Publications by authors named "P A Nygren"

441 Publications

A phase 2a clinical study on the safety and efficacy of individualized dosed mebendazole in patients with advanced gastrointestinal cancer.

Sci Rep 2021 Apr 26;11(1):8981. Epub 2021 Apr 26.

Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

Mebendazole is used extensively for treatment of local gut helminthic and invasive echinococcus infections. Anticancer effects of mebendazole have been shown in experimental cancer models and in case studies in patients with advanced cancer. Given these observations, the aims of this study were to investigate safety and efficacy of individualized dosed mebendazole in the cancer indication. Patients with treatment refractory gastrointestinal cancer were treated with individualized dose adjusted mebendazole up to 4 g/day to target a serum concentration of 300 ng/ml. Efficacy and safety were assessed by CT-scans, clinical surveillance and blood sampling. Eleven patients were included in the study and 10 started the treatment phase. Two patients stopped treatment prior to and the remaining eight after tumour evaluation by CT-scan at 8 weeks, all due to progressive disease. Four patients also fulfilled criteria suggested for hyperprogression. Only five patients reached the target serum-mebendazole concentration. No severe adverse effects were observed. Individualized dose adjusted mebendazole is safe and well tolerated in patients with advanced cancer but all patients experienced rapid progressive disease. New approaches such as prodrug development and combination with other anticancer drugs seem needed for further exploration of mebendazole as an anticancer drug.
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http://dx.doi.org/10.1038/s41598-021-88433-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076239PMC
April 2021

Does exercise intensity matter for fatigue during (neo-)adjuvant cancer treatment? The Phys-Can randomized clinical trial.

Scand J Med Sci Sports 2021 May 2;31(5):1144-1159. Epub 2021 Mar 2.

Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.

Exercise during cancer treatment improves cancer-related fatigue (CRF), but the importance of exercise intensity for CRF is unclear. We compared the effects of high- vs low-to-moderate-intensity exercise with or without additional behavior change support (BCS) on CRF in patients undergoing (neo-)adjuvant cancer treatment. This was a multicenter, 2x2 factorial design randomized controlled trial (Clinical Trials NCT02473003) in Sweden. Participants recently diagnosed with breast (n = 457), prostate (n = 97) or colorectal (n = 23) cancer undergoing (neo-)adjuvant treatment were randomized to high intensity (n = 144), low-to-moderate intensity (n = 144), high intensity with BCS (n = 144) or low-to-moderate intensity with BCS (n = 145). The 6-month exercise intervention included supervised resistance training and home-based endurance training. CRF was assessed by Multidimensional Fatigue Inventory (MFI, five subscales score range 4-20), and Functional Assessment of Chronic Illness Therapy-Fatigue scale (FACIT-F, score range 0-52). Multiple linear regression for main factorial effects was performed according to intention-to-treat, with post-intervention CRF as primary endpoint. Overall, 577 participants (mean age 58.7 years) were randomized. Participants randomized to high- vs low-to-moderate-intensity exercise had lower physical fatigue (MFI Physical Fatigue subscale; mean difference -1.05 [95% CI: -1.85, -0.25]), but the difference was not clinically important (ie <2). We found no differences in other CRF dimensions and no effect of additional BCS. There were few minor adverse events. For CRF, patients undergoing (neo-)adjuvant treatment for breast, prostate or colorectal cancer can safely exercise at high- or low-to-moderate intensity, according to their own preferences. Additional BCS does not provide extra benefit for CRF in supervised, well-controlled exercise interventions.
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http://dx.doi.org/10.1111/sms.13930DOI Listing
May 2021

Mebendazole is unique among tubulin-active drugs in activating the MEK-ERK pathway.

Sci Rep 2020 08 4;10(1):13124. Epub 2020 Aug 4.

Division of Cancer Pharmacology and Computational Medicine, Department of Medical Sciences, Uppsala University, 75185, Uppsala, Sweden.

We recently showed that the anti-helminthic compound mebendazole (MBZ) has immunomodulating activity in monocyte/macrophage models and induces ERK signalling. In the present study we investigated whether MBZ induced ERK activation is shared by other tubulin binding agents (TBAs) and if it is observable also in other human cell types. Curated gene signatures for a panel of TBAs in the LINCS Connectivity Map (CMap) database showed a unique strong negative correlation of MBZ with MEK/ERK inhibitors indicating ERK activation also in non-haematological cell lines. L1000 gene expression signatures for MBZ treated THP-1 monocytes also connected negatively to MEK inhibitors. MEK/ERK phosphoprotein activity testing of a number of TBAs showed that only MBZ increased the activity in both THP-1 monocytes and PMA differentiated macrophages. Distal effects on ERK phosphorylation of the substrate P90RSK and release of IL1B followed the same pattern. The effect of MBZ on MEK/ERK phosphorylation was inhibited by RAF/MEK/ERK inhibitors in THP-1 models, CD3/IL2 stimulated PBMCs and a MAPK reporter HEK-293 cell line. MBZ was also shown to increase ERK activity in CD4+ T-cells from lupus patients with known defective ERK signalling. Given these mechanistic features MBZ is suggested suitable for treatment of diseases characterized by defective ERK signalling, notably difficult to treat autoimmune diseases.
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http://dx.doi.org/10.1038/s41598-020-68986-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403428PMC
August 2020

Cocreated internet-based stepped care for individuals with cancer and concurrent symptoms of anxiety and depression: Results from the U-CARE AdultCan randomized controlled trial.

Psychooncology 2020 12 22;29(12):2012-2018. Epub 2020 Sep 22.

Department of Immunology, Genetics and Pathology, Section of Experimental and Clinical Oncology, Uppsala University, Uppsala, Sweden.

Objective: The aim was to evaluate the effects of cocreated internet-based stepped care (iCAN-DO) on anxiety, depression, posttraumatic stress, and health-related quality of life (HRQoL) in individuals with cancer and self-reported anxiety and/or depression symptoms, compared with standard care.

Methods: Clinically recruited individuals with breast, colorectal, or prostate cancer underwent online screening with the Hospital Anxiety and Depression Scale (HADS). Those with anxiety and/or depression symptoms (>7 on any of the HADS subscales) were randomized to iCAN-DO or standard care. iCAN-DO comprised psychoeducation and self-care strategies (step 1) and internet-based cognitive behavioral therapy (iCBT, step 2). Data were collected before randomization and at 1, 4, 7, and 10 months and analyzed with intention-to-treat regression analysis and randomization tests.

Results: Online screening identified 245 (27%) of 909 individuals who reported anxiety and/or depression symptoms. They were randomized to iCAN-DO (n  = 124) or standard care (n = 121). Of them 49% completed the 10-month assessment, and in the iCAN-DO group 85% accessed step 1 and 13% underwent iCBT. iCAN-DO decreased the levels of symptoms of depression (-0.54, 95% confidence interval: -1.08 to -0.01, P < .05) and the proportion of individuals with symptoms of depression (P < .01) at 10 months, compared with standard care, according to HADS. There were no significant effects on anxiety, posttraumatic stress, or HRQoL.

Conclusion: Internet-based stepped care improves symptoms of depression in individuals with cancer. Further studies are needed to gain knowledge on how to optimize and implement internet-based support in oncology care.
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http://dx.doi.org/10.1002/pon.5489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821133PMC
December 2020

Ultrasound-guided Percutaneous Irreversible Electroporation for Treatment of Locally Recurrent Pancreatic Cancer After Surgical Resection.

Anticancer Res 2020 May;40(5):2771-2775

Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.

Background/aim: Irreversible electroporation (IRE) has recently been used as an experimental treatment for cancers including locally advanced pancreatic cancer. There is very limited data on IRE in pancreatic cancer that is locally recurrent after surgical resection. The aim of this study was to evaluate the safety and efficacy of IRE in this setting.

Patients And Methods: Ten patients with locally recurrent pancreatic cancer without distant metastases after surgical resection were included and treated with ultrasound-guided percutaneous IRE.

Results: Two patients had severe complications, of whom one died. Median disease-free survival was 3.3 months and overall median survival after IRE and resection was 16.5 and 42.7 months, respectively. Two patients are alive 42.1 and 23.9 months after the IRE without signs of local recurrence.

Conclusion: Percutaneous IRE in locally recurrent pancreatic cancer following curative resection is feasible, but should be regarded as a high-risk procedure that, at present, cannot be recommended outside of clinical trials. Further research is needed to select patients who might benefit from this treatment.
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http://dx.doi.org/10.21873/anticanres.14249DOI Listing
May 2020