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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.

Background: The aim was to investigate time trends for incidence and long-term net survival in the morphologic subtypes and stages of cervical cancer in Sweden during the period 1960 to 2014. Methods: Women with invasive cervical cancer were identified through the Swedish Cancer Registry. Incidence and net survival were calculated according to morphology, age at diagnosis, and FIGO stage at diagnosis. Results: In total, 29,579 cases of invasive cervical cancer between 1960 and 2014 were included. The age-standardized incidence for squamous cell carcinoma (SCC) decreased until 2000; thereafter, the incidence rate stagnated, and a small increase was found in 2014. The incidence of adenocarcinoma continuously increased. The age-standardized 5-year net survival increased. However, decreasing net survival with increasing age was found. A higher stage at diagnosis showed a worse net survival. SCC and adenocarcinoma did not statistically differ as regards net survival in the last years of the study. Conclusions: Age-standardized 5-year net survival improved between 1960 and 2014. A positive trend for short- and long-term net survival was seen for women ages 18 to 64 years but long-term net survival for women ≥75 years decreased. In this study, age and FIGO stage at diagnosis were found to be important prognostic factors in determining net survival. The morphologies, SCC, and adenocarcinoma did not statistically differ as regards net survival in the last years of the study. Impact: This study demonstrates longitudinal data on cervical cancer in Sweden for over 50 years with sub analyses on morphology, age, and stage at diagnosis.

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

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.

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 Analysis of survival trends in epithelial ovarian cancer with regard to age, tumour site and morphological subgroup in Sweden 1960 to 2014. Methodology Nation-wide population-based study on data from the Swedish Cancer Registry. 46 350 women aged 18 or older with a diagnosis of epithelial ovarian, fallopian tube, peritoneal or undesignated site cancer 1960 to 2014 were included. Analyses of age-standardised incidence and relative survival (RS) were done and time trend graphs modelled according to age, tumour site and morphological subgroup. Results Overall incidence of ovarian, tubal, peritoneal and undesignated site cancer declined since 1980. Median age at diagnosis increased. Serous cancer increased in incidence. RS at 1-, 2- and 5-years improved since 1960 although not for the youngest and the oldest patients. 10-year RS did not improve. Best RS was found for fallopian tube cancer and worst RS for undesignated site cancer. Among the histological subgroups endometrioid cancer had the best RS. RS improved most for endometrioid and mucinous cancer. Conclusion Survival in epithelial ovarian, tubal, peritoneal and undesignated site cancer in Sweden has improved over the last six decades. Advances in epithelial ovarian cancer treatment have extended life for the first 5 years from diagnosis but not long-term survival. Disclosure Nothing to disclose.

Kappa opioid receptor (KOR) is an important mediator of pain signaling and it is targeted for the treatment of various pains. Pharmacophore based mining of databases led to the identification of 2-aminobenzimidazole derivative as KOR agonists with selectivity over the other opioid receptors DOR and MOR. A short SAR exploration with the objective of identifying more polar and hence less brain penetrant agonists is described herewith. Modeling studies of the recently published structures of KOR, DOR and MOR are used to explain the receptor selectivity. The synthesis, biological evaluation and SAR of novel benzimidazole derivatives as KOR agonists are described. The in vivo proof of principle for anti-nociceptive effect with a lead compound from this series is exemplified.

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.

Ingenol 3-benzoates were investigated with respect to chemical stability, pro-inflammatory effects, cell death induction and PKCδ activation. A correlation between structure, chemical stability and biological activity was found and compared to ingenol mebutate (ingenol 3-angelate) used for field treatment of actinic keratosis. We also provided further support for involvement of PKCδ for induction of oxidative burst and cytokine release. Molecular modeling and dynamics calculations corroborated the essential interactions between key compounds and C1 domain of PKCδ.

Ingenol mebutate is the active ingredient in Picato® a new drug for the treatment of actinic keratosis. A number of derivatives related to ingenol mebutate were prepared by chemical synthesis from ingenol with the purpose of investigating the SAR and potency in assays relating to pro-inflammatory effects (induction of PMN oxidative burst and keratinocyte cytokine release), the potential of cell death induction, as well as the chemical stability. By modifications of the ingenol scaffold several prerequisites for activity were identified. The chemical stability of the compounds could be linked to an acyl migration mechanism. We were able to find analogues of ingenol mebutate with comparable in vitro properties. Some key features for potent and more stable ingenol derivatives have been identified.

A high-yielding method was developed for the preparation of ingenol 3-angelate (PEP005, ingenol mebutate) via the corresponding 5,20-acetonide without concomitant isomerization of the angelate (Z-form) to the corresponding tiglate (E-form). The general scope of the stereoconservative esterification method was further evaluated on several different alcohols, giving the angelates in up to quantitative yield without isomerization to the tiglate.

Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the melanin concentrating hormone (MCH) and its receptor 1. The development of MCHR1 antagonists are described with a specific perspective on different chemotypes investigated in efforts to overcome hERG liabilities while having orally active, potent and selective compounds with sufficient brain penetration. A chemometric comparison of ∼2000 diverse MCHR1 and ∼1000 diverse hERG ligands underline the structural similarities. A binding pocket analysis of a MCHR1 model and recent X-ray structures of GPCRs invoked in selectivity issues indicate a way to support future drug design.

Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays a role in metabolic and CNS disorders. The modeling-supported design, synthesis and multi-parameter optimization (biological activity, solubility, metabolic stability, hERG) of novel quinazoline derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified. Clusters of refined hMCHR1 homology models derived from the X-ray structure of the β2-adrenergic receptor, including extracellular loops, were developed and used to guide the design.

Ovarian cancer is the most common cause of death from a gynecologic cancer. Every year around 700 women contracts ovarian cancer in Sweden. The overall survival is among the highest in Europe, but still long term relative survival is only 46%. It is a long-held myth that ovarian cancer is a disease without symptoms. Almost 90% of women have symptoms, even in the early stages. Symptoms that should arise suspicion of ovarian cancer and initiate diagnostic work-up are continuous abdominal extension, early feeling of satiety, pelvic or abdominal pain, urinary urge and postmenopausal bleeding. Women's awareness of symptoms and willingness to seek medical advice and the organization of the health care system are important factors determining cancer survival. Ovarian cancer is a heterogeneous group of diseases with different tumor traits and prognosis. Personalized medicine and preventive measures recognizing recent knowledge about tumor biology will positively affect survival.

An efficient computational method for hit and lead identification is described. The method that incorporate ligand information from physicogenetically related 7TM receptors, i.e. receptors with similar physicochemical features in the ligand binding pockets, have been developed to aid the construction of pharmacophore queries for mining of vendor and in-house databases to produce small focused libraries for a specific GPCR target. The physicogenetically related targets could be complementary to phylogenetically derived receptors and convey more relevance for the structure-based design approaches suitable for GPCR targets associated with no or limited ligand information. The approach is useful not only in identification of hits but also in the hit-to-lead process as constructed homology receptor models, SAR information and pharmacophore features are collectively utilized in the design of proprietary new lead series. This site-directed drug discovery approach of making smaller receptor-specific libraries displays important advantages over conventional HTS-based generation of hits. The methodology has been exemplified with the CRTH2 receptor, which was associated with minimal ligand information, to produce a small diverse library containing several useful hit series which were further converted into drugable lead series. The use of ligand and QSAR information in scaffold hopping was exemplified with MCH1R antagonists, which had been obtained via chemogenomics-enriched design. Finally, an example on how ligand relationships can be used in identifying receptor relationships was given with CCR2 antagonists to highlight the 3D relationships of GPCR targets not directly evident from either phylogenetic or physicogenetic relationships.

Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays role in several disorders such as obesity, stress, depression and anxiety. The synthesis and biological evaluation of novel benzimidazole derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified.

The SAR features have been further explored for (2-benzhydryl-4-phenyl-thiazol-5-yl)acetic acids as CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) antagonists. The introduction of a nitrogen or a methyl substituent in the benzhydrylic position offer two alternative drugable scaffolds attractive for unsymmetrically substituted derivatives. An imidazole analogue lacks activity due to formation of a favored coplanar intramolecular hydrogen bond. The pyrimidine derivative 18 represents a potent and selective compound that will be subject to continued investigations.

Udgivelsesdato: 2009-Dec-4 Structure-activity relationships of three related series of 4-phenylthiazol-5-ylacetic acids, derived from two hits emanating from a focused library obtained by in silico screening, have been explored as CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) antagonists. Several compounds with double digit nanomolar binding affinity and full antagonistic efficacy for human CRTH2 receptor were obtained in all subclasses. The most potent compound was [2-(4-chloro-benzyl)-4-(4-phenoxy-phenyl)-thiazol-5-yl]acetic acid having an binding affinity of 3.7nM and functional antagonistic effect of 66nM in a BRET and 12nM in a cAMP assay with no functional activity for the other PGD2 DP receptor (27muM in cAMP).

A series of amides, amidines and amidoximes have been made from the corresponding nitrile compounds, to provide potent antagonists and inverse agonists for the CB1 receptor with considerably lower lipophiliciy, higher polar surface area and improved plasma/brain ratios compared to the centrally acting rimonabant. Extensive investigations of ADME and in vivo pharmacological properties led to selection of the amide series and specifically the 4-(4-fluorophenyl)piperidin-4-ol derivative D4. A clear improvement in the peripheral profile over rimonabant was seen, although some contribution of central effect on the pronounced weight reduction in obese mice cannot be ruled out.

Endometrial cancer generally has a good prognosis because most cases are diagnosed in stage I. It is possible to identify subgroups of patients with early stage endometrial cancer with a poor prognosis. Despite a traditional generous use of adjuvant radiotherapy those patients have less than an 80% 5-year overall survival. In this group there is a need for an effective systemic adjuvant therapy. Two randomised studies have shown better response rates but no significant difference in overall survival for doxorubicin-cisplatin vs doxorubicin in advanced or recurrent endometrial cancer. Mainly on the basis of the superior response rates, doxorubicin-cisplatin was for many years regarded as the standard chemotherapy in endometrial cancer. GOG-177 was the first phase III study on chemotherapy in advanced or recurrent endometrial cancer that showed a survival advantage. Paclitaxel-doxorubicin-cisplatin was better than doxorubicin-cisplatin, but the toxicity of the three-drug regimen has precluded general acceptance. Paclitaxel-carboplatin has rendered high response rates in endometrial cancer and is widely used, despite the lack of evidence based on randomised studies. GOG-122 was a pivotal randomised study that compared doxorubicin-cisplatin with whole abdominal radiotherapy in advanced optimally operated endometrial cancer and showed that chemotherapy with doxorubicin-cisplatin resulted in superior survival. Two recent studies have compared adjuvant chemotherapy (cyclophosphamide-doxorubicin-cisplatin) with adjuvant radiotherapy in early stage endometrial cancer. Both studies failed to show a difference between the treatments, but neither was powered to show non-inferiority. Another study (NSGO-EC-9501/EORTC-55991) compared adjuvant radiotherapy plus chemotherapy with adjuvant radiotherapy and showed better survival with the combination. The implications of these studies are discussed.

We conducted an evaluation of incidence and survival of women with borderline ovarian tumors in Sweden.All women diagnosed with borderline ovarian tumor in the Swedish Cancer Register 1960-2007 (n = 6252) combined with follow up in the Swedish Death Registry to 1 July 2009 were included. Estimation of age-standardized relative survival rate according to time periods for diagnosis.The incidence of borderline ovarian tumors increased during the study period, with a steep increase during the 1980s. The age standardized 5-year relative survival including all borderline tumors diagnosed 2000-07 was 97% (95% CI 92-99%). In women aged ≤64 years, the 10-year relative survival related to age at diagnosis of borderline tumors ranged from 95 to 98% and was 89% in women aged 65-74 years. In a multivariable analysis including age and decade of diagnosis relative survival for every decade increased. The 10-year relative survival in women with mucinous and serous borderline tumors did not differ significantly (p = 0.121).Results of the present study are reassuring about long-term survival in women with borderline ovarian tumors. The age-standardized relative survival rate increased across time periods for diagnosis. There was no difference in long-term survival between mucinous and serous borderline ovarian tumors.

Hits from an in silico derived focused library for CRTH2 were transformed into highly selective antagonists with favorable ADME properties. Oral administration of 4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetic acid (19) inhibited peribronchial eosinophilia and mucus cell hyperplasia in a mouse model of allergic asthma, supporting the therapeutic potential of this novel compound class. In addition, this selective pharmacological tool compound provides further evidence for CRTH2 as a relevant therapeutic target for treatment of Th2- and eosinophil-related inflammation.

A management program for FIGO stage I-II nonserous, nonclear-cell adenocarcinomas was evaluated. Histopathology and DNA ploidy were used to estimate postoperatively the risk of progression or death of disease and to tailor treatment. The patient material was a population-based consecutive cohort of all women with endometrial cancer in the Southern Swedish Health Care Region diagnosed between June 1993 and June 1996 (n = 553). Of these, 335 were eligible for the management program. Patients estimated to be at low risk were treated by surgery only, while high-risk patients also received vaginal brachytherapy. A large low-risk group consisting of 84% (n = 283) of the patients with an estimated disease-specific 5-year survival of 96% (95% CI = 93-98%) was identified. The high-risk group (n = 52, 16%) showed a worse outcome with an 80% 5-year disease-specific survival (95% CI = 65-89%). The difference in survival between the groups was highly significant (P < 0.0001). Half of the progressions were distant in the high-risk group. Although there is a clear indication for adjuvant therapy for this group, locoregional radiotherapy could be expected to fail in cases with distant progression. Thus, effective systemic treatments need to be developed. Low-risk patients, constituting the majority (84%) of the patients, can be safely treated by surgery only.

To evaluate current surgical cervical cancer treatment in Sweden 2008-12.Analysis of data in the Swedish National Quality Register for Gynecological Surgery (GynOP).A total of 249 cervical cancer patients undergoing surgery.Analysis of prospectively gathered preoperative and postoperative data including patient-reported information.Mean operating time, blood loss/transfusion, length of hospital stay, return to activities of daily living.The patients undergoing laparoscopic robot-assisted surgery (n = 64) or laparotomy (n = 185) did not differ in age, body mass index, American Society of Anesthesiologists score, International Federation of Gynecology and Obstetrics (FIGO) stage or mean operating time. Blood loss was higher in the laparotomy group (p0.001). Thirteen patients in the laparotomy group (7%) received a blood transfusion, but none in the robot group. Intraoperative complications were more common in the laparotomy group (p = 0.03). Re-admission or operations did not differ between the groups. The number of pelvic lymph nodes removed was significantly higher in the laparotomy group (median 31 vs. 24, p0.001). There was no difference regarding the number of patients with lymph node metastases in the two groups. The postoperative length of hospital stay was longer in the laparotomy group compared with the robot group (6.1 days vs. 2.1 days, p = 0.01). The patient-reported time to resume normal activities of daily living was longer in the laparotomy than the robot group (13.4 days vs. 9.7 days, p = 0.04).Laparoscopic robotic-assisted surgery is preferable to laparotomy for cervical cancer patients because it entails a significantly shorter hospital stay, less blood loss, fewer intraoperative complications and shorter time to normal daily activities.

Previous studies including various tumor types have shown different associations between tumor tissue levels of plasminogen activator inhibitor 2 (PAI-2) and patient survival. High tumor tissue concentrations of PAI-2 have been associated with good prognosis in patients with breast cancer, small cell lung cancer and ovarian cancer, but with poor histologic differentiation and poor prognosis in patients with colorectal cancer. On the other hand, high tumor tissue concentrations of urokinase plasminogen activator (uPA), uPA receptor (R) and PAI-1 have more consistently been associated with poor histologic differentiation and poor prognosis. Our study quantified PAI-2 and uPAR using specific enzyme-linked immunosorbent assays in homogenates of 274 samples of endometrial cancer tissue. The prognostic power of each factor was analyzed in the subgroup of patients with early stage disease, i.e., International Federation of Gynecology and Oncology (FIGO) surgical stage I-II (n = 188). This group had a median follow-up time of 6.8 years (range 0.7-9.9), and 23 progressions were observed. The 80(th) percentile for PAI-2 and uPAR was used to dichotomize the material, and the results were analyzed for associations with clinical data including progression-free survival. The results were also compared with DNA ploidy status, S-phase fraction, uPA and PAI-1, which we reported in a previous study (Fredstorp Lidebring et al., Eur J Cancer 2001; in press). A high PAI-2 level was associated with shorter progression-free survival in univariate analysis and was an independent prognostic factor in bivariate analyses, which included PAI-1, uPA and DNA ploidy status. In contrast, a high level of uPAR had no association with prognosis in early stage endometrial cancer. The combination of high PAI-2 and PAI-1 levels in tumors revealed a small group of stage I-II patients with an accumulative progression rate of 50%.

The indications for adjuvant therapy in endometrial cancer are briefly reviewed. The importance of systemic adjuvant therapy is emphasized. A short summary of randomized studies on adjuvant chemotherapy versus radiotherapy and on adjuvant sequential chemotherapy plus radiotherapy versus radiotherapy alone is given. On the basis of the present results from randomized trials, a combination of adjuvant radiotherapy and platinum-based chemotherapy seems to be most effective.

Dose-dense administration of paclitaxel as well as intraperitoneal administration of platinum and paclitaxel as first-line treatments provide similar advantages compared with standard treatment in advanced ovarian cancer. Both approaches, however, need to be confirmed by additional studies. a low dose of pegylated liposomal doxorubicin combined with carboplatin is superior to standard paclitaxel and carboplatin in relapsed platinum-sensitive ovarian cancer.

Novel 4,5-, 4,6-disubstituted and 4,5,6-trisubstituted 3-hydroxyanthranilic acid derivatives were synthesized and their ability to reduce the production of the excitotoxin quinolinic acid (QUIN) by inhibition of brain 3-hydroxyanthranilic acid dioxygenase (3-HAO) was subsequently investigated. The potency of the compounds to inhibit 3-HAO was assayed in rat brain homogenate, while chemical stability of certain compounds was studied by HPLC. The data were used to generate quantitative structure-activity relationship (QSAR) models for potency of 3-HAO inhibition and compound stability. Compounds with longer half-lives were obtained when the difference between the HOMO and LUMO was increased, while electron withdrawing groups in the 4- and 5-positions increased the potency of 3-HAO inhibition. Selected compounds that showed high potency in vitro were also found to be efficacious inhibitors in vivo after cerebral administration in rats.

This article examines the impact of prognostic factors, adjuvant therapy, and randomized trials on the overall survival of patients with endometrial cancer. The potential role of radiation therapy as an adjuvant therapy, as well as the role of lymph node dissection, in the treatment of endometrial carcinomas is reviewed.

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)

A convergent enantioselective total synthesis of the natural product (-)-balanol (1) is described. In addition to benzophenone fragment 8, key intermediates are chiral bicyclic aziridine 3 and the corresponding epoxide 4, both of which undergo highly regio- and stereoselective nucleophilic ring-opening reactions, allowing control of the two stereogenic centres of the target molecule. The structure and reactivity of 3 and 4 have been investigated in some detail.

In this chapter, the evidence on the role of adjuvant radiotherapy and/or chemotherapy in the treatment of patients with endometrial cancer is discussed, with emphasis on the controversial issues and pro/con discussions. Ongoing issues of debate for which future trials should provide evidence are highlighted. Risk-based treatment selection is emphasized, with the aim of sparing many patients with low-risk endometrial cancer unnecessary toxicities of adjuvant treatment. Ongoing and future research is mainly directed at investigating the role of adjuvant chemotherapy in patients with high-risk disease to improve outcomes.

BACKGROUND: The locoregional failure rate remains high in advanced cervical carcinoma. Chemotherapy (CT) was added to radiotherapy (RT) in order to increase disease control and to improve 5-year survival.METHODS: CT + RT included cisplatin administered 100mg/m2, d.1 plus 5-fluorouracil 1000 mg/m2 D.1 to 5, ci (120 hrs), q every 3rd week for 3 cycles, followed by RT. RT included external beam irradiation 64.8 Gy in 1.8 Gy fractions, five days a week, by 4-field box technique. The median follow-up was 46 months. Ninety-four patients were evaluable for survival, 47 in the CT + RT group and 47 in the RT group. Ninety-two patients were evaluable for response. Known prognostic factors were equally distributed between the two groups.RESULTS: Of the 43 patients evaluable before RT, 31 (72%) achieved a partial or complete response after CT alone. After RT, 52 patients attained a complete response, 25 in the CT + RT group and 27 in the RT-group. Sixty-three patients developed distant metastases or local relapse, 30 in the CT + RT group and 33 in the RT group. In the CT + RT group 6 of the 9 patients with metastases also had local progression at relapse, in the RT group, 7 of 17 patients. The survival rates for the two groups are not statistically different. Thirty-seven patients are alive, 29 have no evidence of disease. Fifty-seven have died, 29 in the CT + RT group and 28 in the RT group. Fifty-four deaths were related to cancer, and 3 to therapy.CONCLUSIONS: Sequential CT and RT did not improve the survival, local control, or metastasis rate compared with RT alone. (Less)

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 crystal structures and absolute configurations of two potent dopamine-D 2 receptor antagonists, FLB 457, (-)-(S)-3-bromo-5,6-dimethoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]benzamide, and FLB 463, (-)-(S)-3-bromo-5,6-dimethoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]salicylamide, have been determined by X-ray diffraction methods. The crystal structure of FLB 457 was derived from its salt with hydrobromide, C 16 H 24 BrN 2 O 3 +Br - , crystallizing in the orthorhombic space group P2 1 2 1 2 1 , a = 28.900(18), b = 8.747 (3), c = 7.585 (1)A, Z = 4, and FLB 463 from its methylsulfonate salt, C 16 H 24 BrN 2 O 4 + CH 3 SO 3 - , crystallizing in the monoclinic space group P2 1 , a = 15.264 (5), b = 8.087 (4), c = 8.541 (3)A, β = 93.44 (5)°, Z = 2. FLB 457 and FLB 463 are two potential antipsychotic agents with extremely high and stereospecific blocking affinity for the dopamine D 2 -receptors both in vitro and in vivo. The biological activities are confined to the S-enantiomeric forms. The molecular conformations of the two examined compounds are almost identical, despite differences in their anionic environments. The benzamide moieties are essentially planar, stabilized by an intramolecular hydrogen bond between the amide group and the 6-methoxy (ortho) O atom, reinforced by a second intramolecular hydrogen bond between the other ortho-substituent (2-hydroxyl group) and the carbonyl O atom in FLB 463. In both structures, the 5-methoxy group is coplanar with the benzene ring plane, while the methyl part of the 6-methoxy group is directed away from the aromatic plane. The conformation of the amide side chain, which is associated with the area of greatest conformational flexibility, adopts a folded (+)-perpendicular-gauche trend. In both crystals, the molecular packing schemes are mainly achieved through salt bridging. A weak hydrogen bond joins the bromide anion to the protonated pyrrolidine nitrogen of FLB 457, whereas the methylsulfonate anion is more closely connected to the FLB 463 cationic nucleus via a complex hydrogen-bonding scheme, involving the pyrrolidine nitrogen as well as the amide nitrogen. Except for the salt interactions, the intermolecular forces are mainly of normal or weak van der Waals character.

Three different routes to the hexahydroazepine unit of the natural products balanol ( 1 ) and ophiocordin ( 2 ) are described. The common starting material is the chiral epoxy alcohol 3 which is converted to the balanol degradation product 10 (Scheme 1) or to suitably protected derivatives thereof: 15 (Scheme 2) and 19 (Scheme 3). A key step in the first route is the acid-catalysed ring-opening of bicyclic aziridine 8 which proceeds in good chemical yield (71% isolated) and with remarkable regioselectivity (98:2 in favour of the desired regioisomer).

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.

There have been no controlled clinical trials supporting the use of primary cytoreductive surgery. The question remains as to whether the observed survival benefits for patients subjected to primary cytoreductive surgery are an effect of surgical skill or tumour biology. The proponents of tumour biology claim that cytoreductive surgery is a selective procedure, choosing patients with better prognosis. This paper discusses indirect evidence in the literature in support of, or in contradiction to, this hypothesis.