| 1. |
- Albertsson, Per, 1964, et al.
(författare)
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Astatine-211 based radionuclide therapy: Current clinical trial landscape
- 2023
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Ingår i: Frontiers in Medicine. - : Frontiers Media SA. - 2296-858X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Astatine-211 (At-211) has physical properties that make it one of the top candidates for use as a radiation source for alpha particle-based radionuclide therapy, also referred to as targeted alpha therapy (TAT). Here, we summarize the main results of the completed clinical trials, further describe ongoing trials, and discuss future prospects.
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| 2. |
- Albertsson, Per, 1964, et al.
(författare)
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Positron emission tomography and computed tomographic (PET/CT) imaging for radiation therapy planning in anal cancer: A systematic review and meta-analysis
- 2018
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Ingår i: Critical reviews in oncology/hematology. - : Elsevier BV. - 1040-8428. ; 126, s. 6-12
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Forskningsöversikt (refereegranskat)abstract
- To improve the accuracy of chemoradiation therapy in anal cancer patients PET/CT is frequently used in the planning of radiation therapy. A systematic review was performed to assess impact on survival, quality of life, symptom score, change in target definition and treatment intention. Systematic literature searches were conducted in Medline, EMBASE, the Cochrane Library, and Centre for Reviews and Dissemination. Ten cross-sectional studies were identified. No data were available on survival or quality of life. The summary estimate of the proportion of patients in which PET/CT had an impact on the target definition, was 23% (95% CI 16;33). The corresponding summary estimate of a change in treatment intent from curative to palliative was 3% (95% CI 2;6). Almost one in four patients had a change in target definition, which supports the use of PET/CT in radiation therapy planning, but the consequence regarding survival and quality of life is still uncertain.
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| 3. |
- Chakarova, Roumiana, et al.
(författare)
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An automated Monte Carlo QC system for volumetric modulated arc therapy: Possibilities and challenges
- 2018
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Ingår i: Physica Medica-European Journal of Medical Physics. - : Elsevier BV. - 1120-1797. ; 51, s. 32-37
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To develop and implement an automated Monte Carlo (MC) system for patient specific VMAT quality control in a patient geometry that generates treatment planning system (TPS) compliant DICOM objects and includes a module for 3D analysis of dose deviations. Also, the aims were to recommend diagnose specific tolerance criteria and an evaluation procedure. Methods: The EGSnrc code package formed the basis for development of the MC system. The workflow consists of a number of modules connected to a TPS by means of manual DICOM exports and imports which were executed sequentially without user interaction. DVH comparison was performed in the TPS. In addition, MC-and TPS dose distributions were analysed by applying the normalized dose difference (NDD) formalism. NDD failure maps and a pass rate for a certain threshold were obtained. 170 clinical plans (prostate, thorax, head-and-neck and gynecological) were selected for analysis. Results: Agreement within 1.5% was found between clinical-and MC data for the mean dose to the target volumes and within 3% for parameters more sensitive to the shape of the DVH e.g. D-98% PTV. Regarding the NDD analysis, tolerance criteria 2%/3 mm were established for prostate plans and 3%/3 mm for the rest of the cases. Conclusions: An automated MC system was developed and implemented. Evaluation procedure is recommended with NDD-analysis as a first step. For pass rate < 95%, the evaluation continues with comparison of DVH parameters. For deviations larger than 2%, a visual inspection of the clinical-and MC dose distributions is performed.
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| 4. |
- Drevin, Jennifer, et al.
(författare)
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Childhood abuse and unplanned pregnancies : a cross-sectional study of women in the Norwegian Mother and Child Cohort Study
- 2020
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Ingår i: British Journal of Obstetrics and Gynecology. - : Wiley. - 1470-0328 .- 1471-0528. ; 127:4, s. 438-446
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Tidskriftsartikel (refereegranskat)abstract
- Objective To study if childhood emotional, physical and sexual abuse are determinants for having an unplanned pregnancy, if the categories of abuse interact, and if a potential bias due to the selection of the participants (collider stratification bias) could explain the effect of childhood abuse.Design A cross-sectional study.Setting The study is based on the Norwegian Mother and Child Cohort Study (MoBa) and uses data from the Medical Birth Registry of Norway.Sample Women participating in the MoBa for the first time, >= 18 years of age who responded to questions regarding childhood abuse and pregnancy planning (n = 76 197).Methods Data were collected using questionnaires. We conducted analyses using modified Poisson regressions and the relative excess risks due to interaction (RERI). Sensitivity analyses were performed.Main outcome measure An unplanned pregnancy (yes/no).Results Exposure to childhood emotional (adjusted relative risk (RR) 1.14, 95% CI 1.10-1.19), physical (adjusted RR 1.11, 95% CI 1.04-1.18) and sexual (adjusted RR 1.20, 95% CI 1.14-1.27) abuse increased the risk of having an unplanned pregnancy. The effects could not be explained by the collider stratification bias. The different combinations of categories of abuse did not show any interaction effects.Conclusions Childhood emotional, physical and sexual abuses separately increase the risk of having an unplanned pregnancy. The results indicate that victims of childhood abuse are in greater need of support to achieve their reproductive goals. Tweetable abstract Childhood abuse increases the risk of having an unplanned pregnancy. #reproductivehealth #epitwitter.
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| 5. |
- Dutta, Nikita, 1992, et al.
(författare)
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Combinatory analysis of immune cell subsets and tumor-specific genetic variants predict clinical response to PD-1 blockade in patients with non-small cell lung cancer
- 2023
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Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Immunotherapy by blocking programmed death protein-1 (PD-1) or programmed death protein-ligand1 (PD-L1) with antibodies (PD-1 blockade) has revolutionized treatment options for patients with non-small cell lung cancer (NSCLC). However, the benefit of immunotherapy is limited to a subset of patients. This study aimed to investigate the value of combining immune and genetic variables analyzed within 3-4 weeks after the start of PD-1 blockade therapy to predict long-term clinical response.Blood collected from patients with NSCLC were analyzed for changes in the frequency and concentration of immune cells using a clinical flow cytometry assay. Next-generation sequencing (NGS) was performed on DNA extracted from archival tumor biopsies of the same patients. Patients were categorized as clinical responders or non-responders based on the 9 months' assessment after the start of therapy.We report a significant increase in the post-treatment frequency of activated effector memory CD4+ and CD8+ T-cells compared with pre-treatment levels in the blood. Baseline frequencies of B cells but not NK cells, T cells, or regulatory T cells were associated with the clinical response to PD-1 blockade. NGS of tumor tissues identified pathogenic or likely pathogenic mutations in tumor protein P53, Kirsten rat sarcoma virus, Kelch-like ECH-associated protein 1, neurogenic locus notch homolog protein 1, and serine/threonine kinase 11, primarily in the responder group. Finally, multivariate analysis of combined immune and genetic factors but neither alone, could discriminate between responders and non-responders.Combined analyses of select immune cell subsets and genetic mutations could predict early clinical responses to immunotherapy in patients with NSCLC and after validation, can guide clinical precision medicine efforts.
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| 6. |
- Eklund, Ella A, et al.
(författare)
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Assessing the prognostic value of KRAS mutation combined with tumor size in stage I-II non-small cell lung cancer: a retrospective analysis
- 2024
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Ingår i: FRONTIERS IN ONCOLOGY. - 2234-943X. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background: KRAS mutation status is a well-established independent prognostic factor in advanced non-small cell lung cancer (NSCLC), yet its role in early-stage disease is unclear. Here, we investigate the prognostic value of combining survival data on KRAS mutation status and tumor size in stage I-II NSCLC. Methods: We studied the combined impact of KRAS mutational status and tumor size on overall survival (OS) in patients with stage I-II NSCLC. We performed a retrospective study including 310 diagnosed patients with early (stage I-II) NSCLCs. All molecularly assessed patients diagnosed with stage I-II NSCLC between 2016-2018 in the V & auml;stra G & ouml;taland Region of western Sweden were screened in this multi-center retrospective study. The primary study outcome was overall survival. Results: Out of 310 patients with stage I-II NSCLC, 37% harbored an activating mutation in the KRAS gene. Our study confirmed staging and tumor size as prognostic factors. However, KRAS mutational status was not found to impact OS and there was no difference in the risk of death when combining KRAS mutational status and primary tumor size. Conclusions: In our patient cohort, KRAS mutations in combination with primary tumor size did not impact prognosis in stage I-II NSCLC.
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| 7. |
- Eklund, Ella A, et al.
(författare)
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KRAS mutations impact clinical outcome in metastatic non-small cell lung cancer.
- 2022
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:9
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Tidskriftsartikel (refereegranskat)abstract
- There is an urgent need to identify new predictive biomarkers for treatment response to both platinum doublet chemotherapy (PT) and immune checkpoint blockade (ICB). Here, we evaluated whether treatment outcome could be affected by KRAS mutational status in patients with metastatic (Stage IV) non-small cell lung cancer (NSCLC). All consecutive patients molecularly assessed and diagnosed between 2016-2018 with Stage IV NSCLC in the region of West Sweden were included in this multi-center retrospective study. The primary study outcome was overall survival (OS). Out of 580 Stage IV NSCLC patients, 35.5% harbored an activating mutation in the KRAS gene (KRASMUT). Compared to KRAS wild-type (KRASWT), KRASMUT was a negative factor for OS (p = 0.014). On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.478, 95% CI 1.207-1.709, p < 0.001). When treated with first-line platinum doublet (n = 195), KRASMUT was a negative factor for survival (p = 0.018), with median OS of 9 months vs. KRASWT at 11 months. On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.564, 95% CI 1.124-2.177, p = 0.008). KRASMUT patients with high PD-L1 expression (PD-L1high) had better OS than PD-L1highKRASWT patients (p = 0.036). In response to first-line ICB, KRASMUT patients had a significantly (p = 0.006) better outcome than KRASWT patients, with a median OS of 23 vs. 6 months. On multivariable Cox analysis, KRASMUT status was an independent prognostic factor for better OS (HR 0.349, 95% CI 0.148-0.822, p = 0.016). kRAS mutations are associated with better response to treatment with immune checkpoint blockade and worse response to platinum doublet chemotherapy as well as shorter general OS in Stage IV NSCLC.
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| 8. |
- Gunnarsson, Kerstin, et al.
(författare)
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Stereotactic radiotherapy for brain metastases in patients with lung cancer; outcome and toxicity in clinical practice.
- 2022
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Ingår i: Reports of practical oncology and radiotherapy : journal of Greatpoland Cancer Center in Poznan and Polish Society of Radiation Oncology. - 1507-1367. ; 27:3, s. 410-418
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Tidskriftsartikel (refereegranskat)abstract
- Stereotactic radiotherapy (SRT) is an established modality for treating limited brain metastases (BMs). This study aimed to assess the real-life treatment outcome and associated prognostic factors for survival in a consecutive lung cancer cohort receiving SRT for BMs.A retrospective review and analysis of patients with lung cancer with BMs treated with SRT in western Sweden between 2002 and 2017 were performed. Data were collected from patient charts and the radiotherapy dose planning system.One hundred nine patients corresponding to 139 lesions were assessed; the majority were treated with single-fractionated SRT with 20 Gy. The median overall survival (OS) was 6.1 months, with a 12-month survival rate of 24%. The estimated overall disease control rate (DCR) was 84% at a median time of three months. On multivariate analysis, WHO performance status (PS) (p = 0.002) and smoking status (p = 0.005) were significant predictive factors for survival. Four percent of the patients experienced possible grade III-IV toxicity, and previously administered cranial radiation therapy was a significant independent factor (p = 0.03) associated with the risk of developing acute toxicity.SRT due to brain metastases from lung cancer is a well-tolerated treatment. When selecting patients suitable for treatment, PS and extracranial disease progression should be considered. Smoking cessation is probably of value even in this palliative setting. The goal of SRT for BMs is not only to improve survival but also to provide symptom relief, and future studies on SRT should assess patient-reported outcomes in addition to survival.
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| 9. |
- Hallqvist, Andreas, 1973, et al.
(författare)
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Accelerated hyperfractionated radiotherapy and concomitant chemotherapy in small cell lung cancer limited-disease. Dose response, feasibility and outcome for patients treated in western Sweden, 1998-2004.
- 2007
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Ingår i: Pubmed. - : Informa UK Limited. - 0284-186X. ; , s. 1-6
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Tidskriftsartikel (refereegranskat)abstract
- Addition of thoracic radiation therapy (TRT) to chemotherapy (CHT) can increase overall survival in patients with small cell lung cancer limited-disease (SCLC-LD). Accelerated fractionation and early concurrent platinum-based CHT, in combination with prophylactic cranial irradiation, represent up-front treatment for this group of patients. Optimised and tailored local and systemic treatment is important. These concepts were applied when a new regional treatment programme was designed at Sahlgrenska University Hospital in 1997. The planned treatment consisted of six courses of CHT (carboplatin/etoposide) + TRT+/-prophylactic cranial irradiation (PCI). Standard TRT was prescribed as 1.5 Gy BID to a total of 60 Gy during 4 weeks, starting concomitantly with the second or third course of CHT. However, patients with large tumour burdens, poor general condition and/or poor lung function received 45 Gy, 1.5 Gy BID, during 3 weeks. PCI in 15 fractions to a total dose of 30 Gy was administered to all patients with complete remission (CR) and "good" partial remission (PR) at response evaluation. Eighty consecutive patients were treated between January 1998 and December 2004. Forty-six patients were given 60 Gy and 34 patients 45 Gy. Acute toxicity occurred as esophagitis grade III (RTOG/EORTC) in 16% and as pneumonitis grade I-II in10%. There were no differences in toxicity between the two groups. Three- and five-year overall survival was 25% and 16%, respectively. Median survival was 20.8 months with no significant difference between the two groups. In conclusion, TRT with a total dose of 60 or 45 Gy is feasible with comparable toxicity and no difference in local control or survival. Distant metastasis is the main cause of death in this disease; the future challenge is thus further improvement of the systemic therapy combined with optimised local TRT.
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| 10. |
- Hallqvist, Andreas, 1973, et al.
(författare)
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Concurrent cetuximab and radiotherapy after docetaxel-cisplatin induction chemotherapy in stage III NSCLC : Satellite-A phase II study from the Swedish Lung Cancer Study Group
- 2011
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Ingår i: Lung Cancer. - : Elsevier BV. - 0169-5002 .- 1872-8332. ; 71:2, s. 166-172
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Tidskriftsartikel (refereegranskat)abstract
- Background: Several attempts to increase the locoregional control in locally advanced lung cancer including concurrent chemotherapy, accelerated fractionation and dose escalation have been made during the last years. As the EGFR directed antibody cetuximab has shown activity concurrent with radiotherapy in squamous cell carcinoma of the head and neck, as well as in stage IV NSCLC combined with chemotherapy, we wanted to investigate radiotherapy with concurrent cetuximab in locally advanced NSCLC, a tumour type often over expressing the EGF-receptor. Methods: Between February 2006 and August 2007 75 patients in stage Ill NSCLC with good performance status (PS 0 or 1) and adequate lung function (FEV1 > 1.0) were enrolled in this phase II study at eight institutions. Treatment consisted of 2 cycles of induction chemotherapy, docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) with 3 weeks interval. An initial dose of cetuximab 400 mg/m(2) was given before start of 3D-CRT to 68 Gy with 2 Gy per fraction in 7 weeks concurrent with weekly cetuximab 250 mg/m(2). Toxicity was scored weekly during radiotherapy (CTC 3.0), and after treatment the patients were followed every third month with CT-scans, toxicity scoring and QLQ. Results: Seventy-one patients were eligible for analysis as four were incorrectly enrolled. Histology: adenocarcinoma 49%, squamous cell carcinoma 39% and other NSCLC 12%. The majority had PS 0 (62.5%), median age 62.2 (42-81), 50% were women and 37% had a pre-treatment weight loss > 5%. Toxicity: esophagitis grade 1-2: 72%; grade 3:1.4%. Hypersensitivity reactions grade 3-4: 5.6%. Febrile neutropenia grade 3-4: 15.4%. Skin reactions grade 1-2: 74%; grade 3: 4.2%. Diarrhoea grade 1-2: 38%; grade 3: 11.3%. Pneumonitis grade 1-2: 26.8%; grade 3: 4.2%; grade 5:1.4%. The median follow-up was 39 months for patients alive and the median survival was 17 months with a 1-, 2- and 3-year OS of 66%, 37% and 29% respectively. Until now local or regional failure has occurred in 20 patients and 22 patients have developed distant metastases. Weight loss, PS and stage were predictive for survival in univariate as well as in multivariate analysis. Conclusion: Induction chemotherapy followed by concurrent cetuximab and RT to 68 Gy is clearly feasible with promising survival. Toxicity, e.g. pneumonitis and esophagitis is low compared to most schedules with concurrent chemotherapy. This treatment strategy should be evaluated in a randomised manner vs. concurrent chemoradiotherapy to find out if it is a valid treatment option.
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| 11. |
- Hallqvist, Andreas, 1973, et al.
(författare)
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Dose escalation to 84 Gy with concurrent chemotherapy in stage III NSCLC appears excessively toxic: Results from a prematurely terminated randomized phase II trial
- 2018
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Ingår i: Lung Cancer. - : Elsevier BV. - 0169-5002 .- 1872-8332. ; 122, s. 180-186
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Concurrent chemoradiotherapy is the mainstay treatment for NSCLC stage III disease. To investigate whether radiation dose escalation based on individual normal tissue constraints can improve outcome, the Swedish lung cancer study group launched this randomized phase II trial. Materials and Methods: NSCLC patients with stage III disease, good performance status (0-1) and adequate lung function (FEV1 > 1.0 L and CO diffusion capacity > 40%) received three cycles of cisplatin (75 mg/m(2) day 1) and vinorelbine (25 mg/m(2) day 1 and 8) every third week. Radiotherapy started concurrently with the second cycle, with either 2 Gy daily, 5 days a week, to 68 Gy (A) or escalated therapy (B) based on constraints to the spinal cord, esophagus and lungs up to 84 Gy by adding an extra fraction of 2 Gy per week. Results: A pre-planned safety analysis revealed excessive toxicity and decreased survival in the escalated arm, and the study was stopped. Thirty-six patients were included during 2011-2013 (56% male, 78% with adenocarcinoma, 64% with PS 0 and 53% with stage IIIB). The median progression-free survival (PFS) and overall survival (OS) were 11 and 17 months in arm B compared to the encouraging results of 28 and 45 months in the standard arm. The 1- and 3-year survival rates were 56% and 33% (B) and 72% and 56% (A), respectively. There were seven toxicity-related deaths due to esophageal perforations and pneumonitis: five in the escalated group and two with standard treatment. Conclusion: Dose-escalated concurrent chemoradiotherapy to 84 Gy to primary tumor and nodal disease is hazardous, with a high risk of excessive toxicity, whereas modern standard dose chemoradiotherapy with proper staging given in the control arm shows a promising outcome with a median survival of 45 months and a 3-year survival of 56% (NCT01664663).
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| 12. |
- Hallqvist, Andreas, 1973, et al.
(författare)
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Health related quality of life in locally advanced NSCLC treated with high dose radiotherapy and concurrent chemotherapy or cetuximab - Pooled results from two prospective clinical trials.
- 2012
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Ingår i: Radiotherapy and oncology. - : Elsevier BV. - 1879-0887 .- 0167-8140. ; 104:1, s. 39-44
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Tidskriftsartikel (refereegranskat)abstract
- Background In non-small cell lung cancer (NSCLC) stage III, data on patient reported health-related quality of life (HRQL) are scarce, especially regarding concurrent chemoradiotherapy. Aims To evaluate HRQL in patients treated with high dose radiotherapy combined with concurrent chemotherapy or the antibody cetuximab. Methods The study population comprised all patients enroled in either of two phase II trials in locally advanced NSCLC performed in Sweden 2002–2007. The RAKET trial investigated three different ways of increasing local control (accelerated hyperfractionated treatment or concurrent daily or weekly chemotherapy). The Satellite trial evaluated the addition of cetuximab to thoracic irradiation. HRQL was measured at four time points: At baseline, before radiotherapy, 4–6 weeks after radiotherapy and at 3 months follow-up, using the EORTC QLQ-C30 and LC14 set of questionnaires. Results 154/220 patients (65%) who completed HRQL assessments at all time points were included in the longitudinal study. There was a significant decline over time regarding most functioning measures. Dyspnoea and fatigue gradually deteriorated without recovery after completed treatment. Chemotherapy related symptoms showed a transient deterioration, whereas radiotherapy related esophagitis had not fully recovered at 3 months. Patients with stage IIIA disease tended to recover better regarding global QL, fatigue and dyspnoea compared to patients with stage IIIB. Patients with WHO performance status (PS) 0 reported improved global QL and less fatigue over time compared with PS 1. Concurrent chemotherapy was associated with more pronounced fatigue and dysphagia, and worse global QL compared with concurrent cetuximab. Baseline physical functioning was an independent predictor of overall survival. Conclusion Patients undergoing high dose thoracic radiotherapy combined with chemotherapy or cetuximab reported a gradual deterioration in functioning, dyspnoea and fatigue, while treatment related side effects were transient. Radiotherapy with concurrent cetuximab had less negative impact on HRQL than concurrent chemoradiation.
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| 13. |
- Hallqvist, Andreas, 1973, et al.
(författare)
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Immune checkpoint blockade and biomarkers of clinical response in non–small cell lung cancer
- 2020
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 92:6
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Tidskriftsartikel (refereegranskat)abstract
- Immunotherapy with PD-1 and PD-L1 inhibitors has revolutionized the treatment for patients with NSCLC the last years with increased overall survival and in particular increased number of long-time survivors in patients with metastatic disease. It is now a treatment of choice for patients with distant metastases (stage IV) and in conjunction with chemoradiotherapy for patients with limited spread confined to the chest (stage III). PD-1 inhibition has been proven to be superior to standard chemotherapy, both as a single treatment and when combined with either chemotherapy or CTLA-4 inhibition. Despite the success of immunotherapy, the majority of patients do not respond or relapse within a short time frame. Biomarkers that would help to properly select patients with a high likelihood of clinical response to PD-1 and PD-L1 inhibitors are scarce and far from optimal, and only one (PD-L1 expression) has reached clinical practice. Thus for immunotherapy to be effective, the discovery and validation of additional biomarkers is critical for patient selection and prediction of clinical response. In this mini-review, we give an overview of current clinical management of NSCLC including treatment landscape with regard to immunotherapy, as well as discuss the current genetic and immune cell biomarker studies and their potential for introduction into clinical practice. © 2020 The Authors. Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Scandinavian Foundation for Immunology
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| 14. |
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| 15. |
- Hallqvist, Andreas, 1973, et al.
(författare)
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Intraperitoneal alpha-Emitting Radioimmunotherapy with At-211 in Relapsed Ovarian Cancer: Long-Term Follow-up with Individual Absorbed Dose Estimations
- 2019
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 60:8, s. 1073-1079
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Tidskriftsartikel (refereegranskat)abstract
- Eliminating microscopic residual disease with alpha-particle radiation is theoretically appealing. After extensive preclinical work with alpha-particle-emitting At-211, we performed a phase I trial with intraperitoneal alpha-particle therapy in epithelial ovarian cancer using At-211 conjugated to MX35, the antigen-binding fragments-F(ab')(2)-of a mouse monoclonal antibody. We now present clinical outcome data and toxicity in a long-term follow-up with individual absorbed dose estimations. Methods: Twelve patients with relapsed epithelial ovarian cancer, achieving a second complete or nearly complete response with chemotherapy, received intraperitoneal treatment with escalating (20-215 MBq/L) activity concentrations of At-211-MX35 F(ab')(2). Results: The activity concentration was escalated to 215 MBq/L without any dose-limiting toxicities. Most toxicities were low-grade and likely related to the treatment procedure, not clearly linked to the alpha-particle irradiation, with no observed hematologic toxicity. One grade 3 fatigue and 1 grade 4 intestinal perforation during catheter implantation were observed. Four patients had a survival of more than 6 y, one of whom did not relapse. At progression, chemotherapy was given without signs of reduced tolerability. Overall median survival was 35 mo, with a 1-, 2-, 5-, and 10-y survival of 100%, 83%, 50%, and 25%, respectively. Calculations of the absorbed doses showed that a lower specific activity is associated with a lower single-cell dose, whereas a high specific activity may result in a lower central dose in microtumors. Individual differences in absorbed dose to possible microtumors were due to variations in administered activity and the specific activity. Conclusion: No apparent signs of radiation-induced toxicity or decreased tolerance to relapse therapy were observed. The dosimetric calculations show that further optimization is advisable to increase the efficacy and reduce possible long-term toxicity.
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| 16. |
- Hallqvist, Andreas, 1973, et al.
(författare)
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Mutated KRAS is an independent negative prognostic factor for survival in NSCLC stage III disease treated with high-dose radiotherapy.
- 2012
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Ingår i: Lung Cancer International. - : Hindawi Limited. - 2090-3200 .- 2090-3197. ; 2012
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Tidskriftsartikel (refereegranskat)abstract
- Background. The main attention regarding prognostic and predictive markers in NSCLC directs towards the EGFR-targeted pathway, where the most studied genetic alterations include EGFR mutations, EGFR copy number, and KRAS mutations. We wanted to explore the prognostic impact of mutated KRAS in the stage III setting treated with high-dose radiochemotherapy. Methods. Samples were obtained from patients participating in two prospective studies of locally advanced NSCLC receiving combined radiochemotherapy: the RAKET study, a randomized phase II study where patients were treated with induction chemotherapy (carboplatin/paclitaxel) followed by concurrent radiochemotherapy, and the Satellite trial, a phase II study with induction chemotherapy (cisplatin/docetaxel) followed by radiotherapy concurrent cetuximab. The samples were analysed regarding KRAS mutations, EGFR mutations, and EGFR FISH positivity. Results. Patients with mutated KRAS had a significantly inferior survival, which maintained its significance in a multivariate analysis when other possible prognostic factors were taken into account. The prevalence of KRAS mutations, EGFR mutations, and EGFR FISH positivity were 28.8%, 7.5%, and 19.7%, respectively. Conclusion. Mutated KRAS is an independent negative prognostic factor for survival in NSCLC stage III disease treated with combined radiochemotherapy. The prevalence of KRAS mutations and EGFR mutations are as expected in this Scandinavian population.
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| 17. |
- Hallqvist, Andreas, 1973
(författare)
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Optimization of radiotherapy in locally advanced lung cancer
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lung cancer is the leading cause of cancer death worldwide as well as in Sweden, where the incidence is around 3500 new cases per year. About 50% have distant metastases by the time of diagnosis and are treated with palliative intent. Early stages where the tumour is confined to the lung without regional spread constitute around 20% and may be candidates for surgery aiming to cure. The remaining 30% represent an intermediate group where the patients have metastasized to regional lymph nodes in the thorax making them inappropriate for surgery. They do not however have distant metastases and this group, often referred to as locally advanced lung cancer or stage III lung cancer, may be suitable for oncologic treatment with radiotherapy and chemotherapy with curative intent. It is established that a combination of these two modalities should be used, but since long term survival is still poor with a 5-year survival of 5-25%, there are many questions on how to further improve the treatment strategies. This thesis aims to evaluate different approaches to optimize radiotherapy for this patient group with locally advanced lung cancer analysing one retrospective study, two prospective trials and also looking into clinical and genetic prognostic factors as well as studying Health Related Quality of Life (HRQL) during intense combined therapy. In the first study we analyse a new treatment protocol for limited Small Cell Lung Cancer (SCLC), that was initiated in 1997, consisting of concurrent chemoradiotherapy, where the radiotherapy was delivered with 1.5 Gy, twice a day, five days a week to a total dose of 60 or 45 Gy depending on lung function, performance status and tumour burden. Complete responders and good partial responders were given prophylactic cranial irradiation to 30 Gy in 15 fractions. The results show that it is clearly feasible to give 60 Gy with concurrent chemotherapy to this patient population. Median survival was 20.8 months with a 3- and 5-year survival of 25% and 16%. There was no survival difference between the two dose groups even if there was a negative selection in the low dose group. The second study evaluates the RAKET trial, a three-armed randomized phase II trial which compares three different ways of intensifying the local treatment in locally advanced Non Small Cell Lung Cancer (NSCLC); either by hyperfractionated accelerated radiotherapy or with concurrent chemotherapy on a weekly or daily basis. The median survival was 17.8 months and 3- and 5-year survival were 31% and 24% respectively. The three strategies were equal in regard to efficacy and toxicity. In the third study we analyse outcome in the Satellite trial, a one-armed phase II study addressing the same patient population as in the RAKET trial i.e. NSCLC stage III, receiving induction chemotherapy followed by radiotherapy concurrent with the antibody cetuximab. This treatment had previously showed good results in head and neck cancer but had not been studied in NSCLC together with thoracic irradiation. The results show that it is feasible with comparable survival data to the previous trial with concurrent chemotherapy. The median survival was 17 months and 3-year survival 29%. Furthermore we found less toxicity with this regimen compared to what usually is described in concurrent chemoradiation. We also observed an immense impact on survival regarding basic clinical factor as stage (IIIA or IIIB), performance status (0, 1) and pre diagnostic weight loss. In the fourth paper we analyse the prevalence of important genetic alterations in NSCLC, namely EGFR mutations, EGFR FISH positivity and KRAS mutations and investigate their possible prognostic impact in stage III disease. The results show that the prevalence figures are as expected in an unselected population of Caucasians with EGFR mutations, EGFR FISH positivity and KRAS mutations being present in 7.5%, 19.7% and 28.8% respectively. EGFR FISH positive patients in the Satellite trial (paper III) had a trend towards inferior survival but most importantly mutated KRAS was found to be an independent prognostic marker for survival in multivariate analysis. Finally in the fifth study we evaluate HRQL in patients treated with high dose radiotherapy and concurrent chemotherapy or cetuximab. This was done by using the EORTC QLQ C30 and LC14 questionnaires during therapy and at three months follow-up. The results show that most patients experience a gradual decline in nearly all functional scales. Treatment related side effects return towards base-line but there is for the majority a persistent worsening of dyspnoea and fatigue. Patients with stage IIIA and/or performance status 0 seem to tolerate combined treatment better with regard to HRQL, and concurrent radiotherapy with cetuximab influences HRQL less than concurrent chemoradiation.
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| 18. |
- Hallqvist, Andreas, 1973, et al.
(författare)
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Optimizing the Schedule of PARP Inhibitors in Combination with 177Lu-DOTATATE: A Dosimetry Rationale.
- 2021
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Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 9:11
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Tidskriftsartikel (refereegranskat)abstract
- 177Lu-DOTATATE for neuroendocrine tumours is considered a low-toxicity treatment and may therefore be combined with other pharmaceuticals to potentiate its efficacy. One approach is to add a poly-[ADP-ribose]-polymerase (PARP) inhibitor to decrease the ability of tumour cells to repair 177Lu-induced DNA damage. To decrease the risk of side effects, the sequencing should be optimized according to the tumour-to-normal tissue enhanced dose ratio (TNED). The aim of this study was to investigate how to enhance 177Lu-DOTATATE by optimal timing of the addition of a PARP inhibitor. Biokinetic modelling was performed based on the absorbed dose to the bone marrow, kidneys and tumour; determined from SPECT/CT and planar images from 17 patients treated with 177Lu-DOTATATE. To investigate the theoretical enhanced biological effect of a PARP inhibitor during 177Lu-DOTATATE treatment, the concept of relative biological effectiveness (RBE) was used, and PARP inhibitor administration was simulated over different time intervals. The absorbed dose rate for the tumour tissue demonstrated an initial increase phase until 12 h after infusion followed by a slow decrease. In contrast, the bone marrow showed a rapid initial dose rate decrease. Twenty-eight days after infusion of 177Lu-DOTATATE, the full absorbed dose to the bone marrow and kidney was reached. Using an RBE value of 2 for both the tumour and normal tissues, the TNED was increased compared to 177Lu-DOTATATE alone. According to the modelling, the PARP inhibitor should be introduced approximately 24 h after the start of 177Lu-DOTATATE treatment and be continued for up to four weeks to optimize the TNED. Based on these results, a phase I trial assessing the combination of olaparib and 177Lu-DOTATATE in somatostatin receptor-positive tumours was launched in 2020 (NCT04375267).
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| 19. |
- Hemmingsson, Jens, 1986, et al.
(författare)
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Specific Uptake in the Bone Marrow Causes High Absorbed Red Marrow Doses During [177Lu]Lu-DOTATATE Treatment.
- 2023
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Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - 1535-5667. ; 64:9, s. 1456-1462
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Tidskriftsartikel (refereegranskat)abstract
- Bone marrow suppression is a common side effect after [177Lu]Lu-DOTATATE treatment of neuroendocrine neoplasms. Neuroendocrine neoplasms share expression of somatostatin receptor type 2 with CD34-positive hematopoietic progenitor cells, potentially leading to active uptake in the radiosensitive red marrow region where these cells are located. This study aimed to identify and quantify specific red marrow uptake using SPECT/CT images collected after the first treatment cycle. Methods: Seventeen patients diagnosed with neuroendocrine neoplasms were treated with [177Lu]Lu-DOTATATE. Seven of them had confirmed bone metastases. After the first treatment cycle, each patient went through 4 SPECT/CT imaging sessions 4, 24, 48, and 168h after administration. Monte Carlo-based reconstructions were used to quantify activity concentrations in tumors and multiple skeletal sites presumed to house red marrow: the T9-L5 vertebrae and the ilium portion of the hip bones. The activity concentration from the descending aorta was used as input in a compartment model intended to establish a pure red marrow biodistribution by separating the nonspecific blood-based contribution from the specific activity concentration in red marrow. The biodistributions from the compartment model were used to perform red marrow dosimetry at each skeletal site. Results: Increased uptake of [177Lu]Lu-DOTATATE was observed in the T9-L5 vertebrae and hip bones in all 17 patients compared with activity concentrations in the aorta. The mean specific red marrow uptake was 49% (range, 0%-93%) higher than the nonspecific uptake. The median (±SD) total absorbed dose to the red marrow was 0.056±0.023Gy/GBq and 0.043±0.022Gy/GBq for the mean of all vertebrae and hip bones, respectively. The patients with bone metastases had an absorbed dose of 0.085±0.046Gy/GBq and 0.069±0.033Gy/GBq for the vertebrae and hip bones, respectively. The red marrow elimination phase was statistically slower in patients with fast tumor elimination, which is in line with transferrin transport of 177Lu back to the red marrow. Conclusion: Our results suggest that specific red marrow uptake of [177Lu]Lu-DOTATATE is in line with observations of somatostatin receptor type 2-expressing hematopoietic progenitor cells within the bone marrow. Blood-based dosimetry methods fail to account for the prolonged elimination of specific uptake and underestimate the absorbed dose to red marrow.
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| 20. |
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| 21. |
- Isaksson, Johan, et al.
(författare)
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KRAS G12C mutant non-small cell lung cancer linked to female sex and high risk of CNS metastasis : Population-based demographics and survival data from the National Swedish Lung Cancer Registry
- 2023
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Ingår i: Clinical Lung Cancer. - : Elsevier. - 1525-7304 .- 1938-0690. ; 24:6, s. 507-518
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundReal-world data on demographics related to KRAS mutation subtypes are crucial as targeted drugs against the p.G12C variant have been approved.MethodWe identified 6183 NSCLC patients with reported NGS-based KRAS status in the Swedish national lung cancer registry between 2016 and 2019. Following exclusion of other targetable drivers, three cohorts were studied: KRAS-G12C (n = 848), KRAS-other (n = 1161), and driver negative KRAS-wild-type (wt) (n = 3349).ResultsThe prevalence of KRAS mutations and the p.G12C variant respectively was 38%/16% in adenocarcinoma, 28%/13% in NSCLC-NOS and 6%/2% in squamous cell carcinoma. Women were enriched in the KRAS-G12C (65%) and KRAS-other (59%) cohorts versus KRAS-wt (48%). A high proportion of KRAS-G12C patients in stage IV (28%) presented with CNS metastasis (vs. KRAS-other [19%] and KRAS-wt [18%]). No difference in survival between the mutation cohorts was seen in stage I-IIIA. In stage IV, median overall survival (mOS) from date of diagnosis was shorter for KRAS-G12C and KRAS-other (5.8 months/5.2 months) vs. KRAS wt (6.4 months). Women had better outcome in the stage IV cohorts, except in KRAS-G12C subgroup where mOS was similar between men and women. Notably, CNS metastasis did not impact survival in stage IV KRAS-G12C, but was associated with poorer survival, as expected, in KRAS-other and KRAS-wt.ConclusionThe KRAS p.G12C variant is a prevalent targetable driver in Sweden and significantly associated with female sex and presence of CNS metastasis. We show novel survival effects linked to KRAS p.G12C mutations in these subgroups with implications for clinical practice.
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| 22. |
- Leidermark, Erik, 1981, et al.
(författare)
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Estimating the risk for secondary cancer following targeted alpha therapy with astatine-211 intraperitoneal radioimmunotherapy.
- 2022
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Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - : Society of Nuclear Medicine. - 1535-5667. ; 64:1, s. 165-172
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Tidskriftsartikel (refereegranskat)abstract
- Intraperitoneal 211At-based targeted alpha therapy (TAT) may hold most promise as an adjuvant therapy following surgery and chemotherapy in epithelial ovarian cancer to eradicate any remaining undetectable disease. This implies it will also be delivered to patients possibly already cured by the primary treatment. An estimate of long-term risks is therefore sought whether to justify the treatment. Methods: Baseline data for risk estimates of alpha-particle irradiation were collected from published studies on excess cancer induction and mortality for subjects exposed to either 224Ra treatments or Thorotrast contrast agent (25% ThO2 colloid, containing 232Th). Organ dosimetry for 224Ra and Thorotrast irradiation were taken from the literature. These organ-specific risks were then applied for our previously reported dosimetry for intraperitoneal (i.p.) 211At-TAT patients. Results: Risk could be estimated for 10 different organ or organ groups. The calculated excess relative risk per Gray (ERR/Gy) could be sorted into two groups. In the lower ERR/Gy group, up to approx. 5, were: Trachea, bronchus and lung 0.52 (CI 95% 0.21-0.82), Stomach 1.4 (CI 95% -5.0-7.9), Lymphoid and hematopoietic system 2.17 (CI 95% 1.7-2.7), Bone and articular cartilage 2.6 (CI 95% 2.0-3.3), Breast 3.45 (CI 95% -10-17) and Colon 4.5 (CI 95% -3.5-13). In the higher ERR/Gy group, ranging from approx. 10 to 15 were: Urinary bladder 10.1 (CI 95% 1.4-23), Liver 14.2 (CI 95% 13-16), Kidney 14.9 (CI 95% 3.9-26) and Lip, oral cavity and pharynx 15.20 (CI 95% 2.73-27.63). Applying a typical candidate patient (female, age 65 years) and correcting for reference population mortality rate, a total estimated excess mortality of an i.p. 211At-mAb treatment amounted to 1.13 per 100 treated. More than half of this excess originated from urinary bladder and kidney, 0.29 and 0.34 respectively. Depending on various adjustments in calculation and assumptions on competing risks excess mortality could range from 0.11 - 1.84 per 100 treated. Conclusion: Published epidemiological data on life-long detriment following alpha-particle irradiation and its dosimetry allowed calculations to estimate the risk for secondary cancer following 211At-based i.p. TAT. Measures to reduce dose to the urinary organs may further decrease the estimated relative low risk for secondary cancer from 211At-mAb based i.p. TAT.
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| 23. |
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| 24. |
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| 25. |
- Nyman, Jan, 1956, et al.
(författare)
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How to improve loco-regional control in stages IIIa-b NSCLC? Results of a three-armed randomized trial from the Swedish Lung Cancer Study Group.
- 2009
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Ingår i: Lung cancer (Amsterdam, Netherlands). - : Elsevier BV. - 1872-8332 .- 0169-5002. ; 65:1, s. 62-7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A combination of chemotherapy and radiotherapy is the treatment base for locally advanced non-small cell lung cancer (NSCLC). However, both loco-regional and distant failure is frequent. Attempts to improve the loco-regional control were made in three separate phase II studies in Swedish University Hospitals, where accelerated radiotherapy or concurrent daily or weekly chemotherapy with conventional radiotherapy were tested. Comparatively good results from these studies lead to this national randomized phase II study, the RAKET-study, where the different concepts were investigated on a wider basis for further phase III studies. METHODS: Inoperable stage III non-small cell lung cancer patients in good performance status (PS<2) were equally randomized to either of three arms in eight institutions. All arms started with two cycles of induction chemotherapy: paclitaxel 200 mg/m2 and carboplatin AUC6. Arm A: a third identical cycle was given concomitant with start of accelerated radiotherapy, 1.7 Gy BID to 64.6 Gy in 4.5 weeks. Arm B consisted of daily concomitant paclitaxel 12 mg/m2 with conventionally fractionated radiotherapy: 2 Gy to 60 Gy in 6 weeks. Arm C: weekly concomitant paclitaxel 60 mg/m2 and identical radiotherapy to 60 Gy. Primary endpoint: TTP. Secondary: OS, toxicity, QL and relapse pattern. RESULTS: Between June 2002 and May 2005 152 patients were randomized and of them 151 were evaluable: 78 men and 73 women, median age 62 years (43-78), 55% had performance status 0 and 45% PS 1. Thirty-four percent had stage IIIa and 66% IIIb. Histology: adenocarcinoma 48%, squamous cell carcinoma 32% and 20% non-small cell carcinoma. The three arms were well balanced. Toxicity was manageable with 12% grades 3-4 esophagitis, 1% grades 3-4 pneumonitis and there was no clear difference between the arms. The QL data did not differ either. Median time to progression was 9.8 (8.3-12.7) months (8.8, 10.3 and 9.3 months for arms A, B and C, respectively). Median survival was 17.8 (14.4-23.7) months (17.7, 17.7 and 20.6 months for A, B and C, respectively). The 1-, 3- and 5-year overall survival was 63, 31 and 24%. Sixty-nine percent of the patients relapsed with distant metastases initially and 31% had loco-regional tumor progression, without significant differences between treatment arms. Thirty-four percent developed brain metastases. CONCLUSIONS: Treatment results are quite equal by intensifying the loco-regional treatment either by accelerated fractionated radiotherapy or daily or weekly concomitant chemo-radiotherapy both in terms of survival, toxicity and quality of life. The optimal treatment schedule for patients with locally advanced NSCLC is still to be decided and investigated in future clinical studies. Relapse pattern with distant metastases and especially brain metastases is a great problem and need further research for better therapy options and higher cure rate for this patient group.
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| 26. |
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| 27. |
- Palm, Stig, 1964, et al.
(författare)
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Evaluation of therapeutic efficacy of 211At-labeled farletuzumab in an intraperitoneal mouse model of disseminated ovarian cancer
- 2021
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Ingår i: Translational Oncology. - : Elsevier BV. - 1936-5233. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Antibodies labeled with alpha-emitter astatine-211 have previously shown effective in intraperitoneal (i.p.) treatments of ovarian cancer. In the present work we explore the use of investigational farletuzumab, aimed at the folate receptor alpha. The aim was to evaluate the biodistribution and therapeutic effect of 211At-farletuzumab in in-vitro and in-vivo experiments and, using models for radiation dosimetry, to translate the findings to expected clinical result. The activity concentration used for therapy in mice (170 kBq/mL) was chosen to be in agreement with an activity concentration that is anticipated to be clinically relevant in patients (200 MBq/L). Methods: For biodistribution, using intravenous injections and mice carrying subcutaneous (s.c.) tumors, the animals were administered either 211At-farletuzumab (n = 16); or with a combination of 125I-farletuzumab and 211At-MX35 (n = 12). At 1, 3, 10 and 22 h, mice were euthanized and s.c.-tumors and organs weighted and measured for radioactivity. To evaluate therapeutic efficacy, mice were inoculated i.p. with 2 × 106 NIH:OVCAR-3 cells. Twelve days later, the treatments were initiated by i.p.-administration. Specific treatment was given by 211At-labeled farletuzumab (group A; n = 22, 170 kBq/mL) which is specific for OVCAR-3 cells. Control treatments were given by either 211At-labeled rituximab which is unspecific for OVCAR-3 (group B; n = 22, 170 kBq/mL), non-radiolabeled farletuzumab (group C; n = 11) or PBS only (group D; n = 8). Results: The biodistribution of 211At-farletuzumab was similar to that with 125I as radiolabel, and also to that of 211At-labeled MX35 antibody. The tumor-free fraction (TFF) of the three control groups were all low (PBS 12%, unlabeled specific farletuzumab 9% and unspecific 211At-rituximab 14%). TFF following treatment with 211At-farletuzumab was 91%. Conclusion: The current investigation of intraperitoneal therapy with 211At-farletuzumab, delivered at clinically relevant 211At-mAb radioactivity concentrations and specific activities, showed a 6 to 10-fold increase (treated versus controls) in antitumor efficacy. This observation warrants further clinical testing. © 2020 The Authors
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| 28. |
- Petterson, Jennie, et al.
(författare)
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Pulmonary adenocarcinoma in situ and minimally invasive adenocarcinomas in European patients have less KRAS and more EGFR mutations compared to advanced adenocarcinomas.
- 2024
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Ingår i: International Journal of Molecular Sciences. - 1661-6596 .- 1422-0067. ; 25:5
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Tidskriftsartikel (refereegranskat)abstract
- Pulmonary adenocarcinoma (ADC) is a very diverse disease, both genetically and histologically, which displays extensive intratumor heterogeneity with numerous acquired mutations. ADC is the most common type of lung cancer and is believed to arise from adenocarcinoma in situ (AIS) which then progresses to minimally invasive adenocarcinoma (MIA). In patients of European ethnicity, we analyzed genetic mutations in AIS (n = 10) and MIA (n = 18) and compared the number of genetic mutations with advanced ADC (n = 2419). Using next-generation sequencing, the number of different mutations detected in both AIS (87.5%) and MIA (94.5%) were higher (p < 0.001) than in advanced ADC (53.7%). In contrast to the high number of mutations in Kirsten rat sarcoma virus gene (KRAS) in advanced ADC (34.6%), there was only one case of AIS with KRAS G12C mutation (3.5%; p < 0.001) and no cases of MIA with KRAS mutation (p < 0.001). In contrast to the modest prevalence of epidermal growth factor receptor (EGFR) mutations in advanced ADC (15.0%), the fraction of EGFR mutant cases was higher in both in AIS (22.2%) and MIA (59.5%; p < 0.001). The EGFR exon 19 deletion mutation was more common in both MIA (50%; n = 6/12) and ADC (41%; n = 149/363), whereas p.L858R was more prevalent in AIS (75%; n = 3/4). In contrast to pulmonary advanced ADC, KRAS driver mutations are less common, whereas mutations in EGFR are more common, in detectable AIS and MIA.
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| 29. |
- Ragnarsson, Oskar, et al.
(författare)
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Successful Treatment with Selpercatinib for Ectopic Cushing’s Syndrome Due to Medullary Thyroid Cancer
- 2022
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Ingår i: Current Oncology. - : MDPI AG. - 1718-7729. ; 29, s. 3494-3498
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Tidskriftsartikel (refereegranskat)abstract
- Selpercatinib, a RET kinase inhibitor, is an effective treatment for patients with medullary thyroid cancer with RET mutations. In this paper, we present the case of a 62-year-old man with ectopic Cushing’s syndrome due to medullary thyroid cancer who received treatment with selper-catinib. Six months later, all the cushingoid features had resolved, and s-calcitonin had decreased from 580 pmol/L to 3.5 pmol/L (normal < 3). After further 6 months, s-calcitonin had normalized (1.5 pmol/L), and radiological evaluation showed a profound tumour volume reduction. We are aware of two other cases where treatment with selpercatinib has also been successful. Thus, selperca-tinib may be a promising treatment alternative in patients with ectopic Cushing’s syndrome due to medullary thyroid cancer, especially when other treatment options are ineffective or not tolerated.
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| 30. |
- Stervik, Louise, 1993, et al.
(författare)
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Analysis of early respiratory-related mortality after radiation therapy of non-small-cell lung cancer : feasibility of automatic data extraction for dose–response studies
- 2020
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Ingår i: Acta Oncologica. - 0284-186X. ; 59:6, s. 628-635
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To examine the feasibility of automatic data extraction from clinical radiation therapy (RT) databases at four hospitals to investigate the impact of mean lung dose (MLD) and age on the risk of early respiratory-related death and early overall death for patients treated with RT for non-small-cell lung cancer (NSCLC). Material and methods: We included adult patients with NSCLC receiving curatively intended RT between 2002 and 2017 at four hospitals. A script was developed to automatically extract RT-related data. The cause of death for patients deceased within 180 days of the start of RT was retrospectively assessed. Using logistic regression, the risks of respiratory-related death and of overall death within 90 and 180 days were investigated using MLD and age as variables. Results: Altogether, 1785 patients were included in the analysis of early overall mortality and 1655 of early respiratory-related mortality. The respiratory-related mortalities within 90 and 180 days were 0.9% (15/1655) and 3.6% (60/1655). The overall mortalities within 90 and 180 days were 2.5% (45/1785) and 10.6% (190/1785). Higher MLD and older age were associated with an increased risk of respiratory-related death within 180 days and overall death within 90 and 180 days (all p<.05). For example, the risk of respiratory-related death within 180 days and their 95% confidence interval for patients aged 65 and 75 years with MLDs of 20 Gy was according to our logistic model 3.8% (2.6–5.0%) and 7.7% (5.5–10%), respectively. Conclusions: Automatic data extraction was successfully used to pool data from four hospitals. MLD and age were associated with the risk of respiratory-related death within 180 days of the start of RT and with overall death within 90 and 180 days. A model quantifying the risk of respiratory-related death within 180 days was formulated.
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| 31. |
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| 32. |
- Sundlöv, Anna, et al.
(författare)
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Phase II trial demonstrates the efficacy and safety of individualized, dosimetry-based Lu-177-DOTATATE treatment of NET patients
- 2022
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 49:11, s. 3830-3840
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Radionuclide therapy with Lu-177-DOTATATE is well established for patients with advanced somatostatin receptor-positive neuroendocrine tumors with a standard schedule of 7.4 GBq at four occasions. However, this approach does not consider individual variability affecting the tumor radiation dose or dose to organs at risk. Therefore, it is important to assess more personalized strategies. The aim of this phase II trial was to evaluate individualized Lu-177-DOTATATE for which the number of cycles varied based on renal dosimetry. Methods Patients were eligible if they had a progressive, somatostatin receptor-positive neuroendocrine tumor with a Ki 67 labeling index <20%. They received cycles of 7.4 GBq of Lu-177-DOTATATE at 10 +/- 2-week intervals until a predefined radiation dose to the kidneys was reached. The primary endpoint was objective tumor response (RECIST v 1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity (CTCAE v. 4.0). Results Ninety-six patients who had received a median of 5 cycles (range 1-9) were evaluable for efficacy. The objective tumor response was 16% partial response, 66% stable disease, and 19% progressive disease. The median PFS and OS were 29 months and 47 months, respectively, and were significantly associated with kidney dose, performance status, and Ki 67 levels but not with tumor origin. The overall toxicity was mild, and the most common events were grade 1-2 anemia, thrombocytopenia, fatigue, nausea, and diarrhea. Grade 3-4 toxicity occurred in <10% of patients and was mostly hematological, with no grade 3-4 renal toxicity. Conclusion Individualized treatment with Lu-177-DOTATATE based on renal dosimetry is clearly feasible with low toxicity and promising efficacy, showing the potential to further improve outcome beyond the standard approach, and should be further assessed in randomized trials.
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| 33. |
- Sundström, Johan, Professor, 1971-, et al.
(författare)
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Risk factors for subarachnoid haemorrhage : a nationwide cohort of 950 000 adults
- 2019
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Ingår i: International Journal of Epidemiology. - : Oxford University Press. - 0300-5771 .- 1464-3685. ; 48:6, s. 2018-2025
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Subarachnoid haemorrhage (SAH) is a devastating disease, with high mortality rate and substantial disability among survivors. Its causes are poorly understood. We aimed to investigate risk factors for SAH using a novel nationwide cohort consortium.METHODS: We obtained individual participant data of 949 683 persons (330 334 women) between 25 and 90 years old, with no history of SAH at baseline, from 21 population-based cohorts. Outcomes were obtained from the Swedish Patient and Causes of Death Registries.RESULTS: During 13 704 959 person-years of follow-up, 2659 cases of first-ever fatal or non-fatal SAH occurred, with an age-standardized incidence rate of 9.0 [95% confidence interval (CI) (7.4-10.6)/100 000 person-years] in men and 13.8 [(11.4-16.2)/100 000 person-years] in women. The incidence rate increased exponentially with higher age. In multivariable-adjusted Poisson models, marked sex interactions for current smoking and body mass index (BMI) were observed. Current smoking conferred a rate ratio (RR) of 2.24 (95% CI 1.95-2.57) in women and 1.62 (1.47-1.79) in men. One standard deviation higher BMI was associated with an RR of 0.86 (0.81-0.92) in women and 1.02 (0.96-1.08) in men. Higher blood pressure and lower education level were also associated with higher risk of SAH.CONCLUSIONS: The risk of SAH is 45% higher in women than in men, with substantial sex differences in risk factor strengths. In particular, a markedly stronger adverse effect of smoking in women may motivate targeted public health initiatives.
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| 34. |
- Sundström, Patrik, et al.
(författare)
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Immune checkpoint blockade improves the activation and function of circulating mucosal-associated invariant T (MAIT) cells in patients with non-small cell lung cancer
- 2024
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Ingår i: OncoImmunology. - 2162-4011 .- 2162-402X. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Mucosal-associated invariant T (MAIT) cells constitute one of the most numerous unconventional T cell subsets, and are characterized by rapid release of Th1- and Th17-associated cytokines and increased cytotoxic functions following activation. MAIT cells accumulate in tumor tissue but show an exhausted phenotype. Here, we investigated if immune checkpoint blockade (ICB) with antibodies to PD-1 or PD-L1 affects the function of circulating MAIT cells from non-small cell lung cancer patients. ICB increased the proliferation and co-expression of the activation markers HLA-DR and CD38 on MAIT cells in most patients after the first treatment cycle, irrespective of treatment outcome. Furthermore, production of cytokines, especially TNF and IL-2, also increased after treatment, as did MAIT cell polyfunctionality. These results indicate that MAIT cells respond to ICB, and that MAIT cell reinvigoration may contribute to tumor regression in patients undergoing immune checkpoint therapy.
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