Publications by authors named "Johan Hansson"

195 Publications

Co-expression of MTH1 and PMS2 is associated with advanced disease and disease progression after therapy in melanoma.

J Invest Dermatol 2021 Aug 18. Epub 2021 Aug 18.

Department of Oncology-Pathology, Karolinska Institutet, S-171 64 Stockholm, Sweden. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2021.07.166DOI Listing
August 2021

PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma.

Sci Rep 2021 May 26;11(1):11023. Epub 2021 May 26.

Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.

BRAF inhibitors (BRAFi) selectively target oncogenic BRAF and are effective in 80% of advanced cutaneous malignant melanoma cases carrying the V600 mutation. However, the development of drug resistance limits their clinical efficacy. Better characterization of the underlying molecular processes is needed to further improve treatments. We previously demonstrated that transcription of PTEN is negatively regulated by the PTEN pseudogene antisense RNA, PTENP1-AS, and here we investigated the impact of this transcript on clinical outcome and BRAFi resistance in melanoma. We observed that increased expression levels of PTENP1-AS in BRAFi resistant cells associated with enrichment of EZH2 and H3K27me3 at the PTEN promoter, consequently reducing the expression levels of PTEN. Further, we showed that targeting of the PTENP1-AS transcript sensitized resistant cells to BRAFi treatment and that high expression of PTENP1-AS in stage III melanoma correlated with poor survival. Collectively, the data presented here show that PTENP1-AS is a promising target for re-sensitizing cells to BRAFi and also a possible prognostic marker for clinical outcome in stage III melanoma.
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http://dx.doi.org/10.1038/s41598-021-89389-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155038PMC
May 2021

Predicting anti-PD-1 responders in malignant melanoma from the frequency of S100A9+ monocytes in the blood.

J Immunother Cancer 2021 May;9(5)

Department of Medicine, Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Stockholm, Sweden

Background: While programmed cell death receptor 1 (PD-1) blockade treatment has revolutionized treatment of patients with melanoma, clinical outcomes are highly variable, and only a fraction of patients show durable responses. Therefore, there is a clear need for predictive biomarkers to select patients who will benefit from the treatment.

Method: To identify potential predictive markers for response to PD-1 checkpoint blockade immunotherapy, we conducted single-cell RNA sequencing analyses of peripheral blood mononuclear cells (PBMC) (n=8), as well as an in-depth immune monitoring study (n=20) by flow cytometry in patients with advanced melanoma undergoing treatment with nivolumab at Karolinska University Hospital. Blood samples were collected before the start of treatment and at the time of the second dose.

Results: Unbiased single-cell RNA sequencing of PBMC in patients with melanoma uncovered that a higher frequency of monocytes and a lower ratio of CD4+ T cells to monocyte were inversely associated with overall survival. Similarly, S100A9 expression in the monocytic subset was correlated inversely with overall survival. These results were confirmed by a flow cytometry-based analysis in an independent patient cohort.

Conclusion: Our results suggest that monocytic cell populations can critically determine the outcome of PD-1 blockade, particularly the subset expressing S100A9, which should be further explored as a possible predictive biomarker. Detailed knowledge of the biological role of S100A9+ monocytes is of high translational relevance.
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http://dx.doi.org/10.1136/jitc-2020-002171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108662PMC
May 2021

Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families.

BMC Public Health 2021 04 23;21(1):692. Epub 2021 Apr 23.

Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands.

Background: Individuals from melanoma-prone families have similar or reduced sun-protective behaviors compared to the general population. Studies on trends in sun-related behaviors have been temporally and geographically limited.

Methods: Individuals from an international consortium of melanoma-prone families (GenoMEL) were retrospectively asked about sunscreen use, sun exposure (time spent outside), sunburns, and sunbed use at several timepoints over their lifetime. Generalized linear mixed models were used to examine the association between these outcomes and birth cohort defined by decade spans, after adjusting for covariates.

Results: A total of 2407 participants from 547 families across 17 centers were analyzed. Sunscreen use increased across subsequent birth cohorts, and although the likelihood of sunburns increased until the 1950s birth cohort, it decreased thereafter. Average sun exposure did not change across the birth cohorts, and the likelihood of sunbed use increased in more recent birth cohorts. We generally did not find any differences in sun-related behavior when comparing melanoma cases to non-cases. Melanoma cases had increased sunscreen use, decreased sun exposure, and decreased odds of sunburn and sunbed use after melanoma diagnosis compared to before diagnosis.

Conclusions: Although sunscreen use has increased and the likelihood of sunburns has decreased in more recent birth cohorts, individuals in melanoma-prone families have not reduced their overall sun exposure and had an increased likelihood of sunbed use in more recent birth cohorts. These observations demonstrate partial improvements in melanoma prevention and suggest that additional intervention strategies may be needed to achieve optimal sun-protective behavior in melanoma-prone families.
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http://dx.doi.org/10.1186/s12889-021-10424-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063451PMC
April 2021

TRIM study protocol - a prospective randomized multicenter Trial to assess the Role of Imaging during follow-up after radical surgery of stage IIB-C and III cutaneous malignant Melanoma.

BMC Cancer 2020 Dec 7;20(1):1197. Epub 2020 Dec 7.

Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck laboratory, 75185, Uppsala, Sweden.

Background: The incidence of cutaneous malignant melanoma (CMM) is increasing worldwide. In Sweden, over 4600 cases were diagnosed in 2018. The prognosis after radical surgery varies considerably with tumor stage. In recent years, new treatment options have become available for metastatic CMM. Early onset of treatment seems to improve outcome, which suggests that early detection of recurrent disease should be beneficial. Consequently, in several countries imaging is a part of the routine follow-up program after surgery of high risk CMM. However, imaging has drawbacks, including resources required (costs, personnel, equipment) and the radiation exposure. Furthermore, many patients experience anxiety in waiting for the imaging results and investigations of irrelevant findings is another factor that also could cause worry and lead to decreased quality of life. Hence, the impact of imaging in this setting is important to address and no randomized study has previously been conducted. The Swedish national guidelines stipulate follow-up for 3 years by clinical examinations only.

Methods: The TRIM study is a prospective randomized multicenter trial evaluating the potential benefit of imaging and blood tests during follow-up after radical surgery for high-risk CMM, compared to clinical examinations only. Primary endpoint is overall survival (OS) at 5 years. Secondary endpoints are survival from diagnosis of relapse and health-related quality of life (HRQoL). Eligible for inclusion are patients radically operated for CMM stage IIB-C or III with sufficient renal function for iv contrast-enhanced CT and who are expected to be fit for treatment in case of recurrence. The planned number of patients is > 1300. Patients are randomized to clinical examinations for 3 years +/- whole-body imaging with CT or FDG-PET/CT and laboratory tests including S100B protein and LDH. This academic study is supported by the Swedish Melanoma Study Group.

Discussion: This is the first randomized prospective trial on the potential benefit of imaging as a part of the follow-up scheme after radical surgery for high-risk CMM.

Results: The first patient was recruited in June 2017 and as of April 2020, almost 500 patients had been included at 19 centers in Sweden.

Trial Registration: ClinicalTrials.gov , NCT03116412 . Registered 17 April 2017, https://clinicaltrials.gov/ct2/show/study/NCT03116412.
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http://dx.doi.org/10.1186/s12885-020-07632-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720485PMC
December 2020

Inhibiting insulin and mTOR signaling by afatinib and crizotinib combination fosters broad cytotoxic effects in cutaneous malignant melanoma.

Cell Death Dis 2020 10 20;11(10):882. Epub 2020 Oct 20.

Department of Oncology-Pathology, Karolinska Institutet, 171 64, Stockholm, Sweden.

Current treatment modalities for disseminated cutaneous malignant melanoma (CMM) improve survival, however disease progression commonly ensues. In a previous study we identified afatinib and crizotinib in combination as a novel potential therapy for CMM independent of BRAF/NRAS mutation status. Herein, we elucidate the underlying mechanisms of the combination treatment effect to find biomarkers and novel targets for development of therapy that may provide clinical benefit by proteomic analysis of CMM cell lines and xenografts using mass spectrometry based analysis and reverse phase protein array. Identified candidates were validated using immunoblotting or immunofluorescence. Our analysis revealed that mTOR/Insulin signaling pathways were significantly decreased by the afatinib and crizotinib combination treatment. Both in vitro and in vivo analyses showed that the combination treatment downregulated pRPS6KB1 and pRPS6, downstream of mTOR signaling, and IRS-1 in the insulin signaling pathway, specifically ablating IRS-1 nuclear signal. Silencing of RPS6 and IRS-1 alone had a similar effect on cell death, which was further induced when IRS-1 and RPS6 were concomitantly silenced in the CMM cell lines. Silencing of IRS-1 and RPS6 resulted in reduced sensitivity towards combination treatment. Additionally, we found that IRS-1 and RPS6KB1 expression levels were increased in advanced stages of CMM clinical samples. We could demonstrate that induced resistance towards combination treatment was reversible by a drug holiday. CD171/L1CAM, mTOR and PI3K-p85 were induced in the combination resistant cells whereas AXL and EPHA2, previously identified mediators of resistance to MAPK inhibitor therapy in CMM were downregulated. We also found that CD171/L1CAM and mTOR were increased at progression in tumor biopsies from two matched cases of patients receiving targeted therapy with BRAFi. Overall, these findings provide insights into the molecular mechanisms behind the afatinib and crizotinib combination treatment effect and leverages a platform for discovering novel biomarkers and therapy regimes for CMM treatment.
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http://dx.doi.org/10.1038/s41419-020-03097-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576205PMC
October 2020

Bullous Pemphigoid-like Eruption Triggered by Targeted Therapy for Metastatic Melanoma.

Acta Derm Venereol 2020 Nov 26;100(18):adv00334. Epub 2020 Nov 26.

Oncology-Pathology and Department of Oncology/Skin Cancer Center, Theme Cancer, Karolinska Institutet, Karolinska University Hospital Solna, SE-176 76 Stockholm, Sweden. E-mail:

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http://dx.doi.org/10.2340/00015555-3648DOI Listing
November 2020

PD-1 checkpoint blockade in advanced melanoma patients: NK cells, monocytic subsets and host PD-L1 expression as predictive biomarker candidates.

Oncoimmunology 2020 08 28;9(1):1786888. Epub 2020 Aug 28.

Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.

Blockade of the PD-1 receptor has revolutionized the treatment of metastatic melanoma, with significant increases in overall survival (OS) and a dramatic improvement in patient quality of life. Despite the success of this approach, the number of benefitting patients is limited and there is a need for predictive biomarkers as well as a deeper mechanistic analysis of the cellular populations involved in clinical responses. With the aim to find predictive biomarkers for PD-1 checkpoint blockade, an in-depth immune monitoring study was conducted in 36 advanced melanoma patients receiving pembrolizumab or nivolumab treatment at Karolinska University Hospital. Blood samples were collected before treatment and before administration of the second and fourth doses. Peripheral blood mononuclear cells were isolated and stained for flow cytometric analysis within 2 h of sample collection. Overall survival and progression-free survival (PFS) were inversely correlated with CD69 expression NK cells. In the myeloid compartment, high frequencies of non-classical monocytes and low frequencies of monocytic myeloid derived suppressor cells (MoMDSCs) correlated with response rates and OS. A deeper characterization of monocytic subsets showed that PD-L1 expression in MDSCs, non-classical and intermediate monocytes was significantly increased in patients with shorter PFS in addition to correlating inversely with OS. Our results suggest that cellular populations other than T cells can be critical in the outcome of PD-1 blockade treatment. Specifically, the frequencies of activated NK cells and monocytic subsets are inversely correlated with survival and clinical benefit, suggesting that their role as predictive biomarkers should be further evaluated.
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http://dx.doi.org/10.1080/2162402X.2020.1786888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470181PMC
August 2020

Complete and long-lasting clinical responses in immune checkpoint inhibitor-resistant, metastasized melanoma treated with adoptive T cell transfer combined with DC vaccination.

Oncoimmunology 2020 07 11;9(1):1792058. Epub 2020 Jul 11.

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

Development of T cell-directed immune checkpoint inhibitors (ICI) has revolutionized metastatic melanoma (MM) therapy, but <50% of treated patients experience durable responses. This phase I trial (NCT01946373) investigates the safety/feasibility of tumor-infiltrating lymphocyte (TIL) adoptive cell therapy (ACT) combined with dendritic cell (DC) vaccination in MM patients progressing on ICI. An initial cohort (5 patients) received TIL therapy alone to evaluate safety and allow for optimization of TIL expansion protocols. A second cohort (first-in-man, 5 patients) received TIL combined with autologous tumor lysate-loaded DC vaccination. All patients received cyclophosphamide/fludarabine preconditioning prior to, and intravenous (i.v.) IL-2 after, TIL transfer. The DC vaccine was given as five intradermal injections after TIL and IL-2 administration. [F]-FDG PET/CT radiology was performed to evaluate clinical response, according to RECIST 1.1 (on the CT part). Immunological monitoring was performed by flow cytometry and T-cell receptor (TCR) sequencing. In the safety/optimization cohort, all patients had a mixed response or stable disease, but none durable. In the combination cohort, two patients experienced complete responses (CR) that are still ongoing (>36 and >18 months, respectively). In addition, two patients had partial responses (PR), one still ongoing (>42 months) with only a small bone-lesion remaining, and one of short duration (<4 months). One patient died early during treatment and did not receive DC. Long-lasting persistency of the injected TILs was demonstrated in blood. In summary, we report clinical responses by TIL therapy combined with DC vaccination in 4 out of 4 treated MM patients who previously failed ICI.
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http://dx.doi.org/10.1080/2162402X.2020.1792058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458624PMC
July 2020

Silencing of CEBPB-AS1 modulates CEBPB expression and resensitizes BRAF-inhibitor resistant melanoma cells to vemurafenib.

Melanoma Res 2020 10;30(5):443-454

Department of Oncology and Pathology, Karolinska Institutet, Bioclinicum, Solna.

Introduction of targeted therapy in the treatment of metastatic cutaneous malignant melanoma (CMM) has improved clinical outcome during the last years. However, only in a subset of the CMM patients, this will lead to long-term effects. CEBPB is a transcription factor that has been implicated in various physiological and pathological processes, including cancer development. We have investigated its prognostic impact on CMM and unexpectedly found that higher CEBPB mRNA levels correlated with a longer overall survival. Furthermore, in a small cohort of patients with metastatic CMM treated with BRAF-inhibitors, higher levels of CEBPB mRNA expression in the tumor cells prior treatment correlated to a longer progression-free survival. We have characterized an overlapping antisense transcript, CEBPB-AS1, with the aim to investigate the regulation of CEBPB expression in CMM and its impact on BRAF-inhibitor sensitivity. We demonstrated that silencing of CEBPB-AS1 resulted in epigenetic modifications in the CEBPB promoter and in increased CEBPB mRNA and protein levels, inhibited proliferation and partially resensitized BRAF-inhibitor resistant CMM cells to this drug-induced apoptosis. Our data suggest that targeting CEBPB-AS1 may represent a valuable tool to sensitize CMM cells to the BRAF-inhibitor-based therapies.
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http://dx.doi.org/10.1097/CMR.0000000000000675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469874PMC
October 2020

Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility.

Nat Genet 2020 05 27;52(5):494-504. Epub 2020 Apr 27.

Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain.

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.
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http://dx.doi.org/10.1038/s41588-020-0611-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255059PMC
May 2020

Immunometabolic Network Interactions of the Kynurenine Pathway in Cutaneous Malignant Melanoma.

Front Oncol 2020 3;10:51. Epub 2020 Feb 3.

Unit of Computational Medicine, Department of Medicine, Centre for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.

Dysregulation of the kynurenine pathway has been regarded as a mechanism of tumor immune escape by the enzymatic activity of indoleamine 2, 3 dioxygenase and kynurenine production. However, the immune-modulatory properties of other kynurenine metabolites such as kynurenic acid, 3-hydroxykynurenine, and anthranilic acid are poorly understood. In this study, plasma from patients diagnosed with metastatic cutaneous malignant melanoma (CMM) was obtained before (PRE) and during treatment (TRM) with inhibitors of mitogen-activated protein kinase pathway (MAPKIs). Immuno-oncology related protein profile and kynurenine metabolites were analyzed by proximity extension assay (PEA) and LC/MS-MS, respectively. Correlation network analyses of the data derived from PEA and LC/MS-MS identified a set of proteins that modulate the differentiation of Th1 cells, which is linked to 3-hydroxykynurenine levels. Moreover, MAPKIs treatments are associated with alteration of 3-hydroxykynurenine and 3hydroxyanthranilic acid (3HAA) concentrations and led to higher "CXCL11," and "KLRD1" expression that are involved in T and NK cells activation. These findings imply that the kynurenine pathway is pathologically relevant in patients with CMM.
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http://dx.doi.org/10.3389/fonc.2020.00051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017805PMC
February 2020

High expression of ID1 in monocytes is strongly associated with phenotypic and functional MDSC markers in advanced melanoma.

Cancer Immunol Immunother 2020 Apr 17;69(4):513-522. Epub 2020 Jan 17.

Department of Oncology-Pathology, Karolinska Institute, Visionsgatan 4, 171 64 Solna, Stockholm, Sweden.

The efficacy of immunotherapies for malignant melanoma is severely hampered by local and systemic immunosuppression mediated by myeloid-derived suppressor cells (MDSC). Inhibitor of differentiation 1 (ID1) is a transcriptional regulator that was shown to be centrally involved in the induction of immunosuppressive properties in myeloid cells in mice, while it was overexpressed in CD11b cells in the blood of late-stage melanoma patients. Therefore, we comprehensively assessed ID1 expression in PBMC from stage III and IV melanoma patients, and studied ID1 regulation in models for human monocyte differentiation towards monocyte-derived dendritic cells. A highly significant elevation of ID1 was observed in CD33CD11bCD14HLA-DR monocytic MDSC in the blood of melanoma patients compared to their HLA-DR counterparts, while expression of ID1 correlated positively with established MDSC markers S100A8/9 and iNOS. Moreover, expression of ID1 in monocytes significantly decreased in PBMC samples taken after surgical removal of melanoma metastases, compared to those taken before surgery. Finally, maturation of monocyte-derived DC coincided with a significant downregulation of ID1. Together, these data indicate that increased ID1 expression is strongly associated with expression of phenotypic and immunosuppressive markers of monocytic MDSC, while downregulation is associated with a more immunogenic myeloid phenotype. As such, ID1 may be an additional phenotypic marker for monocytic MDSC. Investigation of ID1 as a pharmacodynamic biomarker or its use as a target for modulating MDSC is warranted.
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http://dx.doi.org/10.1007/s00262-019-02476-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113206PMC
April 2020

Cancer Neoepitopes for Immunotherapy: Discordance Between Tumor-Infiltrating T Cell Reactivity and Tumor MHC Peptidome Display.

Front Immunol 2019 11;10:2766. Epub 2019 Dec 11.

Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.

Tumor-infiltrating lymphocytes (TIL) are considered enriched for T cells recognizing shared tumor antigens or mutation-derived neoepitopes. We performed exome sequencing and HLA-A02:01 epitope prediction from tumor cell lines from two HLA-A2-positive melanoma patients whose TIL displayed strong tumor reactivity. The potential neoepitopes were screened for recognition using autologous TIL by immunological assays and presentation on tumor major histocompatibility complex class I (MHC-I) molecules by Poisson detection mass spectrometry (MS). TIL from the patients recognized 5/181 and 3/49 of the predicted neoepitopes, respectively. MS screening detected 3/181 neoepitopes on tumor MHC-I from the first patient but only one was also among those recognized by TIL. Consequently, TIL enriched for neoepitope specificity failed to recognize tumor cells, despite being activated by peptides. For the second patient, only after IFN-γ treatment of the tumor cells was one of 49 predicted neoepitopes detected by MS, and this coincided with recognition by TIL sorted for the same specificity. Importantly, specific T cells could be expanded from patient and donor peripheral blood mononuclear cells (PBMC) for all neoepitopes recognized by TIL and/or detected on tumor MHC-I. In summary, stimulating the appropriate inflammatory environment within tumors may promote neoepitope MHC presentation while expanding T cells in blood may circumvent lack of specific TIL. The discordance in detection between physical and functional methods revealed here can be rationalized and used to improve neoantigen-targeted T cell immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2019.02766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918724PMC
October 2020

AXL and CAV-1 play a role for MTH1 inhibitor TH1579 sensitivity in cutaneous malignant melanoma.

Cell Death Differ 2020 07 9;27(7):2081-2098. Epub 2020 Jan 9.

Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, S-171 64, Stockholm, Sweden.

Cutaneous malignant melanoma (CMM) is the deadliest form of skin cancer and clinically challenging due to its propensity to develop therapy resistance. Reactive oxygen species (ROS) can induce DNA damage and play a significant role in CMM. MTH1 protein protects from ROS damage and is often overexpressed in different cancer types including CMM. Herein, we report that MTH1 inhibitor TH1579 induced ROS levels, increased DNA damage responses, caused mitotic arrest and suppressed CMM proliferation leading to cell death both in vitro and in an in vivo xenograft CMM zebrafish disease model. TH1579 was more potent in abrogating cell proliferation and inducing cell death in a heterogeneous co-culture setting when compared with CMM standard treatments, vemurafenib or trametinib, showing its broad anticancer activity. Silencing MTH1 alone exhibited similar cytotoxic effects with concomitant induction of mitotic arrest and ROS induction culminating in cell death in most CMM cell lines tested, further emphasizing the importance of MTH1 in CMM cells. Furthermore, overexpression of receptor tyrosine kinase AXL, previously demonstrated to contribute to BRAF inhibitor resistance, sensitized BRAF mutant and BRAF/NRAS wildtype CMM cells to TH1579. AXL overexpression culminated in increased ROS levels in CMM cells. Moreover, silencing of a protein that has shown opposing effects on cell proliferation, CAV-1, decreased sensitivity to TH1579 in a BRAF inhibitor resistant cell line. AXL-MTH1 and CAV-1-MTH1 mRNA expressions were correlated as seen in CMM clinical samples. Finally, TH1579 in combination with BRAF inhibitor exhibited a more potent cell killing effect in BRAF mutant cells both in vitro and in vivo. In summary, we show that TH1579-mediated efficacy is independent of BRAF/NRAS mutational status but dependent on the expression of AXL and CAV-1.
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http://dx.doi.org/10.1038/s41418-019-0488-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308409PMC
July 2020

Leadership in specialist palliative home care teams: A qualitative study.

J Nurs Manag 2020 Jan 23;28(1):102-111. Epub 2019 Dec 23.

Department of Health Care Sciences, Palliative Research Centre, Ersta Sköndal Bräcke University College, Stockholm, Sweden.

Aim: The aim of this study was to describe team leaders' experiences of facilitators and barriers of leadership in specialist palliative home care teams.

Background: For effective teamwork in specialist palliative care, leadership is crucial; however, defining and agreeing on what leadership comprises may be challenging. In palliative care, teamwork is recognized as imperative for multiprofessional perspectives to meet dying patients' and families' needs.

Methods: Qualitative interviews with 13 team leaders in specialist palliative home care were performed, using the Pettigrew and Whipp framework, and analysed with directed content analysis.

Results: Team leaders' experiences of conditions influencing the organisation and delivery of specialist palliative home care is multifaceted and leaders seem conflicted in their approach to the multiple levels of leadership, vision and responsibilities.

Conclusion: Team leaders in specialist palliative home care described goals of care on differing levels and, for some, fiscal restraints and external pressures influenced their vision and leadership. Team leaders experienced challenges of leadership in relation to organisational issues, feeling burdened by responsibilities, budget restraints and team size.

Implications For Nursing Management: Team leadership is demanding and complex. In specialist palliative home care, affirming values and enabling vision during times of fiscal strain and external pressures, is challenging. For successful leadership that develops both individuals and the health care team, leaders are recommended to adapt the leadership style to the present situation surrounding the team.
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http://dx.doi.org/10.1111/jonm.12902DOI Listing
January 2020

What happened and why? A programme theory-based qualitative evaluation of a healthcare-academia partnership reform in primary care.

BMC Health Serv Res 2019 Nov 1;19(1):785. Epub 2019 Nov 1.

Department of Learning, Informatics, Management and Ethics (LIME), Medical Management Centre (MMC), Karolinska Institutet, 171 77, Stockholm, Sweden.

Background: There is increasing interest in and demands for partnerships between academia and healthcare practices. Few empirical studies have described the influence of such partnerships from a practice perspective. The purpose of this study was to evaluate the impact of a reform launched to increase integration between primary care and academia and to identify potential reasons for why the observed impact occurred in three areas targeted by the reform: research, student education, and continued professional development.

Methods: The study was conducted in Stockholm County, the largest healthcare region in Sweden, at the introduction of a partnership between primary care and academia, including eight coordinating centres and approximately 500 surrounding primary care units. A programme theory-based qualitative approach to evaluation was used, building on document analysis, and in-depth interviews with the centre managers (n = 6) and coordinators (n = 8) conducted 42-66 months after the initiation of the reform.

Results: The analysis showed that the reform had some impact on all three areas targeted by the reform: research, student education, and continued professional development. The input that contributed most extensively to the impact was the establishment of facilitating roles. Most changes occurred at the coordinating centres and primarily in the area of student education. The effect on student education was primarily due to having prior experience in this area and perceptions of timely benefits of students to care practice.

Conclusions: Partnerships between primary care and academia hold the potential of practice impact. To increase integration between primary care and academia, the components of the integration must be understandable and relevant for primary care practitioners, and importantly, compliant with delivery of primary care.
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http://dx.doi.org/10.1186/s12913-019-4665-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825344PMC
November 2019

Implementation of a national policy for improving health and social care: a comparative case study using the Consolidated Framework for Implementation Research.

BMC Health Serv Res 2019 Oct 22;19(1):730. Epub 2019 Oct 22.

Department of Learning, Informatics, Management and Ethics, Medical Management Centre, Karolinska Institutet, SE 171 77, Stockholm, Sweden.

Background: Comprehensive policies are becoming common for addressing wicked problems in health and social care. Success of these policies often varies between target organizations. This variation can often be attributed to contextual factors. However, there is a lack of knowledge about the conditions for successful policy implementation and how context influences this process. The aim of this study was to investigate county-level actors' perspectives on the implementation of a comprehensive national policy in three Swedish counties. The policy focused on developing quality of care for elderly based on the use of national quality registries (NQRs) and to improve coordination of care.

Methods: A comparative case study approach was used. Data was collected longitudinally through documents and interviews. The Consolidated Framework for Implementation Research (CFIR) guided the analysis.

Results: All three counties shared the view that the policy addressed important issues. Still, there was variation regarding how it was perceived and managed. Adaptable features-i.e., NQRs and improvement coaches-were perceived as relevant and useful. However, the counties differed in their perceptions of another policy component-i.e., senior management program-as an opportunity or a disturbance. This program, while tackling complex issues of collaboration, fell short in recognizing the counties' pre-existing conditions and needs and also offered few opportunities for adaptations. Performance bonuses and peer pressure were strong incentives for all counties to implement the policy, despite the poor fit of policy content and local context.

Conclusions: Comprehensive health policies aiming to address wicked problems have better chances of succeeding if the implementation includes assessments of the target organizations' implementation capacity as well as the implicit quid pro quos involved in policy development. Special attention is warranted regarding the use of financial incentives when dealing with wicked problems since the complexity makes it difficult to align incentives with the goals and to assess potential consequences. Other important aspects in the implementation of such policies are the use of collaborative approaches to engage stakeholders with differing perspectives, and the tailoring of policy communication to facilitate shared understanding and commitment.
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http://dx.doi.org/10.1186/s12913-019-4591-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805604PMC
October 2019

Combining ERBB family and MET inhibitors is an effective therapeutic strategy in cutaneous malignant melanoma independent of BRAF/NRAS mutation status.

Cell Death Dis 2019 09 10;10(9):663. Epub 2019 Sep 10.

Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.

Current treatment modalities for disseminated cutaneous malignant melanoma (CMM) improve survival; however, relapses are common. A number of receptor tyrosine kinases (RTKs) including EGFR and MET have been reported to be involved in CMM metastasis and in the development of resistance to therapy, targeting the mitogen-activated protein kinase (MAPK pathway). IHC analysis showed that patients with higher MET protein expression had a significantly shorter overall survival. In addition, silencing of MET caused an upregulation of EGFR and p-AKT, which was abrogated by concomitant silencing of MET and EGFR in CMM cells resistant to MAPK-targeting drugs. We therefore explored novel treatment strategies using clinically approved drugs afatinib (ERBB family inhibitor) and crizotinib (MET inhibitor), to simultaneously block MET and ERBB family RTKs. The effects of the combination were assessed in cell culture and spheroid models using established CMM and patient-derived short-term cell lines, and an in vivo xenograft mouse model. The combination had a synergistic effect, promoting cell death, concomitant with a potent downregulation of migratory and invasive capacity independent of their BRAF/NRAS mutational status. Furthermore, the combination attenuated tumor growth rate, as ascertained by the significant reduction of Ki67 expression and induced DNA damage in vivo. Importantly, this combination therapy had minimal therapy-related toxicity in mice. Lastly, the cell cycle G2 checkpoint kinase WEE1 and the RTK IGF1R, non-canonical targets, were altered upon exposure to the combination. Knockdown of WEE1 abrogated the combination-mediated effects on cell migration and proliferation in BRAF mutant BRAF inhibitor-sensitive cells, whereas WEE1 silencing alone inhibited cell migration in NRAS mutant cells. In summary, our results show that afatinib and crizotinib in combination is a promising alternative targeted therapy option for CMM patients, irrespective of BRAF/NRAS mutational status, as well as for cases where resistance has developed towards BRAF inhibitors.
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http://dx.doi.org/10.1038/s41419-019-1875-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737096PMC
September 2019

Exhaustion of CD4+ T-cells mediated by the Kynurenine Pathway in Melanoma.

Sci Rep 2019 08 21;9(1):12150. Epub 2019 Aug 21.

Unit of Computational Medicine, Department of Medicine, Centre for Molecular Medicine, Karolinska Institute, SE-171 76, Stockholm, Sweden.

Kynurenine pathway (KP) activation by the enzymatic activity of indoleamine 2,3-dioxygenase1 (IDO1) and kynurenine (KYN) production represents an attractive target for reducing tumour progression and improving anti-tumour immunity in multiple cancers. However, immunomodulatory properties of other KP metabolites such as 3-hydroxy kynurenine (3-HK) and kynurenic acid (KYNA) are poorly understood. The association of the kynurenine metabolic pathway with T-cell status in the tumour microenvironment were characterized, using gene expression data of 368 cutaneous skin melanoma (SKCM) patients from the TCGA cohort. Based on the identified correlations, we characterized the production of KYN, 3-HK, and KYNA in vitro using melanoma-derived cell lines and primary CD4+ CD25- T-cells. Activation of the CD4+ T-cells produced IFNγ, which yielded increased levels of KYN and KYNA. Concurrently, kynurenine 3-monooxygenase (KMO) expression and proliferation of CD4+ T-cells were reduced, whereas exhaustion markers such as PD-L1, AHR, FOXP3, and CTLA4 were increased. Additionally, an analysis of the correlation network reconstructed using TCGA-SKCM emphasized KMO and KYNU with high variability among BRAF wild-type compared with V600E, which underscored their role in distinct CD4+ T-cell behavior in tumour immunity. Our results suggest that, in addition to IDO1, there is an alternative immune regulatory mechanism associated with the lower KMO expression and the higher KYNA production, which contributes to dysfunctional effector CD4+ T-cell response.
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http://dx.doi.org/10.1038/s41598-019-48635-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704156PMC
August 2019

Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial.

Lancet Oncol 2019 07 31;20(7):948-960. Epub 2019 May 31.

Melanoma Institute of Australia, The University of Sydney, Sydney, NSW, Australia; Royal North Shore and Mater Hospitals, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Sydney, NSW, Australia.

Background: The outcome of patients with macroscopic stage III melanoma is poor. Neoadjuvant treatment with ipilimumab plus nivolumab at the standard dosing schedule induced pathological responses in a high proportion of patients in two small independent early-phase trials, and no patients with a pathological response have relapsed after a median follow up of 32 months. However, toxicity of the standard ipilimumab plus nivolumab dosing schedule was high, preventing its broader clinical use. The aim of the OpACIN-neo trial was to identify a dosing schedule of ipilimumab plus nivolumab that is less toxic but equally effective.

Methods: OpACIN-neo is a multicentre, open-label, phase 2, randomised, controlled trial. Eligible patients were aged at least 18 years, had a WHO performance status of 0-1, had resectable stage III melanoma involving lymph nodes only, and measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1. Patients were enrolled from three medical centres in Australia, Sweden, and the Netherlands, and were randomly assigned (1:1:1), stratified by site, to one of three neoadjuvant dosing schedules: group A, two cycles of ipilimumab 3 mg/kg plus nivolumab 1 mg/kg once every 3 weeks intravenously; group B, two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg once every 3 weeks intravenously; or group C, two cycles of ipilimumab 3 mg/kg once every 3 weeks directly followed by two cycles of nivolumab 3 mg/kg once every 2 weeks intravenously. The investigators, site staff, and patients were aware of the treatment assignment during the study participation. Pathologists were masked to treatment allocation and all other data. The primary endpoints were the proportion of patients with grade 3-4 immune-related toxicity within the first 12 weeks and the proportion of patients achieving a radiological objective response and pathological response at 6 weeks. Analyses were done in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02977052, and is ongoing with an additional extension cohort and to complete survival analysis.

Findings: Between Nov 24, 2016 and June 28, 2018, 105 patients were screened for eligibility, of whom 89 (85%) eligible patients were enrolled and randomly assigned to one of the three groups. Three patients were excluded after randomisation because they were found to be ineligible, and 86 received at least one dose of study drug; 30 patients in group A, 30 in group B, and 26 in group C (accrual to this group was closed early upon advice of the Data Safety Monitoring Board on June 4, 2018 because of severe adverse events). Within the first 12 weeks, grade 3-4 immune-related adverse events were observed in 12 (40%) of 30 patients in group A, six (20%) of 30 in group B, and 13 (50%) of 26 in group C. The difference in grade 3-4 toxicity between group B and A was -20% (95% CI -46 to 6; p=0·158) and between group C and group A was 10% (-20 to 40; p=0·591). The most common grade 3-4 adverse events were elevated liver enzymes in group A (six [20%)]) and colitis in group C (five [19%]); in group B, none of the grade 3-4 adverse events were seen in more than one patient. One patient (in group A) died 9·5 months after the start of treatment due to the consequences of late-onset immune-related encephalitis, which was possibly treatment-related. 19 (63% [95% CI 44-80]) of 30 patients in group A, 17 (57% [37-75]) of 30 in group B, and nine (35% [17-56]) of 26 in group C achieved a radiological objective response, while pathological responses occurred in 24 (80% [61-92]) patients in group A, 23 (77% [58-90]) in group B, and 17 (65% [44-83]) in group C.

Interpretation: OpACIN-neo identified a tolerable neoadjuvant dosing schedule (group B: two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg) that induces a pathological response in a high proportion of patients and might be suitable for broader clinical use. When more mature data confirm these early observations, this schedule should be tested in randomised phase 3 studies versus adjuvant therapies, which are the current standard-of-care systemic therapy for patients with stage III melanoma.

Funding: Bristol-Myers Squibb.
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http://dx.doi.org/10.1016/S1470-2045(19)30151-2DOI Listing
July 2019

Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT.

J Am Acad Dermatol 2019 Aug 5;81(2):386-394. Epub 2019 Feb 5.

Department of Clinical Sciences, Lund University Hospital Lund, Sweden; Department of Surgery, Lund University Hospital, Lund, Sweden.

Background: Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5%-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether MELPREDICT was generalizable to a global series of families with melanoma and whether performance improvements can be achieved.

Methods: In total, 2116 familial melanoma cases were ascertained by the international GenoMEL Consortium. We recapitulated the MELPREDICT model within our data (GenoMELPREDICT) to assess performance improvements by adding phenotypic risk factors and history of pancreatic cancer. We report areas under the curve (AUC) with 95% confidence intervals (CIs) along with net reclassification indices (NRIs) as performance metrics.

Results: MELPREDICT performed well (AUC 0.752, 95% CI 0.730-0.775), and GenoMELPREDICT performance was similar (AUC 0.748, 95% CI 0.726-0.771). Adding a reported history of pancreatic cancer yielded discriminatory improvement (P < .0001) in GenoMELPREDICT (AUC 0.772, 95% CI 0.750-0.793, NRI 0.40). Including phenotypic risk factors did not improve performance.

Conclusion: The MELPREDICT model functioned well in a global data set of familial melanoma cases. Adding pancreatic cancer history improved model prediction. GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in directing these patients to receive genetic testing or cancer risk counseling.
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http://dx.doi.org/10.1016/j.jaad.2019.01.079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634996PMC
August 2019

Assessment of quality of life using Skindex-16 in patients with advanced basal cell carcinoma treated with vismodegib in the STEVIE study.

Eur J Dermatol 2018 Dec;28(6):775-783

University Hospital Schleswig-Holstein and University of Kiel, Rosalind-Franklin-Str. 7, D-24105 Kiel, Germany.

Health-related quality of life (HRQoL) data are limited in patients with advanced basal cell carcinoma. To report HRQoL outcomes based on STEVIE (NCT01367665), a phase 2 study of vismodegib safety in patients with metastatic BCC or locally advanced BCC that is unsuitable for surgery or radiotherapy. Skindex-16 and MD Anderson Symptom Inventory (MDASI) questionnaires were completed at baseline and at three subsequent visits. Clinically meaningful improvement was defined as a ≥10-point decrease from baseline (Skindex-16) or improvement of at least 3 points from baseline (MDASI). HRQoL-evaluable patients with locally advanced BCC (n = 730) had ≥10-point improvements in Skindex-16 emotion domain scores at all time points. Changes in symptom and function scores in these patients or in any domain scores at any time point in patients with metastatic BCC (n = 10) were not clinically meaningful. Of 10 patients with symptomatic metastatic BCC at baseline, six had ≥3-point improvements in MDASI symptom severity. Skindex-16 and MDASI showed improvement in HRQoL in vismodegib-treated patients with locally advanced or metastatic BCC or BCC.
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http://dx.doi.org/10.1684/ejd.2018.3448DOI Listing
December 2018

Team type, team maturity and team effectiveness in specialist palliative home care: an exploratory questionnaire study.

J Interprof Care 2019 Sep-Oct;33(5):504-511. Epub 2018 Nov 28.

Department of Health Care Sciences, Palliative Research Centre, Ersta Sköndal Bräcke University College , Stockholm , Sweden.

To meet complex needs in persons and families within specialist palliative care, care team members are expected to work together in performing a comprehensive assessment of patient needs. Team type (how integrated team members work) and team maturity (group development) have been identified as components in team effectiveness and productivity. The aim of the study reported in this paper was to identify team types in specialist palliative care in Sweden, and to explore associations between team type, team maturity and team effectiveness in home care teams. A national web-based survey of team types, based on Thylefors questionnaire, and a survey of healthcare professionals using the Group Development Questionnaire (GDQ-SE3) to assess team developmental phase, effectiveness and productivity were used in an exploratory cross-sectional design. The participants were: Specialist palliative care teams in Sweden registered in the Palliative Care Directory (n = 77), and members of 11 specialist palliative home care teams. Teams comprised physicians, registered nurses, social workers, physiotherapists and/or occupational therapists, full-or part-time. Our national web survey results showed that the 77 investigated teams had existed from 7 to 21 years, were foremost of medium size and functioned as inter- or transprofessional teams. Results from the 61 HCPs, representing 11 teams, indicated that more mature teams tended to work in an integrated manner, rather than in parallel. The effectiveness ratio varied from 52% to 86% in teams. Recommendations arising from our findings include the need for clarification of team goals and professional roles together with prioritizing the development of desirable psychosocial traits and team processes in clinical settings.
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http://dx.doi.org/10.1080/13561820.2018.1551861DOI Listing
February 2020

Extracellular microvesicle microRNAs as predictive biomarkers for targeted therapy in metastastic cutaneous malignant melanoma.

PLoS One 2018 6;13(11):e0206942. Epub 2018 Nov 6.

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

Background: Mitogen activated-protein kinase pathway inhibitors (MAPKis) improve treatment outcome in patients with disseminated BRAFV600 mutant cutaneous malignant melanoma (CMM) but responses are of limited duration due to emerging resistance. Although extensive research in mechanisms of resistance is being performed, predictive biomarkers for durable responses are still lacking. We used miRNA qPCR to investigate if different levels of extracellular microvesicle microRNA (EV miRNA) in matched plasma samples collected from patients with metastatic IV BRAFV600 mutated CMM before, during and after therapy with MAPKis could serve as predictive biomarkers.

Materials And Methods: EV miRNAs were extracted from plasma samples from 28 patients collected before and during therapy, measured by quantitative PCR-array and correlated to therapy outcome.

Results: Increased levels of EV let-7g-5p during treatment compared to before treatment (EV let-7g-5p_delta) were associated with better disease control with MAPKis (odds ratio 8568.4, 95% CI = 4.8-1.5e+07, P = 0.000036). Elevated levels of EV miR-497-5p during therapy were associated with prolonged progression free survival (PFS) (hazard ratio = 0.27, 95% CI = 0.13-0.52, P <0.000061).

Conclusions: EV miRNAs let-7g-5p and miR-497-5p were identified as putative novel predictive biomarkers of MAPKi treatment benefit in metastatic CMM patients highlighting the potential relevance of assessing EV miRNA during and after treatment to unravel novel mechanisms of resistance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206942PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219796PMC
April 2019

Actions helping expressed or anticipated needs: Patients with advanced cancer and their family caregivers' experiences of specialist palliative home care teams.

Eur J Cancer Care (Engl) 2018 Nov 9;27(6):e12948. Epub 2018 Oct 9.

Department of Health Care Sciences, Palliative Research Centre, Ersta Sköndal Bräcke University College, Stockholm, Sweden.

Patients with advanced cancer and family caregivers in palliative care face physical, psychological, social and existential challenges, much of the time home alone. Specialist palliative home care team services can be instrumental for sense of security in an uncertain situation. The aim of this study was to describe patients' and family caregivers' experiences of specialist palliative home care team actions that are identified by the participants as helping or hindering interventions. Six patients and seven family caregivers were interviewed using the enhanced critical incident technique. Ninety-five critical incidents and wish list items were identified. Providing adequate resources, keeping promises and being reliable, and creating partnerships are actions by specialist palliative care teams that patients and family caregivers experienced as helping in meeting expressed or anticipated needs in patients and family caregivers. Being reliable and including patients and family caregivers in partnerships help to continue with daily life, even though death may be close. Unmet needs resulted in experiences of disrespect or violation of personal space/integrity.
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http://dx.doi.org/10.1111/ecc.12948DOI Listing
November 2018

Spatially Resolved Transcriptomics Enables Dissection of Genetic Heterogeneity in Stage III Cutaneous Malignant Melanoma.

Cancer Res 2018 10 28;78(20):5970-5979. Epub 2018 Aug 28.

Department of Gene Technology, KTH Royal Institute of Technology, SciLifeLab, Stockholm, Sweden.

Cutaneous malignant melanoma (melanoma) is characterized by a high mutational load, extensive intertumoral and intratumoral genetic heterogeneity, and complex tumor microenvironment (TME) interactions. Further insights into the mechanisms underlying melanoma are crucial for understanding tumor progression and responses to treatment. Here we adapted the technology of spatial transcriptomics (ST) to melanoma lymph node biopsies and successfully sequenced the transcriptomes of over 2,200 tissue domains. Deconvolution combined with traditional approaches for dimensional reduction of transcriptome-wide data enabled us to both visualize the transcriptional landscape within the tissue and identify gene expression profiles linked to specific histologic entities. Our unsupervised analysis revealed a complex spatial intratumoral composition of melanoma metastases that was not evident through morphologic annotation. Each biopsy showed distinct gene expression profiles and included examples of the coexistence of multiple melanoma signatures within a single tumor region as well as shared profiles for lymphoid tissue characterized according to their spatial location and gene expression profiles. The lymphoid area in close proximity to the tumor region displayed a specific expression pattern, which may reflect the TME, a key component to fully understanding tumor progression. In conclusion, using the ST technology to generate gene expression profiles reveals a detailed landscape of melanoma metastases. This should inspire researchers to integrate spatial information into analyses aiming to identify the factors underlying tumor progression and therapy outcome. Applying ST technology to gene expression profiling in melanoma lymph node metastases reveals a complex transcriptional landscape in a spatial context, which is essential for understanding the multiple components of tumor progression and therapy outcome. .
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http://dx.doi.org/10.1158/0008-5472.CAN-18-0747DOI Listing
October 2018

Enhancing policy implementation to improve healthcare practices: The role and strategies of hybrid national-local support structures.

Int J Health Plann Manage 2018 Oct 9;33(4):e1262-e1278. Epub 2018 Aug 9.

Department of Learning, Informatics, Management and Ethics, Medical Management Centre, Karolinska Institutet, Stockholm, Sweden.

Background: In this study, we followed a national initiative to enhance the use of quality indicators gathered in national quality registries (NQRs) for improvement of clinical practices in Swedish healthcare, more specifically by investigating the support strategies of regional support centers with national and local missions. The aim was to increase knowledge on the role, challenges, and strategies of support structures with mixed and complex missions in the healthcare system.

Methods: Documents and 25 semistructured interviews with staff at 6 regional support centers, ie, quality registry centers, formed this multiple case study. Data were analyzed using conventional content analysis.

Results: The centers' strategies varied from developing the NQRs to become more suitable for improvement to supporting healthcare's use of NQRs, from the use of task to process-oriented support strategies, and from taking on national responsibilities to responding to local initiatives. All quality registry centers engaged in initiatives inspired by the Breakthrough Series approach. Some used preexisting change concepts or collaborated with local development units. A main challenge was to overcome a lack of formal mandate to act in the healthcare organizations they served.

Conclusions: Support functions with mixed and complex missions have to use a variation of strategies to reach relevant actors and achieve changes. This study provides valuable input for policy and decision-makers on the support strategies used and challenges of support functions with complex missions situated in-between national and local levels of the healthcare system, here denoted hybrid national-local support structures.
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http://dx.doi.org/10.1002/hpm.2617DOI Listing
October 2018

Increased CD4 T cell lineage commitment determined by CpG methylation correlates with better prognosis in urinary bladder cancer patients.

Clin Epigenetics 2018 08 3;10(1):102. Epub 2018 Aug 3.

Unit of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Background: Urinary bladder cancer is a common malignancy worldwide. Environmental factors and chronic inflammation are correlated with the disease risk. Diagnosis is performed by transurethral resection of the bladder, and patients with muscle invasive disease preferably proceed to radical cystectomy, with or without neoadjuvant chemotherapy. The anti-tumour immune responses, known to be initiated in the tumour and draining lymph nodes, may play a major role in future treatment strategies. Thus, increasing the knowledge of tumour-associated immunological processes is important. Activated CD4 T cells differentiate into four main separate lineages: Th1, Th2, Th17 and Treg, and they are recognized by their effector molecules IFN-γ, IL-13, IL-17A, and the transcription factor Foxp3, respectively. We have previously demonstrated signature CpG sites predictive for lineage commitment of these four major CD4 T cell lineages. Here, we investigate the lineage commitment specifically in tumour, lymph nodes and blood and relate them to the disease stage and response to neoadjuvant chemotherapy.

Results: Blood, tumour and regional lymph nodes were obtained from patients at time of transurethral resection of the bladder and at radical cystectomy. Tumour-infiltrating CD4 lymphocytes were significantly hypomethylated in all four investigated lineage loci compared to CD4 lymphocytes in lymph nodes and blood (lymph nodes vs tumour-infiltrating lymphocytes: IFNG -4229 bp p < 0.0001, IL13 -11 bp p < 0.05, IL17A -122 bp p < 0.01 and FOXP3 -77 bp p > 0.05). Examination of individual lymph nodes displayed different methylation signatures, suggesting possible correlation with future survival. More advanced post-cystectomy tumour stages correlated significantly with increased methylation at the IFNG -4229 bp locus. Patients with complete response to neoadjuvant chemotherapy displayed significant hypomethylation in CD4 T cells for all four investigated loci, most prominently in IFNG p < 0.0001. Neoadjuvant chemotherapy seemed to result in a relocation of Th1-committed CD4 T cells from blood, presumably to the tumour, indicated by shifts in the methylation patterns, whereas no such shifts were seen for lineages corresponding to IL13, IL17A and FOXP3.

Conclusion: Increased lineage commitment in CD4 T cells, as determined by demethylation in predictive CpG sites, is associated with lower post-cystectomy tumour stage, complete response to neoadjuvant chemotherapy and overall better outcome, suggesting epigenetic profiling of CD4 T cell lineages as a useful readout for clinical staging.
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http://dx.doi.org/10.1186/s13148-018-0536-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6076404PMC
August 2018

Leading top-down implementation processes: a qualitative study on the role of managers.

BMC Health Serv Res 2018 07 18;18(1):562. Epub 2018 Jul 18.

Department of Learning, Informatics, Management and Ethics (LIME), Medical Management Centre (MMC), Karolinska Institutet, 171 77, Stockholm, Sweden.

Background: Leadership has been identified as an influential factor in implementation processes in healthcare organizations. However, the processes through which leaders affect implementation outcomes are largely unknown. The purpose of this study is to analyse how managers interpret and make sense of a large scale top-down implementation initiative and what implications this has for the implementation process. This was studied at the implementation of an academic primary healthcare initiative covering 210 primary healthcare centres in central Sweden. The aim of the initiative was to integrate research and education into regular primary healthcare services.

Methods: The study builds on 16 in-depth individual semi-structured interviews with all managers (n = 8) who had operative responsibility for the implementation. Each manager was interviewed twice during the initial phase of the implementation. Data were analysed using a thematic approach guided by theory on managerial role taking based on the Transforming Experience Framework.

Results: How the managers interpreted and made sense of the implementation task built on three factors: how they perceived the different parts of the initiative, how they perceived themselves in relation to these parts, and the resources available for the initiative. Based on how they combined these three factors the managers chose to integrate or separate the different parts of the initiative in their management of the implementation process.

Conclusions: This research emphasizes that managers in healthcare seem to have a substantial impact on how and to what extent different tasks are addressed and prioritized in top-down implementation processes. This has policy implications. To achieve intended implementation outcomes, the authors recognize the necessity of an early and on-going dialogue about how the implementation is perceived by the managers responsible for the implementation.
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http://dx.doi.org/10.1186/s12913-018-3360-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052667PMC
July 2018
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