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| 2. |
- Dalmo, Johanna, et al.
(author)
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Potential renal toxicity biomarkers indicating radiation injury after 177Lu-octreotate treatment
- 2013
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In: Annual congress of the European association of nuclear medicine, october 19-23, 2013, Lyon, France. Posterwalk.
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Conference paper (other academic/artistic)abstract
- The kidneys are one of the most exposed non-tumor tissues and regarded as one of the main dose-limiting organs in peptide receptor radionuclide therapy (PRRT). [177Lu-DOTA0, Tyr3]-octreotate (177Lu-octreotate) has shown promising results in the treatment of somatostatin receptor overexpressing neuroendocrine tumors, but optimization is still needed. The ability to give each patient as much 177Lu-octreotate as possible without inducing nephrotoxicity is necessary for an efficient treatment. However, due to large inter-individual differences in uptake and retention in the kidneys, there is a need for efficient Methods that early can indicate renal injury. A possible way is to identify biomarkers for high risk of radiation nephrotoxicity. The aim of this study was to investigate the potential of using urinary retinol binding protein (RBP), and blood valinhydantoin (VH) as biomarkers of nephrotoxicity on adult mice after 177Lu-octreotate treatment. BALB/c nude mice (n=6/group) were i.v. injected with 60 MBq or 120 MBq of 177Lu-octreotate. The control group was mock treated with saline. Spot urine samples were collected before injection, and 14, 30, 60 and 90 days after injection. Analysis of RBP4 and creatinine was performed using Mouse RBP4 ELISA kit and Creatinine kit from R&D Systems, respectively. Erythrocytes were separated from whole blood samples collected 90 days after injection, and analysed for VH by LC-MS/MS. The ratio between VH and a volumetric standard was calculated. The RBP/creatinine level increased with time in both groups given 177Lu-octreotate, with earlier and higher response for the 120 MBq group. No clear change in VH level between the different groups was observed. The result show that RBP may be a promising new biomarker for radiation induced kidney toxicity. The presently used method based on VH was not sensitive enough to be used as kidney toxicity marker. Further studies on mice are ongoing to validate if RBP4 may be efficient in predicting late nephrotoxicity. In patients, RBP/creatinine levels are followed in urine samples after treatment with 177Lu-octreotate.
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| 3. |
- Mattsson, Johanna, 1985-
(author)
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An integrative strategy for targeted evaluation of biomarker expression in non-small cell lung cancer
- 2016
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Doctoral thesis (other academic/artistic)abstract
- Despite improvements in therapy, the prognosis for non-small cell lung cancer (NSCLC) patients remains poor, and cure is only possible in localized tumors after surgical resection. A new generation of targeted cancer drugs has led to the expectation that lung cancer therapy can be significantly improved, but these drugs are today only an option in a small subset of NSCLC patients, and their effect is temporary. Therefore, the aim of this thesis was to characterize NSCLC in order to find new treatment targets and to evaluate biomarkers that further optimize therapy selection.In Paper I, the expression of the potential treatment targets claudin 6 and claudin 18.2 were evaluated based on immunohistochemical- and gene expression analysis. High ectopic protein and gene expression were demonstrated for both claudins in small subgroups of NSCLC. Clinical trials using humanized monoclonal antibodies against both proteins are ongoing in other cancer forms and may be extended to NSCLC.In Paper II, the prognostic impact of the inflammatory mediator cyclooxygenase 2 (COX-2) was evaluated. No prognostic significance was found in a meta-analysis incorporating gene expression data of 1337 NSCLC patients. Likewise, COX-2 protein expression in tumor cells was not associated with survival in two independent NSCLC cohorts. However, in one of the analyzed cohorts, higher COX-2 expression in the tumor stroma was associated with longer survival and may therefore be a subject for further investigation. In Paper III, tumor and stromal COX-2 protein expression was examined in patients treated with the COX-2 inhibitor celecoxib in order to evaluate if COX-2 expression is a predictive biomarker for benefit of celecoxib therapy. Celecoxib did not prolong overall survival neither in the whole cohort nor in patients stratified according to COX-2 expression in tumor or stromal cells. Noteworthy, a tendency towards longer survival was again demonstrated in patients with high COX-2 stromal expression.In Paper IV, the diagnostic methods for identification of ALK rearrangements were assessed in a large representative Swedish NSCLC population. Fluorescence in situ hybridization (FISH), as the diagnostic standard, was compared to two immunohistochemical assays. ALK gene expression levels were incorporated to supplement the molecular data. The frequency of ALK rearrangements was lower than previously reported. The different methods to detect the ALK fusion demonstrated overlapping results. However, the overlap was poor, so the methods cannot be regarded as interchangeable and should thereby be interpreted with caution when used in clinical diagnostics.In summary, this thesis applied an integrative translational approach to characterize potential new treatment targets and to evaluate the detection of existing predictive biomarkers in NSCLC.
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- Näppä, Ulla, 1960-, et al.
(author)
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Challenging situations when administering palliative chemotherapy : a nursing perspective
- 2014
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In: European Journal of Oncology Nursing. - : Elsevier. - 1462-3889 .- 1532-2122. ; 18:6, s. 591-597
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Journal article (other academic/artistic)abstract
- Palliative chemotherapy treatments (PCT) are becoming more common for patients with incurable cancer; a basic challenge is to optimize tumour response while minimizing side-effects and harm. As registered nurses most often administer PCT, they are most likely to be confronted with difficult situations during PCT administration. This study explores challenging situations experienced by nurses when administering PCT to patients with incurable cancer.Methods: Registered nurses experienced in administering PCT were asked in interviews to recall PCT situations they found challenging. Inspired by the narrative tradition, stories were elicited and analysed using a structural and thematic narrative analysis.Results: A total of twenty-eight stories were narrated by seventeen nurses. Twenty of these were dilemmas that could be sorted into three storylines containing one to three dilemmatic situations each. The six dilemmatic situations broadly related to three interwoven areas: the uncertainty of the outcome when giving potent drugs to vulnerable patients; the difficulty of resisting giving PCT to patients who want it; and insufficient communication between nurses and physician.Conclusion: Nurses who administer PCT are engaged in a complex task that can give rise to a number of dilemmatic situations. The findings may be interpreted as meaning that at least some situations might be preventable if the knowledge and insight of all team members – nurses, physicians, patients, and relatives – are jointly communicated and taken into account when deciding whether or not to give PCT. Forming palliative care teams early in the PCT trajectory, could be beneficial for staff and patients.
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| 5. |
- Näppä, Ulla, 1960-
(author)
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Dilemmas in palliative chemotherapy when approaching end-of-life
- 2014
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Doctoral thesis (other academic/artistic)abstract
- Background When cure is no longer possible, medical care should aim for a transition to palliative care regardless of disease. Patients with incurable cancer are often treated with palliative chemotherapy (PCT), starting with the intent to prolong life and increase quality of life. Eventually, in the late stages of the disease, the patient reaches a transition phase when further PCT neither prolongs life nor adds any predominantly positive effects.Aim of the thesisStudy I: To analyse the proportion of patients with incurable cancer who received palliative chemotherapy during the last month of life, and to identify their discriminative characteristics.Study II: To develop a questionnaire assessing performance status in palliative chemotherapy, and to test its psychometric properties.Study III: To explore challenging situations experienced by registered nurses when administering palliative chemotherapy to patients with incurable cancer.Study IV: To investigate whether routine use of the Performance Status in Palliative Chemotherapy (PSPC) questionnaire in PCT would affect the proportion of patients receiving PCT during the last month of life, hospital admissions, notifications of performance status, documented decisions of ceasing PCT in the medical records, and/or place of death. A secondary aim was to gather registered nurses’ experiences of PSPC in clinical use.Methods In Studies I and IV, information from the medical records of deceased patients with epithelial cancers was used in descriptive analyses of the proportions of patients receiving PCT in counties in northernmost Sweden. A quantitative design was chosen, using non-parametric statistical methods. In Study II, a brief patient-completed questionnaire assessing performance status was developed and psychometrically tested. In Study III, data from research interviews with registered nurses were analysed qualitatively with a narrative thematic approach.Results Studies I and IV showed that about 25% of patients receiving PCT were treated during the last month of life. This group of patients had more hospital admissions, were less likely to die at home, and had fewer instances of documentation of the decision to cease PCT. The questionnaire developed in Study II was shown to have acceptable psychometric qualities such as reliability, validity, and sensitivity to detect deterioration in performance status. Study IV showed that the questionnaire gave nurses valuable information about patients’ performance status. The results also showed that 97% of nurses and 48% of physicians documented their patients’ performance status in the medical records. Study III demonstrated that when nurses administered PCT they considered futile, they could experience dilemmas created by the unforeseeable outcomes of PCT or stemming from insufficient communication between nurses, patients, next-of-kin, and physicians.Conclusions Administration of PCT can create dilemmatic situations for both the patient and medical staff when approaching end-of-life. This is underlined by the finding that some 25% of treated patients received their last round of PCT as late as during the last month of life. The decisions to cease PCT were less likely to be documented for patients who had received PCT within a month before death. Nurses described situations where they felt they were in the middle of the decision-making process regarding whether or not to continue PCT. They found the treatments were given on the authority of someone else; the physician’s recommendation or the patient’s and/or relatives’ request.The unpredictability of PCT was a continuous theme in the work described in this thesis, emphasizing the necessity of individually assessing every patient before PCT in order to minimize the risk of futile treatments. The attempt to develop a reliable and valid questionnaire for systematic assessment of performance status has increased future possibilities to monitor this parameter in PCT when approaching end-of-life. The questionnaire developed as part of this thesis has provided nurses with increased knowledge of patients’ performance status. If routinely used, it may help decrease the proportion of patients receiving PCT during the last month of life, though this remains to be rigorously proven. Further research efforts are needed to progress in the task of optimizing rather than maximizing the use of PCT when approaching end-of-life.
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| 6. |
- Aarnivala, Henri, et al.
(author)
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Reply to Ian J. Cohen
- 2022
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In: Supportive Care in Cancer. - : Springer Nature. - 0941-4355 .- 1433-7339. ; 30:3, s. 1901-1902
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Journal article (other academic/artistic)
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| 7. |
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| 8. |
- Abolhalaj, Milad
(author)
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Potential immunoregulatory role of T and dendritic cells in cancer : Investigations based on transcriptional analysis
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Cancer is a complex disease with various genetic and epigenetic driving factors. Cancer cells form a favored microenvironment to sustain their uncontrolled behavior leading to abnormal growth. With standard treatment including chemotherapy, relapse risk is high due to the resistance that cancer cells can develop against chemotherapy agents. Immuno-oncological therapeutics, as alternatives, have shown very promising clinical results in treatment of patients with different malignancies. Although promising, such treatments are facing many significant challenges, resulting in clinical benefits for only a small group of patients. T cells and dendritic cells, as two of the critical players of the immune response, are currently under investigation for development of novel immunotherapeutic approaches where boosting dendritic cells’ antigen presentation ability and restoring the effector function of T cells are the ultimate goals. In this thesis, a transcritpoic approach was used to gain knowledge on T and dendritic cell subsets in head and neck cancer, acute myeloid leukemia, and bladder cancer. In this regard, paper I and II identify different subsets of dendritic cells in tonsillar and nasopharyngeal cancer where intratumor dendritic cell subsets in tonsillar cancer are found to feature expression of inhibitory receptors and cytokines such as PDL1, PDL2, LAG3, and IL-10. Additionally, paper I introduces an array of functionally-relevant molecules on the surface of different dendritic cell subsets in tonsillar cancer, which may be useful for dendritic cell-targeted therapy given the differences in the function of dendritic cell subsets. Furthermore, selective expression of CD207 in tonsillar and nasopharyngeal cancer is shown as a proof of concept, suggesting the possibility of selective targeting of dendritic cell subsets.With respect to T cells, paper III and IV demonstrate that these are transcriptionally different in acute myeloid leukemia patients with TP53 mutation, as compared to healthy controls. Similar observation was made for T cells in bladder tumors as compared to control tissue, where cellular exhaustion was suggested. For instance, higher expression of exhaustion markers TIM3, TIGIT, CLTA4, and LAG3 was shown for CD8+ T cells in muscle invasive bladder tumors compared to non-muscle invasive tumors and control tissue. Likewise, paper III highlights some features of exhaustion in TP53-mutated acute myeloid leukemia as higher expression of TIM3 by CD8+ T cells was shown compared to corresponding control population. Potentially, the exhaustion markers shown in paper III and IV can be valuable for restoring effector function of exhausted CD8+ T cells in TP53-mutated acute myeloid leukemia and bladder cancer. In conclusion, the results presented provide insights on the immuno-regulatory role of subpopulations of T and Dendritic cells in cancer and can contribute to improved cancer therapy.
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| 9. |
- Abouzayed, Ayman, 1992-
(author)
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Theranostic Targeting of GRPR and PSMA in Prostate Cancer
- 2023
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Doctoral thesis (other academic/artistic)abstract
- This thesis is based on five original articles that investigated the theranostics of prostate cancer by gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA) targeting. GRPR and PSMA are two extensively evaluated prostate cancer cell markers due to their overexpression in the majority of prostate cancer samples. Theranostic targeting of GRPR and PSMA is an attractive strategy to improve the management of prostate cancer patients.Papers I and II focused on the dual targeting of GRPR and PSMA. The effect of linker modification on the affinity for GRPR and PSMA and the pharmacokinetic profile was evaluated. In Paper III, the effect of the GRPR antagonist RM26 conjugation to an albumin-binding domain on the pharmacokinetic profile and its potential use in therapy was investigated. Paper IV focused on developing a GRPR antagonist that was suitable for single-photon emission computed tomography (SPECT) using technetium-99m. In Paper V, the GRPR antagonist developed in Paper IV was translated into a phase I clinical trial to assess safety and dosimetry.Modifying the linkers in GRPR and PSMA heterodimers can largely impact the affinity for both targets. This modification influenced the in vivo targeting specificity and biodistribution, with [125I]I-BO530 in Paper I and [111In]In-BQ7812 in Paper II outperforming other analogues. Our findings in Paper III indicated that the conjugation of an albumin-binding domain to RM26 increased the blood concentration of the radiotracer. This increase led to elevated and stable tumour uptake of [111In]In-DOTA-ABD-RM26 after several days of injection. However, [111In]In-DOTA-ABD-RM26 was also increasingly taken up by various healthy organs. The GRPR antagonist [99mTc]Tc-maSSS-PEG2-RM26, studied in Paper IV, showed high specificity and affinity for GRPR. This resulted in elevated GRPR-mediated uptake. Additionally, maSSS-PEG2-RM26 could be radiolabelled via a straightforward radiolabelling protocol. Clinical evaluation of [99mTc]Tc-maSSS-PEG2-RM26 in prostate and breast cancer patients (Paper V) demonstrated the safety and tolerability of the radiotracer, with favourable dosimetry and no side effects.In conclusion, this thesis evaluated different tools for the theranostic targeting of GRPR and PSMA. The findings warrant further investigation to optimise the reported radiotracers.
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| 10. |
- Abraha, Aynalem, et al.
(author)
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Breaking bad news in cancer care: preferences of patients, family caregivers and general public in Ethiopia
- 2021
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In: International Conference on Communication in Healthcare (ICCH) 2020 Part 2, 15-16 April, 2021.
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Conference paper (other academic/artistic)abstract
- This study explores the preferences of cancer patients, family caregivers, and the general public regarding breaking bad news in an Ethiopian oncology setting. The research was conducted at Tikur Anbessa (Black Lion) Specialized Hospital. The sample consists of patients with a confirmed cancer diagnosis, their family caregivers, and representatives from the general public with 150 subjects per cohort. A comparative cross-sectional study design and a multivariable analysis were used. The patients would like to be informed, which contradicts the perceptions of family caregivers. This creates an ethical dilemma for staff in terms of how much they involve their patients in clinical decision-making. The patients also indicate that information not to be withheld from them. In contrast, the general public prefers information about poor life expectancy to be communicated to family only, which may reflect widespread public perception of cancer as a deadly disease. The findings indicate the complexity of communication concerning breaking bad news in oncology care in Ethiopia. It requires oncologists to probe patient attitudes before information disclosure in order to find a balance between involving patients in communication at the same time as keeping a constructive alliance with family caregivers.
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