| 1. |
- Glimelius, Bengt, et al.
(författare)
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U-CAN : a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.
- 2018
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Ingår i: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 57:2, s. 187-194
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Tidskriftsartikel (refereegranskat)abstract
- Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.
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| 2. |
- Bratulic, Sinisa, 1981, et al.
(författare)
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Noninvasive detection of any-stage cancer using free glycosaminoglycans.
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 119:50
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Tidskriftsartikel (refereegranskat)abstract
- Cancer mortality is exacerbated by late-stage diagnosis. Liquid biopsies based on genomic biomarkers can noninvasively diagnose cancers. However, validation studies have reported ~10% sensitivity to detect stage I cancer in a screening population and specific types, such as brain or genitourinary tumors, remain undetectable. We investigated urine and plasma free glycosaminoglycan profiles (GAGomes) as tumor metabolism biomarkers for multi-cancer early detection (MCED) of 14 cancer types using 2,064 samples from 1,260 cancer or healthy subjects. We observed widespread cancer-specific changes in biofluidic GAGomes recapitulated in an in vivo cancer progression model. We developed three machine learning models based on urine (Nurine = 220 cancer vs. 360 healthy) and plasma (Nplasma = 517 vs. 425) GAGomes that can detect any cancer with an area under the receiver operating characteristic curve of 0.83-0.93 with up to 62% sensitivity to stage I disease at 95% specificity. Undetected patients had a 39 to 50% lower risk of death. GAGomes predicted the putative cancer location with 89% accuracy. In a validation study on a screening-like population requiring ≥ 99% specificity, combined GAGomes predicted any cancer type with poor prognosis within 18 months with 43% sensitivity (21% in stage I; N = 121 and 49 cases). Overall, GAGomes appeared to be powerful MCED metabolic biomarkers, potentially doubling the number of stage I cancers detectable using genomic biomarkers.
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| 3. |
- Daskalakis, Kosmas, et al.
(författare)
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Ex vivo activity of cytotoxic drugs and targeted agents in Small Intestinal NETs
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Small Intestinal Neuroendocrine Tumours (SI-NET) are considered to be generally resistant to systemic treatment. To date predictive markers for drug activity are lacking.Patients and Methods: Tumour samples from 27 patients with SI-NET were analyzed ex vivo for sensitivity to a panel of cytotoxic drugs and targeted agents using a short-term total cell kill assay. Samples of renal cancer, colorectal cancer (CRC), ovarian cancer, and chronic lymphocytic leukemia (CLL) were included for comparison. For the SI-NET subset, drug sensitivity was analyzed in relation to clinico-pathological variables and pre-treatment biomarkers.Results: For standard cytotoxic drugs, SI-NETs demonstrated similar or higher sensitivity to 5-FU, platinums, gemcitabine and doxorubicin compared with CRC. For targeted kinase inhibitors, SI-NET was among the most sensitive diagnoses. CLL and ovarian cancer were generally the most sensitive diagnoses to both cytotoxic drugs and protein kinase inhibitors. The mTOR inhibitor sirolimus exhibited modest cytotoxic activity.Individual SI-NET samples demonstrated great variability in ex vivo sensitivity for most drugs. Cross-resistance between different drugs also varied considerably, being higher among protein kinase inhibitors.Age, stage, grade, peritoneal carcinomatosis and extra-abdominal metastases as well as serum chromogranin A and urine 5-HIAA concentrations at diagnosis did not correlate to drug sensitivity ex vivo.Conclusions: SI-NETs exhibit variable but generally intermediate sensitivity ex vivo to cytotoxic and targeted drugs. Clinico-pathological factors and currently used biomarkers were not clearly associated to ex vivo sensitivity, challenging these criteria for treatment decisions in SI-NETs. The great variability in drug sensitivity calls for individualized selection of therapy.
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| 4. |
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| 5. |
- Daskalakis, Kosmas, et al.
(författare)
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Ex vivo activity of cytotoxic drugs and targeted agents in small intestinal neuroendocrine tumors
- 2018
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Ingår i: Endocrine-Related Cancer. - 1351-0088 .- 1479-6821. ; 25:4, s. 471-480
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Tidskriftsartikel (refereegranskat)abstract
- Small intestinal neuroendocrine tumors (SI-NETs) are generally considered resistant to systemic treatment. To date, predictive markers for drug activity are lacking. Tumor samples from 27 patients with SI-NETs were analyzed ex vivo for sensitivity to a panel of cytotoxic drugs and targeted agents using a short-term total cell kill assay. Samples of renal cancer, colorectal cancer (CRC), ovarian cancer and chronic lymphocytic leukemia (CLL) were included for comparison. For the SI-NET subset, drug sensitivity was analyzed in relation to clinicopathological variables and pre-treatment biomarkers. For cytotoxic drugs, SI-NETs demonstrated similar or higher sensitivity to 5-FU, platinum, gemcitabine and doxorubicin compared with CRC. For several of the targeted kinase inhibitors, SI-NET was among the most sensitive solid tumor types. CLL and ovarian cancer were generally the most sensitive tumor types to both cytotoxic drugs and protein kinase inhibitors. SI-NET was more sensitive to the mTOR inhibitor sirolimus than the other solid tumor types tested. Individual SI-NET samples demonstrated great variability in ex vivo sensitivity for most drugs. Cross-resistance between different drugs also varied considerably, being higher among protein kinase inhibitors. Age, stage, grade, peritoneal carcinomatosis and extra-abdominal metastases as well as serum chromogranin A and urine 5-HIAA concentrations at diagnosis did not correlate to drug sensitivity ex vivo. SI-NETs exhibit intermediate sensitivity ex vivo to cytotoxic and targeted drugs. Clinicopathological factors and currently used biomarkers are not clearly associated to ex vivo sensitivity, challenging these criteria for treatment decisions in SI-NET. The great variability in drug sensitivity calls for individualized selection of therapy.
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| 6. |
- Norlén, Olov
(författare)
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Small Intestinal Neuroendocrine Tumor : A Rare Malignancy with Favorable Outcome
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Small intestinal neuroendocrine tumor (SI-NET) is the most common small bowel tumor in Europe and USA, with an annual incidence of around 0.3-1.3/100000 persons. SI-NETs are the most common type of gastroenteropancreatic NETs (GEP-NETs), and they are known for their ability to produce hormones such as tachykinins and serotonin, as well as for their favorable long-term prognosis in comparison to gastrointestinal adenocarcinoma. The overall aim of the thesis was to investigate unknown or unclear aspects of SI-NET disease, in connection with prognosis, treatment and follow-up. Paper I confirmed several known negative prognostic factors and also showed, for the first time, that para-aortal lymph node metastases and peritoneal carcinomatosis were associated with worse survival by multivariable analyses. Locoregional surgery was associated with a low post-operative mortality, and a prolonged long-term survival by multivariable analysis. In Paper II we continued to investigate peritoneal carcinomatosis and found it be a risk factor not only for death, but also for emergency re-surgery. Furthermore, genetic analyses of samples from primary tumors in patients with and without peritoneal carcinomatosis showed a difference in the DNA between these two groups. In Paper III the outcome after liver surgery and/or radiofrequency ablation of liver metastases was investigated. To summarize, no difference in survival was seen in patients treated with surgery/radiofrequency ablation in comparison with matched controls. However, a superior radiological response of liver metasases and lower U-5-HIAA values were seen in patients subjected to liver surgery and/or radiofrequency ablation compared to matched controls. Paper IV compared ultrasonography, computed tomography and 11C-5HTP-PET in the follow-up after radiofrequency ablation of NET liver metastases. The study concluded that 11C-5HTP-PET depicted all residual tumors after RFA and that it, if used, should be combined with computed tomography for easier interpretation, as RFA areas are not clearly distinguishable with 11C-5HTP-PET alone. Paper V studied gallstone complications after somatostatin analog treatment in SI-NET patients, and concluded that there was a rather high risk to be subjected to a cholecystectomy due to biliary colic, cholecystitis, cholangitis or pancreatitis after primary surgery in somatostatin analog treated patients.
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| 7. |
- Annebäck, Matilda
(författare)
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Hypoparathyroidism after thyroid surgery- rates, risks, prevention and consequences
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hypoparathyroidism is the most common complication after thyroid surgery and associated with short- and long-term consequences. The lack of a consensus on the definition of hypoparathyroidism has led to a broad range in the rates reported in the literature. The overall aim of this thesis was to study different aspects of hypoparathyroidism, in terms rates, risks and long-term impact. Paper I is a case control study, investigating prophylactic, preoperative treatment with active vitamin D and early hypocalcemia after total thyroidectomy. The study showed that patients with preoperative treatment had a lower risk of early hypocalcemia and a reduced length of stay in hospital, compared to patients without treatment. No adverse outcomes were found. Paper II is a population-based retrospective cohort study on the rate and risks for permanent hypoparathyroidism after total thyroidectomy for benign thyroid disease. Data was retrieved from The Swedish National Patient Register, The Swedish Quality Register for Thyroid, Parathyroid and Adrenal Surgery and The Swedish Prescribed Drug Registry. Permanent hypoparathyroidism was defined as dispensation of calcium and/or active vitamin D >12 months after surgery. Among 7852 patients, 12.5% developed permanent hypoparathyroidism. Surgery at low volume centers, parathyroid autotransplantation, female gender and high age were independent risk factors. In Paper III the aim was to validate the high rate of permanent hypoparathyroidism found in Paper II. A regional cohort was extrapolated from the national cohort. A retrospective chart review, of 1636 patients, was performed. Using a strict definition, 6.2 % were found to have definitive permanent hypoparathyroidism. Additionally, 2.5 % were found to have possible permanent hypoparathyroidism. Of these, at least 1.7 % might have been overtreated due to lacking attempts to unwind the treatment. The study also proposed that the rate of low early PTH in a cohort might be useful to predict the rate of permanent hypoparathyroidism. Paper IV investigated health related quality of life (HRQoL) in patients with and without permanent hypoparathyroidism using the same cohort as in Paper III and SF-36 v.2. No impact of definitive hypoparathyroidism on HRQoL could be found. In conclusion, the use of preoperative active vitamin D may be useful as a tool to lower the risk of early hypocalcemia. The risk of permanent hypoparathyroidism after total thyroidectomy is high and there is a need for improved follow up. Permanent hypoparathyroidism may not have a negative effect on HRQoL in most patients.
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| 8. |
- Annebäck, Matilda, et al.
(författare)
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Preoperative prophylactic active vitamin D to streamline total thyroidectomy
- 2022
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Ingår i: BJS Open. - : Oxford University Press (OUP). - 2474-9842. ; 6:3
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundHypocalcaemia is a common complication after total thyroidectomy (TT). Treatment consists of calcium and active vitamin D supplementation. Low levels of vitamin D before surgery have been shown to be a risk factor for postoperative hypocalcaemia, yet studies examining routine preoperative vitamin D supplementation have shown conflicting results. This retrospective cohort study aims to investigate the potential benefit of preoperative active vitamin D supplementation on hypocalcaemia and its symptoms after TT.MethodsThis study included patients undergoing TT at Uppsala University Hospital from January 2013 to December 2020, resulting in a total of 401 patients after exclusion. Routine preoperative alfacalcidol treatment was initiated for all TT patients in January 2017 resulting in two groups for comparison: one group (pre-January 2017) that was prescribed preoperative alfacalcidol and one that was not. Propensity score matching was used to reduce bias. The primary outcome was early postoperative hypocalcaemia (serum calcium, S-Ca less than 2.10 mmol/l); secondary outcomes were symptoms of hypocalcaemia and length of stay.ResultsAfter propensity score matching, there were 108 patients in each group. There were 2 cases with postoperative day one S-Ca less than 2.10 in the treated group and 10 cases in the non-treated group (P < 0.001). No patients in the treated group had a S-Ca below 2.00 mmol/l. Preoperative alfacalcidol was associated with higher mean serum calcium level day one (2.33 versus 2.27, P = 0.022), and reduced duration of hospital stay (P < 0.001). There was also a trend toward fewer symptoms of hypocalcaemia (18.9 per cent versus 30.5 per cent, P = 0.099).ConclusionsProphylactic preoperative alfacalcidol was associated with reduced biochemical hypocalcaemia and duration of hospital stay following TT. Also, with this protocol, it is suggested that routine day 1 postoperative S-Ca measurement is not required.
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| 9. |
- Annebäck, Matilda, et al.
(författare)
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Quality of life in patients with permanent hypoparathyroidism after thyroidectomy: a population-based study with long-term follow up
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundIn recent years, several studies have shown that permanent hypoparathyroidism has a negative impact on health-related quality of life (HRQoL). However, these results could have been affected by short-term follow up, selection bias and confounding factors. The aim of this study was to investigate HRQoL in patients with and without permanent hypoparathyroidism after total thyroidectomy for benign thyroid disease, using a strict definition of permanent hypoparathyroidism and long-term follow up data. A secondary aim was to evaluate if permanent hypoparathyroidism affects the risk of death.Material and MethodsAll patients who underwent total thyroidectomy in a region of Sweden between 2005 and 2015 were assessed for eligibility. All eligible patients were invited to participate in the study through by letter on August, 2021. SF-36v.2 was used to compare HRQoL in patients with and without permanent hypoparathyroidism. ResultsOut of 1636 patients, 1483 patients were invited to participate in the study. In total, 716 (48.3%) patients answered the SF-36v.2 questionnaire and were included in the study cohort. Mean follow-up was 10.9 (SD ±3.2) years. Patients with and without permanent hypoparathyroidism did not differ in baseline characteristics, with the exception that patients with permanent hypoparathyroidism were younger. No difference was found in HRQoL between the groups regarding all health domains and the summary component scores (p>0.05). Survival analysis revealed no increased risk of death in patients with permanent hypoparathyroidism.ConclusionsNo difference in HRQoL was found when comparing patients with and without permanent hypoparathyroidism after total thyroidectomy for benign thyroid disease on long-term follow up. Permanent hypoparathyroidism did not affect mortality in the present study; however, this needs to be further investigated in larger studies
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| 10. |
- Annebäck, Matilda, et al.
(författare)
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Risk of Permanent Hypoparathyroidism After Total Thyroidectomy for Benign Disease : A Nationwide Population-based Cohort Study From Sweden
- 2021
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Ingår i: Annals of Surgery. - : Wolters Kluwer. - 0003-4932 .- 1528-1140. ; 274:6, s. e1202-e1208
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate the prevalence and risk factors for permanent hypoparathyroidism after total thyroidectomy for benign disease in a population-based setting with data independent of input of complication data.SUMMARY OF BACKGROUND DATA: The reported rate of permanent hypoparathyroidism is highly variable and mostly rely on reported complication data from national or institutional registries.METHODS: All patients who underwent total thyroidectomy in Sweden from 2005 to 2015 were identified through Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal Surgery and the Swedish National Patient Register. Patients were matched to outcome data from the Swedish Prescribed Drug Register. Permanent hypoparathyroidism was defined as treatment with calcium and/or active vitamin D more than 1 year after surgery.RESULTS: Seven thousand eight hundred fifty-two patients were included and 938 (12.5%) developed permanent hypoparathyroidism. The risk was lower in patients registered in the quality register (11.0% vs 16%, P < 0.001). In a multivariable analysis there was a higher risk of permanent hypoparathyroidism in patients with parathyroid autotransplantation [Odds ratio (OR) 1.72; 95% confidence interval 1.47-2.01], center-volume <100 thyroidectomies per year (OR 1.22; 1.03-1.44), age above 60 year (OR 1.64; 1.36-1.98) and female sex (OR 1.27; 1.05-1.54). Reported data from the quality register only identified 178 of all 938 patients with permanent hypoparathyroidism.CONCLUSION: The risk of permanent hypoparathyroidism after total thyroidectomy was high and associated with parathyroid autotransplantation, higher age, female sex and surgery at a low volume center. Reported follow-up data might underestimate the rate of permanent hypoparathyroidism.
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