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Objective: To evaluate diagnostic accuracy of novel nanoparticle immunoassays across different histotypes of tubo-ovarian carcinoma (TOC) at diagnosis.

Method: This multicenter observational study consisted of consecutive patients (n = 1,312) having surgery due to suspected ovarian pathology. Serum were analyzed with Sialyl-Thomsen-nouveau (STn) antibody and Macrophage-Galactose-Lectin (MGL) for the detection of cancer antigen 125 (CA125) and 15-3 (CA15-3) glycoforms using CA125 enzyme immunoassay (EIA), CA15-3EIA and HE4EIA as references. Receiver operating characteristics (ROC) were applied and sensitivity at 75 % and 98 % specificity were calculated across histotypes.

Result: TOC was present in 596 patients and 716 had benign disease. CA125STn showed higher sensitivity at 98 % specificity compared with CA125EIA for high grade serous ovarian carcinoma (HGSC) (0.85 vs 0.62, p < 0.001), HGSC early-stage (0.66 vs 0.24, p = 0.003), and HGSC late-stage (0.90 vs 0.69, p < 0.001). CA15-3STn showed higher sensitivity at 98 % specificity compared to CA125EIA for mucinous ovarian carcinoma (0.50 vs 0.16, p = 0.038). No improvements were found for low grade serous carcinoma (LGSC), endometrioid and clear cell histotypes. The best performing combined biomarker test was CA125STn + HE4EIA with higher sensitivity at 98 % specificity for HGSC (0.93 vs 0.86, p < 0.001) and HGSC late-stage (0.97 vs 0.91p < 0.001) compared with CA125EIA + HE4EIA.

Conclusion: The STn glycovariants of CA125 and CA15-3 have improved sensitivity at high specificity for high grade serous and mucinous ovarian carcinoma and often perform better than the commonly used biomarker CA125EIA.

BACKGROUND: In uterine cervical cancer (UCC), tumour staging is performed according to the 2018 International Federation of Gynecology and Obstetrics (FIGO) system, where imaging is incorporated, or the more generic Tumour Node Metastasis (TNM) classification. With the technical development in diagnostic imaging, continuous prospective evaluation of the different imaging methods contributing to stage determination is warranted. The aims of this interim study were to (1) evaluate the performance of radiological FIGO (rFIGO) and T staging (rT) with 2-fluorine-18-fluoro-deoxy-glucose (2[18F]-FDG)-positron emission tomography with computed tomography (PET/CT) and with magnetic resonance imaging (PET/MRI), compared to clinical FIGO (cFIGO) and T (cT) staging based on clinical examination and conventional imaging, in treatment-naïve UCC, and to (2) identify possible MRI biomarkers for early treatment response after radiotherapy.

METHODS: Ten consecutive patients with newly diagnosed UCC from the prospective PRODIGYN (Prognostic and Diagnostic Added Value of Medical Imaging in Staging and Treatment Planning of Gynecological Cancer) study (ethical approval number 2022-04207-01; NCT05855941) were included. Study participants underwent 2[18F]FDG-PET/CT and -PET/MRI, and an additional MRI one week after radiotherapy. Agreement between rFIGO and cFIGO was analysed using Cohen's kappa. Differences in rFIGO between 2[18F]FDG-PET/CT and -PET/MRI were evaluated with Wilcoxon signed ranks test, and added value of rFIGO for metastasis assessment was demonstrated with descriptive statistics.

RESULTS: In 2/10 patients, a higher stage was obtained with rFIGO compared to cFIGO, where presence of metastases led to upstaging. In 3/10, rFIGO was lower than cFIGO, and in 5/10 rFIGO and cFIGO were similar. Degree of agreement between rFIGO and cFIGO was poor, (κ = 0.091, p < 0.005) with 2[18F]FDG-PET/CT and (κ = - 0.010, p > 0.05) with FDG/PET/MRI). There was no significant difference between 2[18F]FDG-PET/CT and -PET/MRI for rFIGO (p = 0.18), or rT stage assessment (p = 0.32). MRI-derived tumour volume and apparent diffusion coefficient (ADC) were most affected on MRI one week after radiotherapy.

CONCLUSIONS: Our results indicate that there is an added value of rFIGO staging with 2[18F]FDG-PET/CT and -PET/MRI compared to clinical examination and conventional radiology, for metastasis assessment in treatment-naïve UCC. In early treatment response evaluation with MRI, ADC and tumour volume may be predictive parameters of interest in future prognostic analyses.

TRIAL REGISTRATION: Clinical Trials, NCT05855941. Registered 02 May 2023, https://clinicaltrials.gov/study/NCT05855941?term=NCT05855941&rank=1 .

Introduction: The primary aim was to determine the occurrence of lymph ascites 4–6 weeks after surgery for endometrial cancer. Secondary aims were to assess risk factors for lymph ascites and the association with lymphedema of the legs.

Material and Methods: This was a post hoc analysis of an observational prospective multicenter study, performed in 14 Swedish hospitals that included 235 women undergoing surgery for early-stage endometrial cancer between June 2014 and January 2018; 116 underwent surgery including pelvic and para-aortic lymphadenectomy and 119 had surgery without lymphadenectomy. Lymph ascites (free intraabdominal fluid or encapsulated pelvic or para-aortic fluid) was assessed by vaginal ultrasound 4–6 weeks postoperatively. Lymphedema was assessed using circumferential measurements of the legs preoperatively and 1 year postoperatively, enabling estimation of leg volume. A BMI-standardized leg volume increase ≥10% was classified as lymphedema. Evaluation of risk factors was performed using multiple logistic regression.

Results: Lymph ascites 4-6-weeks postoperatively occurred in 28.5% (67/235) of the women. The estimated volume of the lymph ascites in these women was mean 28 mL (standard deviation 48 mL) and median 14 mL (interquartile range 2–36 mL). Lymphadenectomy was a risk factor for lymph ascites (aOR 9.97; 95% CI 4.53–21.97) whereas the use of minimally invasive surgery (aOR 0.50; 95% CI 0.25–0.99) reduced the risk. Twenty-two of 231 women (9.5%) developed lymphedema of the legs 1 year after surgery. The presence of lymph ascites was predictive of lymphedema (aOR 3.90; 95% CI 1.52–9.96).

Conclusions: Lymph ascites was common 4–6 weeks after surgery but in a low and clinically insignificant volume. Lymphadenectomy was a strong risk factor for lymph ascites and the use of minimally invasive surgery seemed to reduce the risk. Detection of lymph ascites at early postoperative follow-up may be a means of selecting patients at high risk of developing lymphedema after treatment with endometrial cancer for preventive measures against lymphedema progression.

Endometriosis, affecting 10% of women, is defined as implantation, survival, and growth of endometrium-like/endometriotic tissue outside the uterine cavity, causing inflammation, infertility, pain, and susceptibility to ovarian cancer. Despite extensive studies, its etiology and pathogenesis are poorly understood and largely unknown. The prevailing view is that the immune system of endometriosis patients fails to clear ectopically disseminated endometrium from retrograde menstruation. Exosomes are small extracellular vesicles that exhibit immunomodulatory properties. We studied the role of endometriotic tissue-secreted exosomes in the pathophysiology of endometriosis. Two exosome-mediated mechanisms known to impair the immune response were investigated: 1) downregulation of NKG2D-mediated cytotoxicity and 2) FasL- and TRAIL-induced apoptosis of activated immune cells. We showed that secreted endometriotic exosomes isolated from supernatants of short-term explant cultures carry the NKG2D ligands MICA/B and ULBP1-3 and the proapoptotic molecules FasL and TRAIL on their surface, i.e., signature molecules of exosome-mediated immune suppression. Acting as decoys, these exosomes downregulate the NKG2D receptor, impair NKG2D-mediated cytotoxicity, and induce apoptosis of activated PBMCs and Jurkat cells through the FasL- and TRAIL pathway. The secreted endometriotic exosomes create an immunosuppressive gradient at the ectopic site, forming a “protective shield” around the endometriotic lesions. This gradient guards the endometriotic lesions against clearance by a cytotoxic attack and creates immunologic privilege by induction of apoptosis in activated immune cells. Taken together, our results provide a plausible, exosome-based mechanistic explanation for the immune dysfunction and the compromised immune surveillance in endometriosis and contribute novel insights into the pathogenesis of this enigmatic disease.

Endometriosis, affecting 10% of women, is defined as implantation, survival, and growth of endometriumlike/endometriotic tissue outside the uterine cavity, causing inflammation, infertility, pain andsusceptibility to ovarian cancer. Despite extensive studies, its etiology and pathogenesis are poorlyunderstood and largely unknown. The prevailing view is that the immune system of endometriosispatients fails to clear ectopically disseminated endometrium from retrograde menstruation. Exosomes aresmall extracellular vesicles that exhibit immunomodulatory properties. We studied the role ofendometriotic tissue-secreted exosomes in the pathophysiology of endometriosis. Two exosome-mediatedmechanisms known to impair the immune response were investigated: 1) downregulation of NKG2Dmediatedcytotoxicity and 2) FasL- and TRAIL-induced apoptosis of activated immune cells. We showedthat secreted endometriotic exosomes isolated from supernatants of short-term explant cultures carry theNKG2D ligands MICA/B and ULBP1-3; and the proapoptotic molecules FasL and TRAIL on theirsurface, i.e. signature molecules of exosome-mediated immune suppression. Acting as decoys, theseexosomes downregulate the NKG2D receptor, impair NKG2D-mediated cytotoxicity and induce apoptosisof activated PBMC and Jurkat cells through the FasL- and TRAIL pathway. The secreted endometrioticexosomes create an immunosuppressive gradient at the ectopic site, forming a “protective shield” aroundthe endometriotic lesions. This gradient guards the endometriotic lesions against clearance by a cytotoxicattack and creates immunologic privilege by induction of apoptosis in activated immune cells. Takentogether, our results provide a plausible, exosome-based mechanistic explanation for the immunedysfunction and the compromised immune surveillance in endometriosis and contribute with novelinsights into the pathogenesis of this enigmatic disease.

Background: Without evidence, positive expiratory pressure therapy is a part of rehabilitation worldwide to prevent postoperative hypoxia. Reading aloud could be used as an alternative therapy as lung volumes increases while speaking. We aimed to investigate whether reading aloud is superior to positive expiratory pressure therapy for improving oxygen saturation after abdominal surgery.

Material and Methods: This crossover randomized controlled trial compared reading a text aloud with positive expiratory pressure therapy in patients on postoperative day 1 or 2 after upper gastrointestinal, colorectal, urological, or gynecological abdominal surgery at Umeå University Hospital, Sweden. The primary outcome was the change in peripheral oxygen saturation compared with baseline at 7 min after the intervention. The secondary outcome was transcutaneous carbon dioxide partial pressure change.

Results: This study included 50 patients of which 48 patients were analyzed. Peripheral oxygen saturation rapidly decreased to minimum values below baseline immediately after both interventions and then increased to values above baseline after reading aloud (1%, 95% confidence interval 0.2% to 1%, P = 0.004), but not after positive expiratory pressure therapy (−0.2%, 95% confidence interval −1% to 0.4%, P = 0.436). The difference in oxygen saturation was 1% (95% confidence interval 0.1% to 2%, P = 0.039) at 7 min after termination of the interventions. The interventions reduced transcutaneous carbon dioxide partial pressure by similar amounts.

Conclusions: This trial adds to the evidence against the use of positive expiratory pressure therapy after abdominal surgery. It is even slightly better to read aloud.

Background: Tinzaparin, a low-molecular weight heparin (LMWH), has shown anti-neoplastic properties in animal models and in in vitro studies of human cancer cell lines. The reduction of CA-125 levels during neoadjuvant chemotherapy (NACT) in patients with epithelial ovarian cancer (EOC) co-varies with the prognosis; the larger the decrease in CA-125, the better the prognosis.

Purpose: This study aims to evaluate the potential anti-neoplastic effects of tinzaparin by investigating changes in serum CA-125 levels in advanced EOC patients who receive NACT.

Material and methods: This is an open randomized multicenter pilot trial. Forty patients with EOC selected to receive NACT will be randomized 1:1 to receive daily addition of tinzaparin or no tinzaparin. The processing and treatment of the patients will otherwise follow the recommendations in the Swedish National Guidelines for Ovarian Cancer. Before every cycle of chemotherapy, preoperatively, and 3 weeks after the last cycle of chemotherapy, a panel of biomarkers, including CA-125, will be measured.

Patients: Inclusion criteria are women aged 18 years or older, World Health Organization performance status 0–1, histologically confirmed high-grade serous, endometrioid or clear cell EOC, International Federation of Gynecology and Obstetrics (FIGO) stages III-IV. In addition, a CA-125 level of ≥ 250 kIE/L at diagnosis. Exclusion criteria are contraindications to LMWH, ongoing or recent treatment with unfractionated heparin, LMWH, warfarin or non-vitamin K antagonist oral anticoagulants.

Interpretation: This study will make an important contribution to the knowledge of the anti-neoplastic effects of tinzaparin in EOC patients and may thus guide the planning of a future study on the impact of tinzaparin on survival in EOC.

BACKGROUND: Colorectal anastomotic leakage is consistently more common in men, regardless of tumour location. This fact is largely unexplained but might be a consequence of biological differences including hormonal exposure and not only related to anatomy.

METHODS: This was a retrospective, nationwide registry-based observational study of post-menopausal women operated for colorectal cancer with an anastomosis between 2007 and 2016. Hormonal exposure before surgery, as defined by prescribed drugs affecting oestrogen levels, was related to postoperative anastomotic leakage, using mixed-effects logistic regression models with adjustment for confounding. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were derived. In addition, separate estimates according to tumour location were computed, and a sensitivity analysis excluding topical oestrogen hormone exposure was conducted.

RESULTS: Some 16,535 post-menopausal women were included, of which 16.2% were exposed to drugs increasing oestrogen levels before surgery. In this exposed group compared to the unexposed, leak rates were 3.1 and 3.8%, respectively. After adjustment, a reduction of anastomotic leakage in the exposed group was detected (OR: 0.77; 95% CI: 0.59-0.99). This finding was largely attributed to the rectal cancer subgroup (OR: 0.55; 95% CI: 0.36-0.85), while the exclusion of topical oestrogen drugs further reduced the estimates of the main analysis (OR: 0.63; 95% CI: 0.38-1.02).

CONCLUSIONS: Anastomotic leakage rates are lower in women exposed to hormone replacement therapy before surgery for colorectal cancer, which might explain some of the difference in leak rates between men and women, especially regarding rectal cancer.

Psammocarcinoma (PsC) represents a rare form of low-grade serous tumor of the ovary or peritoneum. Although ovarian cancer generally has a poor prognosis in its late stages, PsC seems to have a more indolent course. We present a patient with a history of unspecific abdominal pain for more than a year, with sudden acute onset of severe inguinal pain. On admission to the hospital, a computed tomography (CT) revealed a pelvic mass of suspected ovarian origin. Radical surgery was attempted but not achieved due to widespread tumor growth. Histopathological evaluation revealed estrogen receptor-positive stage III PsC. Tamoxifen treatment was thus initiated, still maintaining stable disease 10 years later. The patient has undergone extensive radiological work-up, including CT, chest X-ray, 18F-fluoro-deoxy-glucose positron emission tomography (PET)/CT, 99mTc- hydroxymethylene diphosphonate (HDP) bone scintigraphy, 18F-fluoro-thymidine (FLT) PET/CT, Tc-99m depreotide scintigraphy and magnetic resonance imaging. In conclusion, we demonstrate that PsC has characteristic radiological features and different imaging modalities can be suitable in different clinical situations. In contrast to most other ovarian cancers, PsC does not always warrant adjuvant chemotherapy, even in advanced stages. This emphasizes the need for a deeper knowledge of the biological behavior of this rare tumor, to select the optimal treatment strategy.

Problem: Tumors compromise the patients’ immune system to promote their own survival. We have previously reported that HGSC exosomes play a central role, downregulating NKG2D cytotoxicity. Primary surgery's effect on tumor exosomes and NKG2D cytotoxicity in HGSC patients has not been studied before. The overall objective of this study was to explore the effect of surgery on the exosome-induced impairment of NKG2D cytotoxicity in HGSC.

Method of study: Paired pre- and post-operative blood samples were subjected to cell and exosome analyses regarding the NKG2D receptor and ligands, and NKG2D-mediated cytotoxicity. Lymphocytes were phenotyped by immunoflow cytometry. Exosomes, isolated by ultracentrifugation, and characterized by nanoparticle tracking analysis, transmission and immune electron microscopy and western blot were used in functional cytotoxic experiments. HGSC explant culture-derived exosomes, previously studied by us, were used for comparison.

Results: HGSC exosomes from patients’ sera downregulated NKG2D-mediated cytotoxicity in NK cells of healthy donors. In a subgroup of subjects, NKG2D expression on CTLs and NK cells was upregulated after surgery, correlating to a decrease in the concentration of exosomes in postoperative sera. An overall significantly improved NKG2D-mediated cytotoxic response of the HGSC patients’ own NK cells in postoperative compared to preoperative samples was noted.

Conclusions: Surgical removal of the primary tumor has a beneficial effect, relieving the exosome-mediated suppression of NKG2D cytotoxicity in HGSC patients, thus boostering their ability to combat cancer.