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  • Frost, Britt-Marie, et al. (författare)
  • Translocation t(12;21) is related to in vitro cellular drug sensitivity to doxorubicin and etoposide in childhood acute lymphoblastic leukemia
  • 2004
  • Ingår i: Blood. - Washington : American society of hematology. - 0006-4971 .- 1528-0020. ; 104:8, s. 2452-2457
  • Tidskriftsartikel (refereegranskat)abstract
    • The t(12;21) (p13;q22) translocation resulting in ETV6/RUNX1 (previously named TEL/AML1) gene fusion is present in about 25% of children with precursor B-lineage acute lymphoblastic leukemia (B-ALL). We successfully tested 275 precursor BALL samples from children aged 1 to 17 years to determine the relation between t(12;21) and in vitro cellular drug resistance, measured by the fluorometric microculture cytotoxicity assay (FMCA). Samples from 83 patients (30%) were positive for t(12;21). The ETV6/RUNX1(+) samples were significantly more sensitive than ETV6/RUNX1(-) samples to doxorubicin, etoposide, amsacrine, and dexamethasone, whereas the opposite was true for cytarabine. After matching for unevenly distributed patient characteristics, that is, excluding patients with high hyperdiploidy (> 51 chromosomes), t(g;22), t(1;19), or 11q23 rearrangement, the ETV6/RUNX1(+) samples remained significantly more sensitive to doxorubicin (P = .001) and etoposide (P = .001). For the other drugs tested (amsacrine, cytarabine, dexamethasone, prednisolone, vincristine, 6-thioguanine, and 4-hydroper-oxy-cyclophosphamide), no significant difference in cellular drug sensitivity was found. In conclusion, we found that the presence of the t(12;21) translocation in childhood precursor B-ALL is associated with a high tumor cell sensitivity to doxorubicin and etoposide. High throughput techniques should now be used to elucidate the cellular mechanisms by which ETV6/RUNX1 gene fusion is linked to increased sensitivity to these drugs.
  • Godskesen, Tove, et al. (författare)
  • Differences in trial knowledge and motives for participation among cancer patients in phase 3 clinical trials.
  • 2016
  • Ingår i: European Journal of Cancer Care. - 0961-5423 .- 1365-2354. ; 25:3, s. 516-23
  • Tidskriftsartikel (refereegranskat)abstract
    • While participants in clinical oncology trials are essential for the advancement of cancer therapies, factors decisive for patient participation have been described but need further investigation, particularly in the case of phase 3 studies. The aim of this study was to investigate differences in trial knowledge and motives for participation in phase 3 clinical cancer trials in relation to gender, age, education levels and former trial experience. The results of a questionnaire returned from 88 of 96 patients (92%) were analysed using the Mann-Whitney U-test. There were small, barely relevant differences in trial knowledge among patients when stratified by gender, age or education. Participants with former trial experience were less aware about the right to withdraw. Male participants and those aged ≥65 years were significantly more motivated by a feeling of duty, or by the opinions of close ones. Men seem more motivated than women by external factors. With the awareness that elderly and single male participants might be a vulnerable group and participants with former trial experience are less likely to be sufficiently informed, the information consent process should focus more on these patients. We conclude that the informed consent process seems to work well, with good results within most subgroups.
  • Godskesen, Tove, et al. (författare)
  • Hope for a cure and altruism are the main motives behind participation in phase 3 clinical cancer trials.
  • 2015
  • Ingår i: European Journal of Cancer Care. - 0961-5423 .- 1365-2354. ; 24:1, s. 133-41
  • Tidskriftsartikel (refereegranskat)abstract
    • It is necessary to carry out randomised clinical cancer trials (RCTs) in order to evaluate new, potentially useful treatments for future cancer patients. Participation in clinical trials plays an important role in determining whether a new treatment is the best therapy or not. Therefore, it is important to understand on what basis patients decide to participate in clinical trials and to investigate the implications of this understanding for optimising the information process related to study participation. The aims of this study were to (1) describe motives associated with participation in RCTs, (2) assess if patients comprehend the information related to trial enrolment, and (3) describe patient experiences of trial participation. Questionnaires were sent to 96 cancer patients participating in one of nine ongoing clinical phase 3 trials at the Department of Oncology, Uppsala University Hospital in Sweden. Eighty-eight patients completed the questionnaire (response rate 92%); 95% of these were patients in adjuvant therapy and 5% participated in clinical trials on palliative care. Two main reasons for participation were identified: personal hope for a cure and altruism. Patients show adequate understanding of the information provided to them in the consent process and participation entails high patient satisfaction.
  • Godskesen, Tove (författare)
  • Patients in Clinical Cancer Trials : Understanding, Motivation and Hope
  • 2015
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • The overall aim of this thesis was to study participants' understanding of clinical cancer trials,and their motivation for participation. Of particular interest was the question of whether thepatients hoped for a cure resulting from the trial. The thesis was based on four studies andused three methods: interviews, a questionnaire, and empirical bioethics. The results of Study Iindicated that the participants in phase 1 trials understood most of the information provided, butwere unaware of both the very small potential for treatment benefit, and the risk of harm. Patientsin phase 3 trials had a good understanding of the trial, except regarding side effects and their rightto withdraw. Some found it hard to ask questions and felt they needed more information (StudyIII). The participants in phase 1 trials were strongly motivated by the generally unrealistic hopefor therapeutic benefit (Study I). When the chances of a cure are minuscule, as for participantswith end-stage cancer in phase 1 trials, hope can play an important, positive role and offermeaning to one’s remaining life. However, hope for an unrealistic outcome could also deprivepatients of an opportunity to spend their remaining lives, as they would otherwise choose(Study II). The participants in phase 3 trials indicated that their motivation for participationwas multifaceted; the most common motivations included hope of therapeutic benefit, altruism,access to extra clinical examinations or better care, and a wish to repay society for the helpthey had received (Study III). After stratifying and analysing the motivation data by gender,age, education and previous experience of trial participation, males and those aged ≥65 yearswere significantly more motivated to participate out of a desire to reciprocate the help theyhad received, either because of a sense of duty or because their families or friends consideredthat they should attend (Study IV). In conclusion, the informed consent process seems to workrelatively well, with good results within most subgroups. However, patients with end-stagecancer who are participating in phase 1 trials are a vulnerable group as they have very littlepotential for treatment benefit coupled with a tangible risk of harm.
  • Gullbo, Joachim, et al. (författare)
  • Antitumor efficacy and acute toxicity of the novel dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) in vivo.
  • 2004
  • Ingår i: Investigational new drugs. - 0167-6997. ; 22:4, s. 411-20
  • Tidskriftsartikel (refereegranskat)abstract
    • The novel alkylating dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) was evaluated for acute toxicity and antitumor activity in mice, with melphalan as a reference. To determine a safe and tolerable dose for efficacy studies the acute toxicity following intravenous injection in the tail vein was monitored using a 14-day schedule with up to four doses. The highest tested dose, 25 micromoles/kg, was considered close to this level, with minor effects on body weight gain but significant effects on hematological parameters. Melphalan and J1 appeared equitoxic with no statistically significant differences. Subsequently a mouse hollow fiber model was employed with subcutaneous implantation of fibers containing human tumor cells. Three different human tumor cell lines as well as two samples of primary human tumor cells (ovarian carcinoma and chronic lymphatic leukemia) were used as tumor models. At the dose level tested there was a marked and statistically significant decrease in both T-cell leukemia CCRF-CEM and small cell lung cancer NCI-H69 tumor cell growth and viability in response to J1 as compared with both placebo and melphalan treated groups. In primary ovarian carcinoma cells only J1 treatment resulted in significant tumor regression (net cell kill). In summary the results indicate that, despite an expected short half time in the blood circulation, the promising in vitro data from the previous studies of J1 seems translatable into the in vivo situation. At equal doses of alkylating units J1, compared to melphalan, was more active in the mouse hollow-fiber model, but showed similar general toxicity.
  • Gullbo, Joachim, et al. (författare)
  • Structure activity relationship for alkylating dipeptide nitrogen mustard derivatives
  • 2003
  • Ingår i: Oncology Research. - 0965-0407 .- 1555-3906. ; 14:3, s. 113-132
  • Tidskriftsartikel (refereegranskat)abstract
    • The strategy of using small peptides for effective targeting of tumor cells in chemotherapy has proven beneficial. Recently we showed that J1 (L-melphalanyl-p-L-fluorophenylalanine ethyl ester), an alkylating nitrogen mustard-containing dipeptide, exhibited strong cytotoxic activity in fresh human tumor samples in addition to rapid and pronounced inhibition of macromolecular syntheses and cellular respiration in the human tumor lymphoma cell line U-937 GTB. In this study, an additional series of 17 nitrogen mustard-containing dipeptides has been synthesized and analyzed for cytotoxic activity in a panel of 10 human tumor cell lines. The results were compared to the single amino acid mustard derivative melphalan and its ethyl and isopropyl esters. Also P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester), a tripeptide that previously has shown impressive effects in human tumor cells, was used as reference. The tested compounds displayed various activities in the different cell lines but also showed a high correlation, indicating a similar mechanism of action. Factors like amino acid composition, amino acid sequence, modifications of the C- and N-termini, and to a minor extent the lipophilicity of the dipeptide derivatives appear to influence the in vitro activity. The results indicate that the activity of these compounds not only relies on their chemical reactivity, but also on active biological interactions such as transport across membranes and/or enzymatic liberation of reactive molecular entities.
  • Hansson, Johan, 1964- (författare)
  • Loco-regional Treatment of Peritoneal Carcinomatosis: Survival, Morbidity and Quality of Life
  • 2009
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Peritoneal carcinomatosis (PC) is traditionally regarded as a terminal stage of disease with a poor prognosis and systemic chemotherapy is regarded as palliative treatment. In order to improve survival and even to achieve cure for selected patients with PC, cytoreductive surgery and intraperitoneal che-motherapy have been advocated. Despite complete macroscopic removal of tumour, residual microscopic malignant cells might result in recurrence. Intraperitoneal chemotherapy aims to kill residual malignant cells and thereby needs to be distributed in the entire peritoneal cavity. This aggres-sive combined loco-regional treatment has a high risk of morbidity and mor-tality. Whether the increased risks are acceptable to improve survival re-quires investigation and the impact of loco-regional treatment of PC on health-related quality of life (HRQL) needs to bee explored The overall aim of this thesis was to analyse the impact of cytoreductive surgery and intraperitoneal chemotherapy on patients with peritoneal carci-nomatosis. A significant survival improvement (median 32 months) was seen in 18 patients with PC of colorectal origin subjected to loco-regional treatment, in comparison to matched controls treated with systemic chemotherapy (me-dian survival 14 months, Paper I). The results of single-photon emission computer-tomography (SPECT) in 51 patients were correlated to the number of intraperitoneal chemotherapy courses that could be performed without further surgery (Paper II). Postoperative 30-days morbidity and 90-days mortality was investigated in 123 PC-patients after loco-regional treatment. Severe adverse events occurred in 51 (41%) patients. Five patients (4%) had treatment-related mortality. Stoma formation, duration of surgery, periopera-tive blood loss, and extent of PC was associated with morbidity (Paper III). HRQL was investigated in 64 patients. HRQL was negatively affected at 3 months but a partial recovery was seen at 8 months. 30-day morbidity did not have any impact on HRQL at 8 months (Paper IV). This treatment there fore appears justified despite considerable toxicity in view of possible life prolongation.
  • Hassan, Saadia, et al. (författare)
  • Novel activity of acriflavine against colorectal cancer tumor cells
  • 2011
  • Ingår i: Cancer Science. - 1347-9032 .- 1349-7006. ; 102:12, s. 2206-2213
  • Tidskriftsartikel (refereegranskat)abstract
    • A high-throughput screen of the cytotoxic activity of 2000 molecules from a commercial library in three human colon cancer cell lines and two normal cell types identified the acridine acriflavin to be a colorectal cancer (CRC) active drug. Acriflavine was active in cell spheroids, indicating good drug penetration and activity against hypoxic cells. In a validation step based on primary cultures of patient tumor cells, acriflavine was found to be more active against CRC than ovarian cancer and chronic lymphocytic leukemia. This contrasted to the activity pattern of the CRC active standard drugs 5-fluorouracil, irinotecan and oxaliplatin. Mechanistic studies indicated acriflavine to be a dual topoisomerase I and II inhibitor. In conclusion, the strategy used seems promising for identification of new diagnosis-specific cancer drugs.
  • Hauffman, Anna, et al. (författare)
  • 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.
  • 2020
  • Ingår i: Psycho-Oncology. - 1057-9249 .- 1099-1611.
  • Tidskriftsartikel (refereegranskat)abstract
    • 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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