| 1. |
- Milanetto, Anna Caterina, et al.
(författare)
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Health-Related Quality of Life After Surgery for Small Intestinal Neuroendocrine Tumours
- 2018
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Ingår i: World Journal of Surgery. - : Springer Science and Business Media LLC. - 0364-2313 .- 1432-2323. ; 42:10, s. 3231-3239
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Tidskriftsartikel (refereegranskat)abstract
- Background: Overall survival for patients with small intestinal neuroendocrine tumours (siNETs) is long, even with metastatic disease, making quality of life issues relevant. The impact of surgery on quality of life is not known. We investigated determinants of health-related quality of life in patients who had undergone surgery for a siNET. Methods: Patients operated for a siNET between 1998 and 2016 at Skåne University Hospital (Lund, Sweden), who were alive in February 2017, were sent two questionnaires constructed by the European Organisation for Research and Treatment of Cancer (EORTC QLQ-C30, EORTC QLQ-GINET21). Global quality of life, physical function, disease-related worries, diarrhoea and endocrine symptoms were evaluated with linear and logistic regression in relation to patient-, tumour- and treatment-related factors. Statistical analysis was performed using STATA 11®. Results: One hundred patients (84%) completed the questionnaires. Women had worse global quality of life (p = 0.019), more disease-related worries (p < 0.001) and endocrine symptoms (p = 0.017) than men. Older age was associated with more disease-related worries (p = 0.007), but fewer endocrine symptoms (p = 0.034). Non-symptomatic tumour versus symptomatic tumour (p = 0.002), and treatment with somatostatin analogues versus no treatment (p = 0.040) were associated with less diarrhoea. Small versus large bowel resection was associated with better global quality of life (p = 0.036) and physical function (p = 0.035). Conclusions: Male gender, younger age, treatment with somatostatin analogues, non-symptomatic tumour, and small intestinal surgery rather than large bowel surgery were associated with better quality of life.
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| 2. |
- Roth, Daniel, et al.
(författare)
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Dosimetric quantities of neuroendocrine tumors over treatment cycles with 177Lu-DOTA-TATE
- 2022
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 63:3, s. 399-405
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Tidskriftsartikel (refereegranskat)abstract
- Tumor dosimetry was performed for 177Lu-DOTA-TATE with the aims of better understanding i) the range and variation of the tumor absorbed doses (ADs), ii) how different dosimetric quantities evolve over the treatment cycles, and iii) whether this evolution differs depending on the tumor grade. Such information is important for radiobiological interpretation and may inform the design of alternative administration schemes. Methods: Data come from 41 patients with neuroendocrine tumors (NETs) of grade 1 (n = 23) or 2 (n = 18), that had received between 2 and 9 treatment cycles. Dosimetry was performed for 182 individual lesions, giving in total 880 individual AD assessments across all cycles. Hybrid planar-SPECT/CT imaging was used, including quantitative SPECT reconstruction, voxel-based absorbed-dose-rate calculation, semi-automatic image segmentation, and partial-volume correction. Linear mixed-effect models were used to analyze changes over cycles in tumor ADs, absorbed-dose rates and activity concentrations at day-1, effective half-times, and tumor volumes. Tumors smaller than 8 ml were excluded from analyses. Results: Tumor ADs ranged between 2 and 77 Gy per cycle. On average the AD decreased over the cycles, with significantly different rates (P < 0.05) for grade 1 and 2 NETs of 6% and 14% per cycle, respectively. The absorbed-dose rates and activity concentrations at day-1 decreased by similar amounts. The effective half-times were less variable but shorter for grade 2 than grade 1 (P < 0.001). For grade 2 NETS the tumor volumes decreased, with a similar tendency in grade 1. Conclusion: The tumor AD, absorbed-dose rate and activity uptake decrease, in parallel with tumor volumes, between 177Lu-DOTA-TATE treatment cycles, particularly for grade 2 NETs. The effective half-times vary less but are lower for grade 2 than grade 1 NETs. These results may indicate the development of radiation-induced fibrosis and could have implications for the design of future treatment and dosimetry protocols.
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| 3. |
- Stenvall, Anna, et al.
(författare)
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Relationships between uptake of [68Ga]Ga-DOTA-TATE and absorbed dose in [177Lu]Lu-DOTA-TATE therapy
- 2022
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Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Somatostatin receptor 68Ga PET imaging is standard for evaluation of a patient’s suitability for 177Lu peptide receptor radionuclide therapy of neuroendocrine tumours (NETs). The 68Ga PET serves to ensure sufficient somatostatin receptor expression, commonly evaluated qualitatively. The aim of this study is to investigate the quantitative relationships between uptake in 68Ga PET and absorbed doses in 177Lu therapy. Method: Eighteen patients underwent [68Ga]Ga-DOTA-TATE PET imaging within 20 weeks prior to their first cycle of [177Lu]Lu-DOTA-TATE. Absorbed doses for therapy were estimated for tumours, kidney, spleen, and normal liver parenchyma using a hybrid SPECT/CT–planar method. Gallium-68 activity concentrations were retrieved from PET images and also used to calculate SUVs and normalized SUVs, using blood and tissue for normalization. The 68Ga activity concentrations per injected activity, SUVs, and normalized SUVs were compared with 177Lu activity concentrations 1 d post-injection and 177Lu absorbed doses. For tumours, for which there was a variable number per patient, both inter- and intra-patient correlations were analysed. Furthermore, the prediction of 177Lu tumour absorbed doses based on a combination of tumour-specific 68Ga activity concentrations and group-based estimates of the effective half-lives for grade 1 and 2 NETs was explored. Results: For normal organs, only spleen showed a significant correlation between the 68Ga activity concentration and 177Lu absorbed dose (r = 0.6). For tumours, significant, but moderate, correlations were obtained, with respect to both inter-patient (r = 0.7) and intra-patient (r = 0.45) analyses. The correlations to absorbed doses did not improve when using 68Ga SUVs or normalized SUVs. The relationship between activity uptakes for 68Ga PET and 177Lu SPECT was stronger, with correlation coefficients r = 0.8 for both inter- and intra-patient analyses. The 177Lu absorbed dose to tumour could be predicted from the 68Ga activity concentrations with a 95% coverage interval of − 65% to 248%. Conclusions: On a group level, a high uptake of [68Ga]Ga-DOTA-TATE is associated with high absorbed doses at 177Lu-DOTA-TATE therapy, but the relationship has a limited potential with respect to individual absorbed dose planning. Using SUV or SUV normalized to reference tissues do not improve correlations compared with using activity concentration per injected activity.
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| 4. |
- Sundlöv, Anna, et al.
(författare)
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Pituitary function after high-dose 177Lu-DOTATATE therapy and long-term follow-up.
- 2021
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 111:4, s. 344-353
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Tidskriftsartikel (refereegranskat)abstract
- The pituitary gland has a high expression of somatostatin receptors (SSTRs) and is therefore a potential organ at risk for radiation-induced toxicity after 177Lu-DOTATATE treatment.To study changes in pituitary function in patients with neuroendocrine tumors (NETs) treated with dosimetry-based 177Lu-DOTATATE to detect possible late toxicity.68 patients from a phase II clinical trial of dosimetry-based, individualized 177Lu-DOTATATE-therapy were included in this analysis. Patients had received a median of 5 (range 3-9) treatment cycles of 7.4 GBq/cycle. Median follow-up was 30 months (range 11-89). The GH/IGF1-axis, gonadotropins, adrenal and thyroid axes were analyzed from baseline and on a yearly basis thereafter. Percent changes in hormonal levels over time were analyzed statistically using a linear mixed model and described graphically using boxplots. The absorbed radiation dose to the pituitary was estimated based on post-therapeutic imaging, and the results analyzed vs % change in IGF1-levels over time.A statistically significant decrease in the levels of IGF1 was found (p<0.005), which was correlated to the number of treatment cycles (p=0.008) and absorbed radiation dose (p=0.03). A similar decrease, although non-significant, was seen in the gonadotropins in post-menopausal women, while in men there was an increase during the first years post-therapy, after which the levels returned to baseline. No change was observed in the adrenal nor thyroid axes.No signs of severe endocrine disorder were detected, although a significant decrease in the GH/IGF1-axis was found, where dosimetric analyses indicate radiation-induced damage to the pituitary gland as a probable cause.
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| 5. |
- Castellano, Daniel, et al.
(författare)
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The role of RANK-ligand inhibition in cancer : the story of denosumab
- 2011
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Ingår i: The Oncologist. - : Oxford University Press (OUP). - 1549-490X .- 1083-7159. ; 16:2, s. 45-136
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Forskningsöversikt (refereegranskat)abstract
- The diagnosis of bone metastases is an event with certain consequences for the patient. They often mean pain and can also mean pathological fractures, hypercalcemia, and spinal cord compression, all synonymous with a diminished quality of life and often also hospitalization. Since the advent of the intravenous bisphosphonates, things began to look a bit brighter for patients with bone metastases-bone destruction was kept at bay a little longer. The next generation of bone metastasis treatments is well on its way in clinical development, and among them, the most advanced drug is denosumab. Denosumab is a fully human monoclonal antibody that inhibits osteoclast maturation, activation, and function by binding to receptor activator of nuclear factor kappa B ligand, with the final result being a reduced rate of bone resorption. In this review, we give an overview of relevant preclinical and clinical data regarding the use of denosumab in patients with solid tumors in general and prostate cancer in particular.
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| 6. |
- Dam, Gitte, et al.
(författare)
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Nordic 2023 guidelines for the diagnosis and treatment of lung neuroendocrine neoplasms.
- 2023
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 62:5, s. 431-437
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Tidskriftsartikel (refereegranskat)abstract
- Lung neuroendocrine neoplasms (NEN) are a heterogeneous population of neoplasms with different pathology, clinical behavior, and prognosis compared to the more common lung cancers. The diagnostic work-up and treatment of patients with lung- NEN has undergone major recent advances and new methods are currently being introduced into the clinic. These Nordic guidelines summarize and update the Nordic Neuroendocrine Tumor Group's current view on how to diagnose and treat lung NEN-patients and are meant to be useful in the daily practice for clinicians handling these patients. This review reflects our view of the current state of the art of diagnosis and treatment of patients with lung-NEN. Small cell lung carcinoma (SCLC) is not included in these guidelines.
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| 7. |
- Gustafsson, Johan, et al.
(författare)
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SPECT image segmentation for estimation of tumour volume and activity concentration in 177Lu-DOTATATE radionuclide therapy
- 2017
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Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Dosimetry in radionuclide therapy has the potential to allow for a treatment tailored to the individual patient. One therapeutic radiopharmaceutical where patient-specific dosimetry is feasible is 177Lu-DOTATATE, used for the treatment of neuroendocrine tumours. The emission of gamma photons by 177Lu allows for imaging with SPECT (single photon emission computed tomography). One important step for dosimetry using this imaging technique is the SPECT image segmentation, which needs to be robust and accurate for the estimated quantities to be reliable. This work investigates different methods for automatic tumour delineation in 177Lu-DOTATATE SPECT images. Three segmentation methods are considered: a fixed 42% threshold (FT), the Otsu method (OM) and a method based on Fourier surfaces (FS). Effects of including resolution compensation in the iterative SPECT image reconstruction are also studied. Evaluation is performed based on Monte Carlo-simulated SPECT images from 24 h and 336 h post injection (p.i.), for determination of the volume, activity concentration and dice similarity coefficient. In addition, patient data are used to investigate the correspondence of tumour volumes when delineated in SPECT or morphological CT or MR images. Patient data are also used to examine the sensitivity to the operator-dependent initialization. Results: For simulated images from 24 h p.i. reconstructed without resolution compensation, a volume and activity-concentration root-mean-square error below 15% is typically obtained for tumours above approximately 10 cm3 when using OM or FS, while FT performs considerably worse. When including resolution compensation, the tumour volume becomes underestimated and the activity concentration overestimated. The FS method appears to be robust to noise, as seen for the 336 h images. The differences between the tumour volumes estimated from the SPECT images and the volumes estimated from morphological images are generally larger than the discrepancies seen for the simulated data sets. Conclusions: Segmentation results are encouraging for future dosimetry of tumours with volumes above approximately 10 cm3. Using resolution compensation in the reconstruction may have a negative effect on volume estimation.
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| 8. |
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| 9. |
- Gålne, Anni, et al.
(författare)
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AI-based quantification of whole-body tumour burden on somatostatin receptor PET/CT
- 2023
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Ingår i: European Journal of Hybrid Imaging. - 2510-3636. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Segmenting the whole-body somatostatin receptor-expressing tumour volume (SRETVwb) on positron emission tomography/computed tomography (PET/CT) images is highly time-consuming but has shown value as an independent prognostic factor for survival. An automatic method to measure SRETVwb could improve disease status assessment and provide a tool for prognostication. This study aimed to develop an artificial intelligence (AI)-based method to detect and quantify SRETVwb and total lesion somatostatin receptor expression (TLSREwb) from [68Ga]Ga-DOTA-TOC/TATE PET/CT images. Methods: A UNet3D convolutional neural network (CNN) was used to train an AI model with [68Ga]Ga-DOTA-TOC/TATE PET/CT images, where all tumours were manually segmented with a semi-automatic method. The training set consisted of 148 patients, of which 108 had PET-positive tumours. The test group consisted of 30 patients, of which 25 had PET-positive tumours. Two physicians segmented tumours in the test group for comparison with the AI model. Results: There were good correlations between the segmented SRETVwb and TLSREwb by the AI model and the physicians, with Spearman rank correlation coefficients of r = 0.78 and r = 0.73, respectively, for SRETVwb and r = 0.83 and r = 0.81, respectively, for TLSREwb. The sensitivity on a lesion detection level was 80% and 79%, and the positive predictive value was 83% and 84% when comparing the AI model with the two physicians. Conclusion: It was possible to develop an AI model to segment SRETVwb and TLSREwb with high performance. A fully automated method makes quantification of tumour burden achievable and has the potential to be more widely used when assessing PET/CT images.
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| 10. |
- Gålne, Anni, et al.
(författare)
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Retrospective evaluation of the predictive value of tumour burden at baseline [ 68 Ga]Ga-DOTA-TOC or -TATE PET/CT and tumour dosimetry in GEP-NET patients treated with PRRT.
- 2024
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Ingår i: EJNMMI reports. - 3005-074X. ; 8, s. 1-19
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: There is a lack of validated imaging biomarkers for prediction of response to peptide receptor radionuclide therapy (PRRT). The primary objective was to evaluate if tumour burden at baseline PET/CT could predict treatment outcomes to PRRT with [ 177Lu]Lu-DOTA-TATE. Secondary objectives were to evaluate if there was a correlation between tumour burden and mean tumour absorbed dose (AD) during first cycle, and if mean tumour AD or the relative change of tumour burden at first follow-up PET/CT could predict progression free survival (PFS) or overall survival (OS). METHODS: Patients with gastroenteropancreatic neuroendocrine tumour (GEP-NET) treated with [ 177Lu]Lu-DOTA-TATE PRRT were retrospectively included. Tumour burden was quantified from [ 68 Ga]Ga-DOTA-TOC/TATE PET/CT-images at baseline and first follow-up and expressed as; whole-body somatostatin receptor expressing tumour volume (SRETVwb), total lesion somatostatin receptor expression (TLSREwb), largest tumour lesion diameter and highest SUVmax. The relative change of tumour burden was evaluated in three categories. Mean tumour AD was estimated from the first cycle of PRRT. PFS was defined as time from start of PRRT to radiological or clinical progression. OS was evaluated as time to death. Kaplan Meier survival curves and log-rank test were used to compare PFS and OS between different groups. RESULTS: Thirty-one patients had a baseline PET/CT < 6 months before treatment and 25 had a follow-up examination. Median tumour burden was 132 ml (IQR 61-302) at baseline and 71 ml (IQR 36-278) at follow-up. Twenty-two patients had disease progression (median time to progression 17.2 months) and 9 patients had no disease progression (median follow-up 28.7 months). SRETVwb dichotomized by the median at baseline was not associated with longer PFS (p = 0.861) or OS (p = 0.937). Neither TLSREwb, largest tumour lesion or SUVmax showed significant predictive value. There was a moderately strong correlation, however, between SUVmax and mean tumour AD r = 0.705, p < 0.001, but no significant correlation between SRETVwb nor TLSREwb and mean tumour AD. An increase of SRETVwb, TLSREwb or largest tumour lesion at first follow-up PET/CT was significantly correlated with shorter PFS/OS.CONCLUSION: Tumour burden at baseline showed no predictive value of PFS/OS after PRRT in this small retrospective study. An increase of tumour burden was predictive of worse outcome.
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| 11. |
- Hagmarker, Linn, et al.
(författare)
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Bone Marrow Absorbed Doses and Correlations with Hematologic Response During Lu-177-DOTATATE Treatments Are Influenced by Image-Based Dosimetry Method and Presence of Skeletal Metastases
- 2019
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 60:10, s. 1406-1413
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Tidskriftsartikel (refereegranskat)abstract
- This study aimed to compare different image-based methods for bone marrow dosimetry and study the dose-response relationship during treatment with Lu-177-DOTATATE in patients with and without skeletal metastases. Methods: This study included 46 patients with advanced neuroendocrine tumors treated with at least 2 fractions of Lu-177-DOTATATE at Sahlgrenska University Hospital. High- and low-uptake compartments were automatically outlined in planar images collected at 2, 24, 48, and 168 h after injection. The bone marrow absorbed doses were calculated from the cross doses of the high- and low-uptake compartments and the self-dose, using the time-activity concentration curve for the low-uptake compartment. This time-activity concentration curve was adjusted using a fixed constant of 1.8 for the planar dosimetry method and using the activity concentrations in vertebral bodies in SPECT images at 24 h after injection of Lu-177-DOTATATE in 4 hybrid methods: L4-SPECT used the activity concentration in the L4 vertebra, whereas V-SPECT, L-SPECT, and T-SPECT used the median activity concentration in all visible vertebrae, lumbar vertebrae, and thoracic vertebrae, respectively. Results: Using the planar method, L4-SPECT, V-SPECT, L-SPECT, and T-SPECT, the estimated median bone marrow absorbed doses were 0.19, 0.36, 0.40, 0.39, and 0.46 Gy/7.4 GBq, respectively, with respective ranges of 0.12-0.33, 0.15-1.44, 0.19-1.71, 0.21-1.60, and 0.18-2.12 Gy/7.4 GBq. For all methods, the bone marrow absorbed dose significantly correlated with decreased platelet counts. This correlation increased after treatment fraction 2: the Spearman correlation (r(s)) were -0.49 for the planar method, -0.61 for L4-SPECT, -0.63 for V-SPECT, -0.63 for L-SPECT, and -0.57 for T-SPECT. A separate analysis revealed an increased correlation for patients without skeletal metastases using the planar method (r(s) = -0.67). In contrast, hybrid methods had poor correlations for patients without metastases and stronger correlations for patients with skeletal metastases (r(s) = -0.61 to -0.74). The mean bone marrow absorbed doses were 3%-69% higher for patients with skeletal metastases than for patients without. Conclusion: The estimated bone marrow absorbed doses by image-based techniques and the correlation with platelets are influenced by the choice of measured vertebrae and the presence of skeletal metastases.
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| 12. |
- Hagmarker, Linn, et al.
(författare)
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Evaluation of planar versus hybrid SPECT image methodology for bone marrow dosimetry during 177Lu-DOTATATE treatments reveals the obstacles with bone marrow metastases and cross-irradiation for the SPECT activity concentration quantification
- 2018
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Ingår i: 31st Annual Congress of the European Association of Nuclear Medicine (EANM’18). 13-17 October, Dusseldorf, Germany.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Introduction. The aim of this study is to compare the recently developed planar image-based method for bone marrow dosimetry with a hybrid method using SPECT/CT imaging at 24 h.p.i. of 177Lu-DOTATATE. Predictive ability of the methods is compared by investigating correlations of determined absorbed bone marrow dose, with haematological toxicity during the course of four treatment cycles. The aim is also to investigate the activity distribution in the vertebral column, and how the hybrid methodology can be optimized. Methods and Materials. 45 patients with advanced neuroendocrine tumours treated with 177Lu-DOTATATE at Sahlgrenska University Hospital in 2011-2016 (ILUMINET-study, EUDRACT nr 2011-etc) were included in this study. Absorbed bone marrow doses were calculated as the sum of the cross-doses from high-uptake organs and the remainder of the body, and the self-dose. Cross-doses were determined by time-activity curves created using planar images and a two-compartment method in the image platform PhONSAi. The self-dose was calculated using the time-activity concentration curve for the remainder of the body adjusted with the activity concentration determined in spheres placed in the vertebral bodies in SPECT-images. To improve recovery and reduce cross-irradiation of false counts in the SPECT-image, we utilized the Monte Carlo based reconstruction code SARec. Three activity concentrations were calculated to represent the activity concentration in the bone marrow; one mean (mean SPECT) and one median (median SPECT) activity concentration based on all visible vertebras and one where vertebras enclosing metastases were manually excluded (w/o Mets SPECT). Results. The planar method, the hybrid methods mean SPECT, median SPECT, and w/o Mets SPECT, yielded absorbed bone marrow doses after treatment cycle one at 0.19 (0.12-0.32), 0.35 (0.12-1.25), 0.29 (0.11-0.92) and 0.29 (0.15-0.81) Gy/7.4 GBq, respectively. A significant dose-response relationship was established after treatment cycle one between decreased platelet counts and absorbed bone marrow dose using the planar method (p=0.025, r=-0.16). With hybrid methods, a significant correlation was firstly found after treatment cycle two between absorbed dose and decreased platelet counts using median SPECT (p=0.018, r=-0.35). Conclusion. Early significant dose-response relationships were established. Despite using SARec-reconstructed SPECT-imaging for specific measurement of activity concentration in bone marrow cavities, the hybrid methods were not able to perform better than the planar method. The hybrid methods yielded higher absorbed bone marrow doses compared to the planar method as both bone metastases and cross-irradiation will influence the activity quantification. Further studies on minimizing influence of bone metastases and cross-irradiation are on-going.
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| 13. |
- Janson, Eva Tiensuu, et al.
(författare)
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Nordic guidelines 2014 for diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms
- 2014
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Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 53:10, s. 1284-1297
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Forskningsöversikt (refereegranskat)abstract
- BackgroundThe diagnostic work-up and treatment of patients with neuroendocrine neoplasms (NENs) has undergone major recent advances and new methods are currently introduced into the clinic. An update of the WHO classification has resulted in a new nomenclature dividing NENs into neuroendocrine tumours (NETs) including G1 (Ki67 index ≤ 2%) and G2 (Ki67 index 3-20%) tumours and neuroendocrine carcinomas (NECs) with Ki67 index > 20%, G3. Aim. These Nordic guidelines summarise the Nordic Neuroendocrine Tumour Group's current view on how to diagnose and treat NEN-patients and are meant to be useful in the daily practice for clinicians handling these patients.
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| 14. |
- Knappskog, Stian, et al.
(författare)
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Mutation Spectrum in Liquid Versus Solid Biopsies From Patients With Advanced Gastroenteropancreatic Neuroendocrine Carcinoma.
- 2023
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Ingår i: JCO precision oncology. - 2473-4284. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are rare and have a poor prognosis. Most GEP-NEC are diagnosed with metastatic disease, with only minor biopsies available for molecular diagnostics. We assessed the applicability of liquid biopsies for molecular profiling of GEP-NEC.We performed massive parallel sequencing of 76 cancer-related genes in circulating tumor DNA from 50 patients with advanced GEP-NEC and compared findings to previous analyses of solid tumor biopsies from the same patients. Plasma samples were collected before therapy, and the median time span between blood and tissue sampling was 25 days.We detected 178 somatic mutations in the liquid biopsies, 127 (71%) were also detected in the solid biopsies, whereas 51 (29%) were unique to the liquid biopsies. In the same 76 genes, we previously detected 199 somatic mutations (single nucleotide variants) in solid biopsies, of which 127 (64%) were also now detected in liquid biopsies. In exploratory subgroup assessments, concordance was higher in patients with liver metastases (P = 1.5 × 10-5) and increasing with level of liver involvement (P = 1.2 × 10-4). The concordance was similar between GEP-NEC with different primary sites, except being lower in esophageal cases (P = .001). Concordance was not associated with tumor mutation burden. Tumor tissue mutations also detected in liquid biopsies was lower for MSI (40%) versus MSS tumors (70%; P = 7.8 × 10-4). We identified potentially targetable mutations in plasma of 26 (52%) of patients with GEP-NEC; nine patients (18%) had potentially targetable mutation detected only in liquid biopsies.Liquid biopsy analyses may be an applicable alternative to solid biopsies in GEP-NEC. Liquid biopsies may add additional mutations compared with tumor biopsies alone and could be useful for biomarker assessment in clinical trials for these patients.
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| 15. |
- Lindgren, Ola, et al.
(författare)
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The Effect of Radioiodine Treatment on TRAb, Anti-TPO, and Anti-TG in Graves' Disease
- 2019
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Ingår i: European Thyroid Journal. - : Bioscientifica. - 2235-0640 .- 2235-0802. ; 8:2, s. 64-69
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Tidskriftsartikel (refereegranskat)abstract
- Background: In Graves' disease (GD), immunocompetent cells infiltrate thyroid tissue with release of TSH-receptor antibodies (TRAb), and radioiodine treatment is known to elicit an immune response with an increase in TRAb. Objectives: The aim was to study if all patients treated with radioiodine respond with a release of TRAb, anti-thyroperoxidase (anti-TPO), and anti-thyroglobulin (anti-TG). Methods: This is a prospective observational study. GD patients (n = 131) were admitted for treatment with radioiodine. Thyroid antibodies were measured before and 3 months after iodine-131 treatment. Results: After 3 months, a fold change > 1.1 was found in 66% of the GD patients, while the remaining 34% did not have a change or decrease in in TRAb. Anti-TPO and anti-TG also increased; the former showed an increase in 73% and the latter of 52%, while 27 and 48% decreased/were unchanged. A significant positive correlation was found between TRAb and anti-TPO, but not between TRAb and anti-TG. In the group with an increase in TRAb, the median fold change was 5.1, but there were no additional effects of tobacco smoking. The proportion of females below the median age (51.5 years) was significantly higher in the group that increased in TRAb compared to the one that decreased/was unchanged (66 vs. 34%). Conclusions: Treatment with radioiodine elicits an increase in thyroid antibodies, but not in all GD patients. The proportion of responders varied and was affected by age, resulting in a stronger immune response at younger age. However, there were no additional effects of smoking.
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| 16. |
- Morken, Siren, et al.
(författare)
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Phase II study of everolimus and temozolomide as first-line treatment in metastatic high-grade gastroenteropancreatic neuroendocrine neoplasms.
- 2023
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Ingår i: British journal of cancer. - 0007-0920 .- 1532-1827. ; 129:12, s. 1930-1939
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Tidskriftsartikel (refereegranskat)abstract
- The optimal treatment for metastatic high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms when Ki-67 ≤55% is unknown. A prospective multi-centre phase 2 study was performed to evaluate the efficacy andsafety of everolimus and temozolomide as first-line treatment for these patients.Patients received everolimus 10mg daily continuously and temozolomide 150mg/m2 for 7 days every 2 weeks. Endpoints included response, survival, safety and quality of life (QoL). Histopathological re-evaluation according to the 2019 WHO classification was performed.For 37 eligible patients, the primary endpoint with 65% disease control rate (DCR) at 6 months (m) was reached. The response rate was 30%, the median progression-free survival (PFS) 10.2months and the median overall survival (OS) 26.4months. Considering 26 NET G3 patients, 6months DCR was 77% vs. 22% among nine NEC patients (p=0.006). PFS was superior for NET G3 vs. NEC (12.6months vs. 3.4months, Log-rank-test: p=0.133, Breslow-test: p<0.001). OS was significantly better for NET G3 (31.4months vs. 7.8months, p=0.003). Grade 3 and 4 toxicities were reported in 43% and 38%. QoL remained stable during treatment.Everolimus and temozolomide may be a treatment option for selected GEP-NET G3 patients including careful monitoring. Toxicity did not compromise QoL.ClinicalTrials.gov (NTC02248012).
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| 17. |
- Ohlsson, Håkan, et al.
(författare)
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Impact of Specific Bowel Symptoms on Quality of Life in Patients with Midgut Neuroendocrine Tumours
- 2021
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Ingår i: World Journal of Surgery. - : Springer Science and Business Media LLC. - 0364-2313 .- 1432-2323. ; 45, s. 2793-2803
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Patients with midgut neuroendocrine tumours (NETs) suffer from decreased health-related quality of life (HRQoL), in large part due to bowel symptoms. However, it is unknown which bowel symptoms affect HRQoL the most. An enhanced understanding of this is essential to better focus treatment on this aspect of the disease. This study aimed to determine which bowel symptoms affect HRQoL the most in patients with midgut NETs. Methods: Consenting patients with midgut NET completed the Memorial Sloan Kettering Bowel Function Instrument and the HRQoL questionnaire (EORTC QLQ-C30). The correlation between bowel symptoms and HRQoL was analysed using multiple linear regression, adjusting for age, Charlson Comorbidity Index score, presence of metastatic disease, chromogranin A, and BMI yielding ß-coefficients with 95% confidence intervals. Results: Totally, 119 patients with midgut NET completed the questionnaires and were included in the study. Loose stool and bowel frequency ≥ 3/day were the most common bowel symptoms, reported by 47% and 56% of patients, respectively. However, sensitivity to certain types of food and beverages, a feeling of incomplete emptying of the bowel, and soiling were the symptoms most strongly correlated with decreased HRQoL, especially within domains concerning role and social function, with ß-coefficients for the strongest correlated symptoms of 15.0 and 14.6, respectively. Discussion: While symptoms concerning stool consistency and frequency are common in patients with midgut NET, our study suggests that other, more socially stigmatising symptoms affect patients’ HRQoL more. Our findings could help caregivers understand patients’ perceptions of the disease and provide avenues for more directed therapies.
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| 18. |
- Ohlsson, Håkan, et al.
(författare)
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Optimal follow-up with somatostatin receptor PET/CT imaging in patients with small intestinal neuroendocrine tumours
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Ingår i: Journal of Neuroendocrinology. - 0953-8194.
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Tidskriftsartikel (refereegranskat)abstract
- Somatostatin receptor positron emission tomography with computerised tomography imaging (SRI) has a high sensitivity for the detection of small intestinal neuroendocrine tumors (siNET), which makes it ideal for follow-up. The aim of the present study was to investigate whether follow-up with SRI in patients with siNET led to any change in the treatment of the patient and if patient and/or tumour factors were associated with such change. Adults with siNET who had undergone at least two SRI scans between 2013 and 2021 were identified. Data on age, sex, comorbidities, tumour stage, grade, and most recent levels of serum Chromogranin A (CgA) and 24-h urine 5-hydroxyindoleacetic acid (5-HIAA) before each SRI scan were obtained. The major change was defined as new treatment previously not received or discontinuation of ongoing treatment. Univariate and multivariate mixed models logistic regression on variables with a presumed biological relationship with major change and with backwards stepwise exclusion of variables with p > .1 was performed. A total of 164 patients with siNET diagnosis had undergone 570 SRI scans. The median follow-up was 3.1 years. Only 82 of 570, 14%, of SRI scans led to a major change in treatment. Female sex, age below 75 years, elevated or missing CgA, elevated or missing urine 5-HIAA, progress on last SRI scan and distant extrahepatic disease were all independently associated with increased odds ratios for major change after follow-up with SRI. A small proportion of SRI scans (14%) led to a major change in treatment. Six independent risk factors with increased odds of major change, all available before each SRI scan, were identified. While validation of these risk factors is needed in a separate cohort, these findings could help clinicians individualise follow-up for siNET patients in the future.
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| 19. |
- Ohlsson, Håkan, et al.
(författare)
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Relationship between somatostatin receptor expressing tumour volume and health-related quality of life in patients with metastatic GEP-NET
- 2022
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Ingår i: Journal of Neuroendocrinology. - : Wiley. - 0953-8194 .- 1365-2826. ; 34:6
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Tidskriftsartikel (refereegranskat)abstract
- For patients with gastroenteropancreatic neuroendocrine tumours (GEP-NET), health-related quality of life (HRQoL) is important. Meanwhile, whether tumour volume is associated with HRQoL is unknown. Hence, the aim of this study was to assess if total somatostatin receptor expressing tumour volume is correlated with HRQoL in patients with metastatic GEP-NET. Some 71 patients were included in the study. HRQoL and NET-specific symptoms were assessed with EORTC QLQ-C30 and EORTC GI.NET21. A summary score was calculated from the output of the QLQ-C30. Total somatostatin receptor expressing tumour volume was retrospectively evaluated on somatostatin receptor imaging with positron emission tomography-computed tomography (68Ga-DOTA-TATE/TOC PET-CT) in each patient. Simple and multiple linear regression were used to evaluate the correlation between tumour volume and HRQoL, controlling for potential confounders. No correlation was found between total somatostatin receptor expressing tumour volume and QLQ-C30 summary score. Weak positive correlations were found between total tumour volume and the specific symptoms dyspnoea, diarrhoea and flushing. To the best of our knowledge, this is the first study to evaluate the association between total somatostatin expressing tumour volume and HRQoL. Our results indicate that, while tumour volume is weakly associated with symptom severity of the carcinoid syndrome, other factors might impact more on overall HRQoL.
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| 20. |
- Pommergaard, Hans-Christian, et al.
(författare)
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Surgery of the primary tumour in 201 patients with high-grade gastroenteropancreatic neuroendocrine and mixed neuroendocrine-non-neuroendocrine neoplasms
- 2021
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Ingår i: Journal of neuroendocrinology. - : John Wiley & Sons. - 0953-8194 .- 1365-2826. ; 33:5
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Tidskriftsartikel (refereegranskat)abstract
- The benefit of surgery in high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) is uncertain. The present study aimed to investigate outcomes after tumour surgery in patients with high-grade (Ki-67 > 20%) GEP NEN or MiNEN stage I-III or stage IV. We analysed data from patients treated in the period 2007-2015 at eight Nordic university hospitals. Overall survival (OS) and progression-free survival (PFS)/disease-free survival (DFS) were analysed by Kaplan-Meier estimates. Prognostic factors were evaluated using Cox regression. We included 201 surgically resected patients, 143 stage I-III and 58 stage IV, with 68% having neuroendocrine carcinoma, 23% MiNEN, 5% neuroendocrine tumour G3 and 4% uncertain NEN G3. Primary tumours were located in colon/rectum (52%), oesophagus/cardia (19%), pancreas (10%), stomach (7%), jejunum/ileum (5%), duodenum (4%), gallbladder (2%) and anal canal (1%). For patients with stage I-III, median DFS was 12 months (95% confidence interval [CI] = 5.5-18.5) and median OS was 32 months (95% CI = 24.0-40.0). For patients with stage I-III and an R0 resection, median DFS was 21 months (95% CI = 4.9-37.1) and median OS was 39 months (95% CI = 25.0-53.0). For patients with stage IV, median PFS/DFS was 4 months (95% CI = 1.9-6.1) and median OS was 11 months (95% CI = 4.8-17.2). For patients with stage IV and an R0 resection, median DFS was 6 months (95% CI = 0-16.4) and median OS was 32 months (95% CI = 25.5-38.5). Performance status > 1 and colorectal primary were associated with poor prognosis. There was no difference in survival between patients with high-grade GEP NEN and MiNEN. Surgery of the primary tumour in patients with loco-regional high-grade GEP NEN or MiNEN led to good long-term results and should be considered if an R0 resection is considered achievable. Highly selected patients with stage IV disease may also benefit from surgery.
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| 21. |
- Roth, Daniel, et al.
(författare)
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A method for tumor dosimetry based on hybrid planar-SPECT/CT images and semiautomatic segmentation
- 2018
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Ingår i: Medical Physics. - : Wiley. - 0094-2405 .- 2473-4209. ; 45:11, s. 5004-5018
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: A hybrid planar-SPECT/CT method for tumor dosimetry in 177Lu-DOTATATE therapy, applicable to datasets consisting of multiple conjugate-view images and one SPECT/CT, is developed and evaluated. Methods: The imaging protocol includes conjugate-view imaging at 1, 24, 96, and 168 h post infusion (p.i.) and a SPECT/CT acquisition 24 h p.i. The dosimetry method uses the planar images to estimate the shape of the time–activity concentration curve, which is then rescaled to absolute units using the SPECT-derived activity concentration. The resulting time-integrated activity concentration coefficient (TIACC) is used to calculate the tumor-absorbed dose. Semiautomatic segmentation techniques are applied for tumor delineation in both planar and SPECT images, where the planar image segmentation is accomplished using an active-rays-based technique. The selection of tumors is done by visual inspection of planar and SPECT images and applying a set of criteria concerning the tumor visibility and possible interference from superimposed activity uptakes in the planar images. Five different strategies for determining values from planar regions of interest (ROIs), based on entire or partial ROIs, and with and without background correction, are evaluated. Evaluation is performed against a SPECT/CT-based method on data from six patients where sequential conjugate-view and SPECT/CT imaging have been performed in parallel and against ground truths in Monte Carlo simulated images. The patient data are also used to evaluate the interoperator variability and to assess the validity of the developed criteria for tumor selection. Results: For patient images, the hybrid method produces TIACCs that are on average 6% below those of the SPECT/CT only method, with standard deviations for the relative TIACC differences of 8%–11%. Simulations show that the hybrid and SPECT-based methods estimate the TIACCs to within approximately 10% for tumors larger than around 10 ml, while for smaller tumors, all methods underestimate the TIACCs due to underestimations of the activity concentrations in the SPECT images. The planar image segmentation has a low operator dependence, with a median Dice similarity coefficient of 0.97 between operators. The adopted criteria for tumor selection manage to discriminate the tumors for which the absorbed-dose deviations between the hybrid and SPECT methods are the highest. Conclusions: The hybrid method is found suitable for studies of tumor-absorbed doses in radionuclide therapy, provided that selection criteria regarding the visibility and overlapping activities in the planar images are applied.
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| 22. |
- Roth, Daniel, et al.
(författare)
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Characterisation of a hand-held CZT-based gamma camera for 177Lu imaging
- 2020
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Ingår i: EJNMMI Physics. - : Springer Science and Business Media LLC. - 2197-7364. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Currently, hand-held gamma cameras are being developed for 99mTc imaging, mainly for sentinel lymph node detection. These cameras offer advantages, such as mobility and ease of access, and may be useful also for other applications such as biokinetic studies in animals or for imaging of small, superficial structures in patients. In this work, the suitability of a CZT-based hand-held camera for 177Lu imaging is investigated. The energy response of CZT-based detectors combined with the multiple photon emissions of 177Lu poses new challenges compared to 99mTc imaging, and a thorough camera characterisation is thus warranted. Methods: Three collimators (LEHR, LEHS, and MEGP) and three energy windows (55 keV, 113 keV, and 208 keV) are investigated. Characterised camera properties include the system spatial resolution, energy resolution, sensitivity, image uniformity, septal penetration, and temperature dependence. Characterisations are made starting from NEMA guidelines when applicable, with adjustments made when required. The applicability of the camera is demonstrated by imaging of a superficially located tumour in a patient undergoing [177 Lu]Lu-DOTA-TATE therapy. Results: Overall, the results are encouraging. Compared to a conventional gamma camera, the hand-held camera generally has a higher sensitivity for a given collimator. For source-collimator distances below 3 cm, the spatial resolution FWHM is within 6 mm for the LEHR and MEGP collimators. Before uniformity correction, the central field-of-view integral uniformity shows best results for the 113-keV window, with values obtained between 11 and 14%. The corresponding values after uniformity correction are within 3%. Effects of septal penetration are observed but are manageable with a proper combination of collimator and energy window setting. Septal penetration and collimator scatter not only affect the 208-keV window but also contribute with counts in lower windows due to energy-tailing effects. The patient study revealed non-uniform uptake patterns in a region that appeared uniform in a conventional gamma camera image. Conclusions: The results show that the hand-held camera can be used for 177Lu imaging. A 113-keV energy window combined with LEHR or MEGP collimators provides the best image system characteristics.
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| 23. |
- Shahida, Bushra, et al.
(författare)
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Increased risk of Graves´ophthalmopathy in patients with increasing TRAb after radioiodine treatment and the impact of CTLA4 on TRAb titres
- 2022
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Ingår i: Endocrine. - : Springer Science and Business Media LLC. - 1355-008X .- 1559-0100. ; 75:3, s. 856-864
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Treatment of Graves´ disease (GD) with radioiodine increases the risk of developing Graves´ ophthalmopathy (GO), and the link between thyroid and orbital tissue may be the presence of TSH-receptors. Radioiodine increases the titers of TRAb and the aim was to investigate the relationship between GO and TRAb titers after treatment with radioiodine and to define the impact of risk genes. Methods: GD patients without ophthalmopathy or previous treatment with radioiodine were prospectively included at treatment with radioiodine for hyperthyroidism. A follow-up was performed 1 year later for the registration of GO development. The study was performed at a University Hospital Clinic; a referral center of all patients treated with radioiodine in the south of Sweden. The main outcome measures were the development of TRAb, anti-TPO, and anti-TG after 3 months and GO after 12 months and relationship to the genetic background (HLA, CTLA-4, and CYR61). Results: Three months of radioiodine TRAb titers increased in two thirds of patients (p < 0.0005) but not in the other third. Anti-TPO titers were associated with TRAb (R = 0.362, p < 0.0001) but not anti-TG. At follow-up 1 year later (n = 204) 32 patients developed GO with a proportion of 70% in the group increasing in TRAb titers and 30% in the group with unchanged or lower TRAb titers (p-value < 0.0005). Patients with GO had higher titers of TRAb than patients without GO. CTLA-4 (rs231775 SNP) was significantly (p < 0.005) associated with TRAb titers above the median three months after radioiodine. Conclusions: The increase in TRAb titers after treatment with radioiodine is associated with GO and a genetic variation in CTLA-4 is associated with higher titers of TRAb.
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| 24. |
- Sjögreen Gleisner, Katarina, et al.
(författare)
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Long-term retention of 177Lu/177mLu-Dotatate in patients investigated by gamma spectrometry and gamma camera imaging.
- 2015
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 56:7, s. 976-984
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Tidskriftsartikel (refereegranskat)abstract
- Dosimetry in peptide receptor radionuclide therapy using (177)Lu-Dotatate is based on patient imaging during the first week after administration, and determination of the activity retention as a function of time for different tissues. For calculation of the absorbed dose it is generally assumed that the long-term activity retention follows the pattern determined from the first week. This work aims to investigate the validity of this assumption by performing additional patient measurements between 5 and 10 weeks after administration. A further aim is to investigate to what extent absorbed dose values are affected when including these measurements, also taking into account the radionuclide impurity of (177)mLu and build-up of secondary (177)Lu from the (177)mLu decay.
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| 25. |
- Sundlöv, Anna, et al.
(författare)
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Feasibility of simplifying renal dosimetry in Lu-177 peptide receptor radionuclide therapy
- 2018
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Ingår i: Ejnmmi Physics. - : Springer Science and Business Media LLC. - 2197-7364. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Recently, Lu-177-dotatate therapy for neuroendocrine tumours has received regulatory approval. Dosimetry can be used to optimize treatment on an individual basis, but there is no international consensus as to how it should be done. The aim of this study is to determine a feasible and accurate dosimetry method to guide individualized peptide receptor radionuclide therapy (PRRT) for patients with neuroendocrine tumours. As part of a clinical trial on Lu-177-dotatate therapy, renal dosimetry was performed for all patients in each treatment cycle, using a hybrid planar-SPECT/CT method. In the present study, we use the image data acquired from 22 patients and 119 cycles and define a set of alternative treatment planning strategies, each representing a simplification in terms of image acquisition and dosimetric calculations. The results from the simplified strategies are compared to the results from the protocol-prescribed hybrid planar-SPECT/CT-based method by analysing differences both in per-cycle and total cumulative absorbed dose (AD) analyses. Results: In general, the SPECT-based methods gave results that were largely consistent with the protocol-specified hybrid method, both in the per-cycle and cumulative AD analyses. Notably, performing one SPECT/CT per cycle at 96 h yielded ADs that were very similar to the protocol method. The methods using planar dosimetry resulted in larger variations, as expected, while giving 4 cycles to all patients resulted in the largest inter-individual differences in cumulative AD. Conclusions: Performing one SPECT/CT at 96 h in every treatment cycle gives sufficiently reliable dosimetric results to base individualized treatment planning on, with a reasonable demand on resources.
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| 26. |
- Sundlöv, Anna, et al.
(författare)
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Individualised Lu-177-DOTATATE treatment of neuroendocrine tumours based on kidney dosimetry
- 2017
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 44:9, s. 1480-1489
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Tidskriftsartikel (refereegranskat)abstract
- Purpose To present data from an interim analysis of a Phase II trial designed to determine the feasibility, safety, and efficacy of individualising treatment based on renal dosimetry, by giving as many cycles as possible within a maximum renal biologically effective dose (BED). Method Treatment was given with repeated cycles of 7.4 GBq 177Lu-DOTATATE at 8-12-week intervals. Detailed dosimetry was performed in all patients after each cycle using a hybrid method (SPECT + planar imaging). All patients received treatment up to a renal BED of 27 +/- 2 Gy (alpha/beta = 2.6 Gy) (Step 1). Selected patients were offered further treatment up to a renal BED of 40 +/- 2 Gy (Step 2). Renal function was followed by estimation and measurement of the glomerular filtration rate (GFR). Results Fifty-one patients were included in the present analysis. Among the patients who received treatment as planned, the median number of cycles in Step 1 was 5 (range 3-7), and for those who completed Step 2 it was 7 (range 5-8); 73% were able to receive >4 cycles. Although GFR decreased in most patients after the completion of treatment, no grade 3-4 toxicity was observed. Patients with a reduced baseline GFR seemed to have an increased risk of GFR decline. Five patients received treatment in Step 2, none of whom exhibited a significant reduction in renal function. Conclusions Individualising PRRT using renal dosimetry seems feasible and safe and leads to an increased number of cycles in the majority of patients. The trial will continue as planned.
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| 27. |
- 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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| 28. |
- Sundlöv, Anna
(författare)
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Tailoring Radionuclide Therapy of Neuroendocrine Tumors - Bridging the Gaps
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background and Aims: Radionuclide therapy is systemic, targeted radiotherapy. As such, we can apply the basic principles of radiobiology used in everyday practice in radiation oncology, as a means of tailoring the treatment to each patient and optimizing the balance between efficacy and toxicity. The most common type of radionuclide therapy used for the treatment of neuroendocrine tumors, is 177Lu-DOTATATE. It has proven to be safe and effective, even without any tailoring. The aim of the work presented in this thesis is to systematically explore how we can further improve results for patients by tailoring the treatment. Methods and Results: The thesis is based on two clinical trials – Iluminet and Gapetto – which were both designed to address different aspects of the overall aim. The Iluminet trial is a phase II trial in which patients, instead of receiving the standard four cycles of 7.4 GBq of 177Lu-DOTATATE, are treated to the maximum number of cycles within the predefined limits for radiation dose to the kidneys. Safety and efficacy data are collected during treatment and follow-up. The Gapetto trial was a prospective observational study looking at the effect of somatostatin analog treatment on the uptake of 68Ga-DOTATATE in PET/CT. Papers I and II are based on the first 51 patients included in the Iluminet trial. Paper I presents data from an interim analysis of renal function, and also describes the effects that tailoring has on treatment planning. The mean number of treatment cycles the patients received was 5, but there were large interindividual variations. No serious renal toxicity was detected during the 24-month median follow-up. Paper II describes the consequences of simplifying the dosimetric protocol in order to make dosimetry more feasible in clinical practice. The results show that basing dosimetry on just one SPECT-image taken att 96h is as accurate as doing full hybrid dosimetry, which is the reference in the trial protocol. Paper III describes the pituitary function in 68 evaluable patients during long-term follow-up in the Iluminet trial. A significant decrease in IGF1 was detected, which could be secondary to the radiation received by the pituitary gland during treatment with 177Lu-DOTATATE, but other possible explanations are also discussed. Paper IV is based on the Gapetto trial. The SUV values in 68Ga-DOTATATE PET/CT were compared before and after initiating treatment with long-acting somatostatin analogs. The effect of the time from the last injection to the PET/CT was also analyzed. Results showed that the use of somatostatin analogs decreased the SUV in normal tissues, but not in tumor. The time since last injection did not affect the SUV-values. Conclusions: Tailoring radionuclide treatment based on individual dosimetry is feasible and safe, and leads to considerable interindividual variations in the number of treament cycles received. No signs of serious renal or pituitary toxicity have been detected. Dosimetry can be substantially simplified without compromising accuracy. Treatment with long-acting somatostatin analogs improves the tumor-to-normal ratio in 68Ga-DOTATATE PET/CT, and possibly also in the therapeutic setting, i.e. when using 177Lu-DOTATATE to treat neuroendocrine tumors.
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| 29. |
- Venizelos, Andreas, et al.
(författare)
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Germline pathogenic variants in patients with high-grade gastroenteropancreatic neuroendocrine neoplasms.
- 2023
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Ingår i: Endocrine-Related Cancer. - 1351-0088 .- 1479-6821. ; 30:10
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Tidskriftsartikel (refereegranskat)abstract
- High-grade gastroenteropancreatic (HG-GEP) neuroendocrine neoplasms (NENs) are highly aggressive cancers. The molecular etiology of these tumors remains unclear, and the prevalence of pathogenic germline variants in patients with HG-GEP NENs is unknown. We assessed sequencing data of 360 cancer genes in normal tissue from 240 patients with HG-GEP NENs; 198 patients with neuroendocrine carcinomas (NECs) and 42 with grade 3 neuroendocrine tumors (NET G3). Applying strict criteria, we identified pathogenic germline variants and compared the frequency with previously reported data from 33 different cancer types. We found a recurrent MYOC variant in three patients and a recurrent MUTYH variant in two patients, indicating that these genes may be important underlying risk factors for HG-GEP NENs when mutated. Further, germline variants were found in canonical tumor-suppressor genes, such as TP53, RB1, BRIP1 and BAP1. Overall, we found that 4.5% of patients with NEC and 9.5% of patients with NET G3 carry germline pathogenic or highly likely pathogenic variants. Applying identical criteria for variant classification in silico to mined data from 33 other cancer types, the median percentage of patients carrying pathogenic or highly likely pathogenic variants was 3.4% (range: 0-17%). The patients with NEC and pathogenic germline variants had a median overall survival of 9 months, similar to what is generally expected for metastatic GEP NECs. A patient with NET G3 and pathogenic MUTYH variant had much shorter overall survival than expected. The fraction of HG-GEP NENs with germline pathogenic variants is relatively high, but still <10%, meaning that that germline mutations cannot be the major underlying cause of HG-GEP NENs.
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| 30. |
- Venizelos, Andreas, et al.
(författare)
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The molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms
- 2022
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Ingår i: Endocrine-Related Cancer. - 1479-6821. ; 29:1, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- High-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are rare but have a very poor prognosis and represent a severely understudied class of tumours. Molecular data for HG GEP-NEN are limited and treatment strategies for the carcinoma subgroup (HG GEP-NEC) are extrapolated from small-cell lung cancer (SCLC). After pathological re-evaluation, we analysed DNA from tumours and matched blood samples from 181 HG GEP-NEN patients; 152 neuroendocrine carcinomas (NEC) and 29 neuroendocrine tumours (NET G3). Based on sequencing of 360 cancer related genes, we assessed mutations and copy number alterations (CNA). For NEC, frequently mutated genes were TP53 (64%), APC (28%), KRAS (22%) and BRAF (20%). RB1 was only mutated in 14%, but CNAs affecting RB1 were seen in 34%. Other frequent copy number losses were ARID1A (35%), ESR1 (25%) and ATM (31%). Frequent amplifications/gains were found in MYC (51%) and KDM5A (45%). While these molecular features had limited similarities with SCLC, we found potentially targetable alterations in 66% of the NEC samples. Mutations and CNA varied according to primary tumour site with BRAF mutations mainly seen in colon (49%), and FBXW7 mutations mainly seen in rectal cancers (25%). 8/152 (5.3%) NEC were microsatellite instable (MSI). NET G3 had frequent mutations in MEN1 (21%), ATRX (17%), DAXX, SETD2 and TP53 (each 14%). We show molecular differences in HG GEP-NEN, related to morphological differentiation and site of origin. Limited similarities to SCLC and a high fraction of targetable alterations indicates a high potential for better personalized treatments.
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