recorded all decisions as well as the time taken for each decision to be made. From 170 chars, 128 chars were identified by a majority (> 70%) and these chars were then compiled in a char atlas that is now available for download (www.nottingham.ac.uk/~eczehl/charatlas). As would be expected all analysts appeared to become more confident in identifying chars during the exercise, taking less time per image, but with no clear evidence of improvement. Without exception, analysts took longer to make an incorrect decision.

The purpose of this study was to evaluate the role of sequence variants in the CYP2C8, ABCB1 and CYP3A4 genes and the CYP3A4 phenotype for the pharmacokinetics and toxicity of paclitaxel in ovarian cancer patients. Thirty-eight patients were treated with paclitaxel and carboplatin. The genotypes of CYP2C8*1B, *1C, *2, *3, *4, *5, *6, *7, *8 and P404A, ABCB1 G2677T/A and C3435T, as well as CYP3A4*1B, were determined by pyrosequencing. Phenotyping of CYP3A4 was performed in vivo with quinine as a probe. The patients were monitored for toxicity and 23 patients underwent a more extensive neurotoxicity evaluation. Patients heterozygous for G/A in position 2677 in ABCB1 had a significantly higher clearance of paclitaxel than most other ABCB1 variants. A lower clearance of paclitaxel was found for patients heterozygous for CYP2C8*3 when stratified according to the ABCB1 G2677T/A genotype. In addition, the CYP3A4 enzyme activity in vivo affected which metabolic pathway was dominant in each patient, but not the total clearance of paclitaxel. The exposure to paclitaxel correlated to the degree of neurotoxicity. Our findings suggest that interindividual variability in paclitaxel pharmacokinetics might be predicted by ABCB1 and CYP2C8 genotypes and provide useful information for individualized chemotherapy. This is the authors’ version of the following article: Henrik Green, Peter Söderkvist, Per Rosenberg, Rajaa A Mirghani, Per Rymark, Elisabeth Avall Lundqvist and Curt Peterson, Pharmacogenetic Studies of Paclitaxel in the Treatment of Ovarian Cancer, 2009, Basic and clinical pharmacology and toxicology, (104), 2, 130-137. which has been published in final form at: http://dx.doi.org/10.1111/j.1742-7843.2008.00351.x Copyright: Blackwell Publishing http://eu.wiley.com/WileyCDA/Brand/id-35.html

The phenoxyacetic acid herbicide MCPA (2-methyl-4-chlorophenoxyacetic acid) is frequently detected in groundwater beneath Danish agricultural fields. We investigated spatial variation in microbial MCPA mineralization potential in a flat agricultural field of fine sandy soil (USDA classification: Humic Dystrudept) located on the Yoldia plains of Northern Jutland, Denmark. Samples for determination of MCPA mineralization and sorption were collected from the Ap and Bs horizons at 51 sampling sites located in a 200 x 220 m grid. Spatial variation in sorption was low in both horizons (distribution coefficient, 0.36-4.16 L kg(-1)). Sorption correlated strongly with soil organic carbon content in both horizons (CV, 93 and 83%, respectively) and negatively with soil pH. [Ring-(14)C]-MCPA mineralized readily in the Ap horizon, with 49 to 62% of the (14)C-MCPA being converted to (14)CO(2) during the 67-d incubation period. With the subsoil, mineralization of (14)C-MCPA varied considerably between samples (0.5-72.8%). At neither depth was there correlation between (14)C-MCPA mineralization and sorption, soil pH, organic carbon content, clay content, number of colony-forming units (CFU), pseudomonad CFU, or any of the four microbial activity parameters measured. The presence of microbial genes encoding for the TfdA enzyme was quantified using real-time polymerase chain reaction. No correlation was found between MCPA mineralization potential and the natural background number of tfdA genes present in the soil samples. The degradation kinetics suggests that the high (14)C-MCPA mineralization rate detected in soil samples was linked to growth of the MCPA-degrading soil microbial community.

Pesticide mineralization and sorption were determined in 75 soil samples from 15 individually drilled holes through the vadose zone along a 28 km long transect of the Danish outwash plain. Mineralization of the phenoxyacetic acid herbicide MCPA was high both in topsoils and in most subsoils, while metribuzine and methyltriazine-amine was always low. Organic matter and soil pH was shown to be responsible for sorption of MCPA and metribuzine in the topsoils. The sorption of methyltriazine-amine in topsoil was positively correlated with clay and negatively correlated with the pH of the soil. Sorption of glyphosate was tested also high in the subsoils. One-dimensional MACRO modeling of the concentration of MCPA, metribuzine and methyltriazine-amine at 2 m depth calculated that the average concentration of MCPA and methyltriazine-amine in the groundwater was below the administrative limit of 0.1 μg/l in all tested profiles while metribuzine always exceeded the 0.1 μg/l threshold value.