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- Asim, M, et al.
(author)
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Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer
- 2017
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8:1, s. 374-
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Journal article (peer-reviewed)abstract
- Emerging data demonstrate homologous recombination (HR) defects in castration-resistant prostate cancers, rendering these tumours sensitive to PARP inhibition. Here we demonstrate a direct requirement for the androgen receptor (AR) to maintain HR gene expression and HR activity in prostate cancer. We show that PARP-mediated repair pathways are upregulated in prostate cancer following androgen-deprivation therapy (ADT). Furthermore, upregulation of PARP activity is essential for the survival of prostate cancer cells and we demonstrate a synthetic lethality between ADT and PARP inhibition in vivo. Our data suggest that ADT can functionally impair HR prior to the development of castration resistance and that, this potentially could be exploited therapeutically using PARP inhibitors in combination with androgen-deprivation therapy upfront in advanced or high-risk prostate cancer.
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- Veenstra, M M K, et al.
(author)
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Complications and survival after hybrid and fully minimally invasive oesophagectomy
- 2021
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In: BJS Open. - : John Wiley & Sons. - 2474-9842. ; 5:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: Minimally invasive oesophagectomy (MIO) is reported to produce fewer respiratory complications than open oesophagectomy. This study assessed differences in postoperative complications between MIO and hybrid MIO (HMIO) employing thoracoscopy and laparotomy, along with the influence of co-morbidities on postoperative outcomes.METHODS: Patients with oesophageal cancer undergoing three-stage MIO or three-stage HMIO between 1999 and 2018 were identified from a prospectively developed database, which included patient demographics, co-morbidities, preoperative therapies, and cancer stage. The primary outcome was postoperative complications in the two groups. Secondary outcomes included duration of operation, blood transfusion requirement, duration of hospital stay, and overall survival.RESULTS: There were 828 patients, of whom 722 had HMIO and 106 MIO, without significant baseline differences. Median duration of operation was longer for MIO (325 versus 289 min; P < 0.001), but with less blood loss (median 250 versus 300 ml; P < 0.001) and a shorter hospital stay (median 12 versus 13 days; P = 0.006). Respiratory complications were not associated with operative approach (31.1 versus 35.2 per cent for MIO and HMIO respectively; P = 0.426). Anastomotic leak rates (10.4 versus 10.2 per cent) and 90-day mortality (1.0 versus 1.7 per cent) did not differ. Cardiac co-morbidity was associated with more medical and surgical complications. Overall survival was associated with AJCC stage and co-morbidities, but not operative approach.CONCLUSION: MIO had a small benefit in terms of blood loss and hospital stay, but not in operating time. Oncological outcomes were similar in the two groups. Postoperative complications were associated with pre-existing cardiorespiratory co-morbidities rather than operative approach.
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- Busweiler, L A D, et al.
(author)
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International benchmarking in oesophageal and gastric cancer surgery
- 2019
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In: BJS Open. - : Oxford University Press (OUP). - 2474-9842. ; 3:1, s. 62-73
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Journal article (peer-reviewed)abstract
- Background: Benchmarking on an international level might lead to improved outcomes at a national level. The aim of this study was to compare treatment and surgical outcome data from the Swedish National Register for Oesophageal and Gastric Cancer (NREV) and the Dutch Upper Gastrointestinal Cancer Audit (DUCA).Methods: All patients with primary oesophageal or gastric cancer who underwent a resection and were registered in NREV or DUCA between 2012 and 2014 were included. Differences in 30-day mortality were analysed using case mix-adjusted multivariable logistic regression.Results: In total, 4439 patients underwent oesophagectomy (2509 patients) or gastrectomy (1930 patients). Estimated resection rates were comparable. Swedish patients were older but had less advanced disease and less co-morbidity than Dutch patients. Neoadjuvant treatment rates were lower in Sweden than in the Netherlands, both for patients who underwent oesophagectomy (68·6 versus 90·0 per cent respectively; P < 0·001) and for those having gastrectomy (38·3 versus 56·6 per cent; P < 0·001). In Sweden, transthoracic oesophagectomy was performed in 94·7 per cent of patients, whereas in the Netherlands, a transhiatal approach was undertaken in 35·8 per cent. Higher annual procedural volumes per hospital were observed in the Netherlands. Adjusted 30-day and/or in-hospital mortality after gastrectomy was statistically significantly lower in Sweden than in the Netherlands (odds ratio 0·53, 95 per cent c.i. 0·29 to 0·95).Conclusion: For oesophageal and gastric cancer, there are differences in patient, tumour and treatment characteristics between Sweden and the Netherlands. Postoperative mortality in patients with gastric cancer was lower in Sweden.
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- Linder, Gustav, 1981-
(author)
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Esophageal- and Gastroesophageal Junctional Cancer : Aspects on Staging, Treatment and Results
- 2018
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Doctoral thesis (other academic/artistic)abstract
- Esophageal- and gastroesophageal junctional (GEJ) cancer is the sixth cause of cancer-related death worldwide. Some improvements in care are attributed to nationwide disease-specific registries, preoperative staging and increased understanding of mechanisms affecting patient selection. Surgery, however, is a cornerstone for treatment where minimally invasive surgery and increased understanding of perioperative physiology may be beneficial. The aims of this thesis were to validate the Swedish national registry for esophageal and gastric cancer (NREV) and to explore mechanisms in patient selection, perioperative physiology, treatment-related outcomes and staging.A validation study with re-abstracted data on 400 patients determined NREV comparable to other similar registries and to have a completeness of 95.5 %. Overall accuracy was 91.1 % throughout the registry and timeliness to reporting was adequate.In a cohort of 4112 patients from NREV, high education level was associated with an increased probability of being allocated to curative treatment, as was the presence of a multidisciplinary treatment conference. High education level was associated with improved survival.By measuring intramucosal pH (pHi) in 32 patients, to describe perfusion in the gastric conduit during esophagectomy, a reduction in perfusion was seen at all surgical steps altering vascular supply to the conduit but foremost after gastric tube construction by linear stapling. Patients with low pHi on the first postoperative day were more prone to anastomotic insufficiency.In 116 patients undergoing esophagectomy (65 open and 51 minimally invasive), a retrospective cohort study regarding surgical oncological results and postoperative complications was conducted. Lymph node yield was increased, peroperative blood loss and in-hospital stay were reduced with minimally invasive esophagectomy. Postoperative complications were unaffected by surgical approach. In a prospective study of nineteen patients, whole-body integrated PET/MRI was compared to PET/CT in preoperative staging. PET/MRI was safe and feasible. Accuracy and correlations between modalities were good regarding tumor characteristics and N- and M-staging. In T-staging there were discrepancies indicating differences between modalities.The thesis presents data on the quality of NREV for future research and elaborates on patient selection, staging, perioperative physiology and treatment-related outcomes for patients with esophageal- and GEJ cancer.
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- Mege, D, et al.
(author)
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Surgical management of esophageal sarcoma: a multicenter European experience
- 2018
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In: Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus. - : Oxford University Press (OUP). - 1442-2050. ; 31:3
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Journal article (peer-reviewed)abstract
- Esophageal sarcomas are rare and evidence in literature is scarce making their management difficult. The objective is to report surgical and oncological outcomes of esophageal sarcoma in a large multicenter European cohort. This is a retrospective multicenter study including all patients who underwent en-bloc esophagectomy for esophageal sarcoma in seven European tertiary referral centers between 1987 and 2016. The main outcomes and measures are pathological results, early and long-term outcomes. Among 10,936 esophageal resections for cancer, 21 (0.2%) patients with esophageal sarcoma were identified. The majority of tumors was located in the middle (n = 7) and distal (n = 9) third of the esophagus. Neoadjuvant chemoradiotherapy was performed in five patients. All the patients underwent en-bloc transthoracic esophagectomy (19 open, 2 minimally invasive). Postoperative mortality occurred in 1 patient (5%). One patient received adjuvant chemotherapy. Definitive pathological results were carcinosarcoma (n = 7), leiomyosarcoma (n = 5), and other types of sarcoma (n = 9). Microscopic R1 resection was present in one patient (5%) and seven patients (33%) had positive lymph nodes. Median follow-up was 16 (3–79) months in 20 of 21 patients (95%). One-, 3-, and 5-year overall survival rates were 74%, 43%, and 35%, respectively. One-, 3- and 5-years disease-free survival rates were 58%, 40%, and 33%, respectively. Median overall survival was 6 months in N+ patients vs. 37 months for N0 patients (p = 0.06). At the end of the follow-up period, nine patients had died from cancer recurrences (43%), three patients died from other reasons (14%), one patient was still alive with recurrence (5%) and the seven remaining patients were free of disease (33%). Recurrence was local (n = 3), metastatic (n = 3), or both (n = 4). In conclusion, carcinosarcoma and leiomyosarcoma were the most common esophageal sarcoma histological subtypes. Lymph node involvement was seen in one third of cases. A transthoracic en-bloc esophagectomy with radical lymphadenectomy should be the best surgical option to achieve complete resection. Long-term survival remained poor with a high local and distant recurrence rate.
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- Toxopeus, Eelke L. A., et al.
(author)
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Association between Paclitaxel Clearance and Tumor Response in Patients with Esophageal Cancer
- 2019
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In: Cancers. - : MDPI. - 2072-6694. ; 11:2
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Journal article (peer-reviewed)abstract
- Inter-individual variability in paclitaxel pharmacokinetics may play a role in the response to chemotherapy. Therefore, we studied the association between paclitaxel clearance and treatment response in patients with esophageal cancer. All patients who received paclitaxel (plus carboplatin) treatment for esophageal cancer between 2007 and 2013 were included. The treatment was given as neoadjuvant chemoradiotherapy (nCRT), induction chemotherapy (iCT), or palliative chemotherapy (pCT). The treatment response was assessed by the tumor regression grade (TRG) or by the RECIST1.1 criteria, respectively. The unbound paclitaxel clearance (CL) was estimated with NONMEM. The log-transformed clearance was related to response with ANOVA and independent sample t-tests. A total of 166 patients were included, of whom 113 received nCRT, 23 iCT and 30 pCT. In patients receiving nCRT, paclitaxel clearance was not associated with tumor regression grade (p-value = 0.25), nor with pathologically complete response (geometric mean 561.6 L/h) and residual disease (geometric mean 566.1 L/h, p-value = 0.90). In patients who underwent iCT or pCT, also no association between paclitaxel clearance and RECIST outcome was identified (iCT: p-value = 0.08 and pCT: p-value = 0.81, respectively). In conclusion, systemic paclitaxel exposure was not associated with response to common paclitaxel-based treatment regimens for esophageal cancer. Future studies should focus on tumor exposure in relation to systemic exposure and treatment outcome.
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| 26. |
- van den Hoven, M J, et al.
(author)
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Reduction of anionic sites in the glomerular basement membrane by heparanase does not lead to proteinuria
- 2008
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In: Kidney International. - : Elsevier BV. - 0085-2538 .- 1523-1755. ; 73:3, s. 278-287
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Journal article (peer-reviewed)abstract
- Heparan sulfate in the glomerular basement membrane has been considered crucial for charge-selective filtration. In many proteinuric diseases, increased glomerular expression of heparanase is associated with decreased heparan sulfate. Here, we used mice overexpressing heparanase and evaluated the expression of different heparan sulfate domains in the kidney and other tissues measured with anti-heparan sulfate antibodies. Glycosaminoglycan-associated anionic sites were visualized by the cationic dye cupromeronic blue. Transgenic mice showed a differential loss of heparan sulfate domains in several tissues. An unmodified and a sulfated heparan sulfate domain resisted heparanase action in vivo and in vitro. Glycosaminoglycan-associated anionic sites were reduced about fivefold in the glomerular basement membrane of transgenic mice, whereas glomerular ultrastructure and renal function remained normal. Heparanase-resistant heparan sulfate domains may represent remnant chains or chains not susceptible to cleavage. Importantly, the strong reduction of glycosaminoglycan-associated anionic sites in the glomerular basement membrane without development of a clear renal phenotype questions the primary role of heparan sulfate in charge-selective filtration. We cannot, however, exclude that overexpression of heparanase and heparan sulfate loss in the basement membrane in glomerular diseases contributes to proteinuria.
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- Wijnhoven, T, et al.
(author)
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WHO European Childhood Obesity Surveillance Initiative: Impact of Type of Clothing Worn during Anthropometric Measurements and Timing of the Survey on Weight and Body Mass Index Outcome Measures in 6–9-Year-Old Children
- 2016
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In: Epidemiology Research International. - : Hindawi Limited. - 2090-2972 .- 2090-2980. ; 2016, s. 1-16
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Journal article (peer-reviewed)abstract
- Background. The World Health Organization European Childhood Obesity Surveillance Initiative (COSI) conducted examinations in 6–9-year-old children from 16 countries in the first two rounds of data collection. Allowing participating countries to adhere to their local legal requirements or adapt to other circumstances required developing a flexible protocol for anthropometric procedures. Objectives. (1) Review intercountry variation in types of clothing worn by children during weight and height measurements, clothes weight adjustments applied, timing of the survey, and duration of data collection; (2) assess the impact of the observed variation in these practices on the children’s weight or body mass index (BMI) outcome measures. Results. The relative difference between countries’ unadjusted and clothes-adjusted prevalence estimates for overweight was 0.3–11.5%; this figure was 1.4–33.3% for BMI-for-age Z-score values. Monthly fluctuations in mean BMI-for-age Z-score values did not show a systematic seasonal effect. The majority of the monthly BMI-for-age Z-score values did not differ statistically within a country; only 1–3 monthly values were statistically different within some countries. Conclusions. The findings of the present study suggest that the built-in flexibility in the COSI protocol concerning the data collection practices addressed in the paper can be kept and thus do not necessitate a revision of the COSI protocol.
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