Efficacy in diet-induced obese mice of the hepatotropic, peripheral cannabinoid 1 receptor inverse agonist TM38837.

Background And Purpose: The cannabinoid CB receptor has a well-established role in appetite regulation. Drugs antagonizing central CB receptors, most notably rimonabant, induced weight loss and improved the metabolic profile in obese individuals but were discontinued due to psychiatric side effects. However, metabolic benefits were only partially attributable to weight loss, implying a role for peripheral receptors, and peripherally restricted CB receptor antagonists have since been of interest.

Optimizing and characterizing 4-methyl substituted pyrazol-3-carboxamides leading to the peripheral cannabinoid 1 receptor inverse agonist TM38837.

Several series of diverse pyrazole-3-carboxamides functionalized with 4-methylamides, 4-methylcarboxylic acids and 4-methyltetrazoles were prepared from the corresponding 4-cyanomethylpyrazoles and investigated as Cannabinoid receptor 1 (CB1) antagonists and inverse agonists with the aim of making compounds with less CNS (Central Nervous System) mediated side-effects compared to rimonabant. The compounds were evaluated and optimized with respect to lipophilicity, solubility, CB1 potency, metabolism, distribution to brain and liver, effect on weight loss in diet-induced mice models. A few carboxylic acids and tetrazoles were selected as especially promising with the tetrazole TM38837 subsequently demonstrating impressive efficacy in various animal models of obesity, producing considerable weight loss and improvements on plasma markers of inflammation and glucose homeostasis, at doses apparently producing negligible brain exposure.

Increased incidence and improved survival in endometrial cancer in Sweden 1960-2014: a population-based registry survey.

Background: An investigation of trends of incidence and net survival (NS) for endometrial cancer in Sweden.

Methods: Morphologically verified endometrial carcinoma diagnosed 1960 to 2014 were collected from the nation-wide Swedish Cancer Registry. Endometrial cancer patients were assessed with regards to time trends for incidence and 54,825 cases remained for survival analyses.

Time Trends for Incidence and Net Survival of Cervical Cancer in Sweden 1960-2014-A Nationwide Population-Based Study.

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.

Long-term incidence of endometrial cancer after endometrial resection and ablation: A population based Swedish gynecologic cancer group (SweGCG) study.

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 wait time to primary surgery in endometrial cancer - impact on survival and predictive factors: a population-based SweGCG study.

Background: Poor survival rates in different cancer types are sometimes blamed on diagnostic and treatment delays, and it has been suggested that such delays might be related to sociodemographic factors such as education and ethnicity. We examined associations of the wait time from diagnosis to surgery and survival in endometrial cancer (EC) and explored patient and tumour factors influencing the wait time.

Material And Methods: In this historical population-based cohort study, The Swedish Quality Registry for Gynaecologic Cancer (SQRGC) was used to identify EC patients who underwent primary surgery between 2010 and 2018.

Survival in endometrial cancer in relation to minimally invasive surgery or open surgery - a Swedish Gynecologic Cancer Group (SweGCG) study.

Background: The aim of this study was to analyze overall survival in endometrial cancer patients' FIGO stages I-III in relation to surgical approach; minimally invasive (MIS) or open surgery (laparotomy).

Methods: A population-based retrospective study of 7275 endometrial cancer patients included in the Swedish Quality Registry for Gynecologic Cancer diagnosed from 2010 to 2018. Cox proportional hazard models were used in univariable and multivariable survival analyses.

Incidence and survival of epithelial ovarian, fallopian tube, peritoneal, and undesignated abdominal/pelvic cancers in Sweden 1960-2014: A population-based cohort study.

Background: Despite improved surgical and oncological treatment, ovarian cancer continues to be the most lethal of the gynecologic malignancies. We aimed to analyze survival trends in epithelial ovarian cancer with regard to age, tumor site, and morphology in Sweden 1960 to 2014.

Methods: A nationwide population-based study was conducted using data from the Swedish Cancer Registry on 46,350 women aged 18 or older with a diagnosis of epithelial ovarian, fallopian tube, peritoneal, or undesignated abdominal/pelvic cancer 1960 to 2014.

Preoperative and intraoperative assessment of myometrial invasion in endometrial cancer-A Swedish Gynecologic Cancer Group (SweGCG) study.

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.

Implementation of National Guidelines increased survival in advanced ovarian cancer - A population-based nationwide SweGCG study.

Aim: 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.

Method: 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.

Primary treatment and relative survival by stage and age in vulvar squamous cell carcinoma: A population-based SweGCG study.

Objective: 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.

Methods: 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).

Primary treatment patterns and survival of cervical cancer in Sweden: A population-based Swedish Gynecologic Cancer Group Study.

Objective: Survival in cervical cancer has improved little over the last decades. We aimed to elucidate primary treatment patterns and survival.

Methods: Population-based study of patients included in the Swedish Quality Registry for Gynecologic Cancer diagnosed 2011-2015.

Lymphovascular space invasion as a predictive factor for lymph node metastases and survival in endometrioid endometrial cancer - a Swedish Gynecologic Cancer Group (SweGCG) study.

The aim of this study is to evaluate the impact of lymphovascular space invasion (LVSI) on the risk of lymph node metastases and survival in endometrioid endometrial adenocarcinoma. As regard the study design, this is a cohort study based on prospectively recorded data. Patients with endometrioid endometrial adenocarcinoma registered in the Swedish Quality Registry for Gynecologic Cancer 2010-2017 with FIGO stages I-III and verified nodal status were identified ( = 1587).

Lymph node metastases as only qualifier for stage IV serous ovarian cancer confers longer survival than other sites of distant disease - a Swedish Gynecologic Cancer Group (SweGCG) study.

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.

Data quality in the Swedish Quality Register of Gynecologic Cancer - a Swedish Gynecologic Cancer Group (SweGCG) study.

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.

Population-based study of survival for women with serous cancer of the ovary, fallopian tube, peritoneum or undesignated origin - on behalf of the Swedish gynecological cancer group (SweGCG).

Objective: 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.

Methods: 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.

Ingenol Disoxate: A Novel 4-Isoxazolecarboxylate Ester of Ingenol with Improved Properties for Treatment of Actinic Keratosis and Other Non-Melanoma Skin Cancers.

Introduction: Ingenol mebutate gel (Picato, LEO Pharma A/S) is approved for the field treatment of actinic keratosis and is characterized by high sustained clearance of actinic lesions. The inherent propensity of ingenol mebutate towards chemical rearrangement necessitates refrigeration of the final product. We sought to identify novel ingenol derivatives with enhanced chemical stability and similar or improved in vitro potency and in vivo efficacy.

A population-based registry study evaluating surgery in newly diagnosed uterine cancer.

Introduction: The aim was to evaluate surgical treatment of newly diagnosed uterine cancer in a Swedish population.

Material And Methods: Data in the GynOp registry from 2008 to 2014 were analyzed.

Results: In total, 3443 cases were included: 430 (12%) were robotic-assisted laparoscopic, 272 (8%) laparoscopic, and 2741 (80%) abdominal operations.

Long-term survival in women with borderline ovarian tumors: a population-based survey of borderline ovarian tumors in Sweden 1960-2007.

Introduction: We conducted an evaluation of incidence and survival of women with borderline ovarian tumors in Sweden.

Material And Methods: 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.

[Hope for improvement of survival in ovarian cancer].

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%.

Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists.

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.

Robot-assisted surgery in cervical cancer patients reduces the time to normal activities of daily living.

Objective: To evaluate current surgical cervical cancer treatment in Sweden 2008-12.

Design And Setting: Analysis of data in the Swedish National Quality Register for Gynecological Surgery (GynOP).

Sample: A total of 249 cervical cancer patients undergoing surgery.

Synthesis, biological evaluation and SAR of 3-benzoates of ingenol for treatment of actinic keratosis and non-melanoma skin cancer.

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.

Syntheses, biological evaluation and SAR of ingenol mebutate analogues for treatment of actinic keratosis and non-melanoma skin cancer.

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.

Melanin concentrating hormone receptor 1 (MCHR1) antagonists-Still a viable approach for obesity treatment?

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.