| 1. |
- Almlöv, Karin, et al.
(author)
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MRI Lymph Node Evaluation for Prediction of Metastases in Rectal Cancer
- 2020
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In: Anticancer Research. - : International Institute of Anticancer Research. - 0250-7005 .- 1791-7530. ; 40:5, s. 2757-2763
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Journal article (peer-reviewed)abstract
- Aim: To explore whether the size and characteristics of the largest regional lymph node in patients with rectal cancer, based on magnetic resonance imaging (MRI), following neoadjuvant therapy and before surgery, is able to identify patients at high risk of developing metachronous metastases.Patients and Methods: A retrospective case–control study with data from the Swedish Colo-Rectal Cancer Registry. Forty patients were identified with metachronous metastases (M+), and 40 patients without metastases (M0) were matched as controls.Results: Patients with M+ disease were more likely to have a regional lymph node measuring ≥5 mm than patients with M0. (87% vs. 65%, p=0.02). There was also a significant difference between the groups regarding the presence of an irregular border of the largest lymph node (68% vs. 40%, p=0.01).Conclusion: Lymph nodes measuring ≥5 mm with/without displaying irregular borders at MRI performed after neoadjuvant therapy emerged as risk factors for metachronous metastases in patients with rectal cancer. Intensified follow-up programmes may be indicated in these patients.
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| 2. |
- Asowed, Mustafa, et al.
(author)
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Activity and safety of KEES-an oral multi-drug chemo-hormonal metronomic combination regimen in metastatic castration-resistant prostate cancer
- 2023
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In: BMC Cancer. - : BioMed Central (BMC). - 1471-2407. ; 23
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Journal article (peer-reviewed)abstract
- Background: Metastatic castration-resistant prostate cancer (mCRPC) remains a therapeutic challenge and evidence for late-line treatments in real-life is limited. The present study investigates the efficacy and safety of an oral metronomic chemo-hormonal regimen including cyclophosphamide, etoposide, estramustine, ketoconazole and prednisolone (KEES) administered in a consecutive biweekly schedule.Methods: A retrospective cohort study in two Swedish regions was conducted. Overall (OS) and progression-free survival (PFS), biochemical response rate (bRR) and toxicities were analyzed.Results: One hundred and twenty-three patients treated with KEES after initial treatment with at least a taxane or an androgen-receptor targeting agents (ARTA) were identified. Of those, 95 (77%) had received both agents and were the primary analysis population. Median (95% CI) OS and PFS in the pre-treated population were 12.3 (10.1-15.0) and 4.4 (3.8-5.5) months, respectively. Biochemical response, defined as >= 50% prostate-specific antigen (PSA) reduction, occurred in 26 patients (29%), and any PSA reduction in 59 (65%). PFS was independent of prior treatments used, and KEES seemed to be effective in late treatment lines. The bRR was higher compared to historical data of metronomic treatments in docetaxel and ARTA pre-treated populations. In multivariable analyses, performance status (PS) >= 2 and increasing alkaline phosphatase (ALP) predicted for worse OS. Nausea, fatigue, thromboembolic events and bone marrow suppression were the predominant toxicities.Conclusions: KEES demonstrated meaningful efficacy in heavily pre-treated CRPC patients, especially those with PS 0-1 and lower baseline ALP, and had an acceptable toxicity profile.
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| 3. |
- Aughton, Karen, et al.
(author)
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hENT1 Predicts Benefit from Gemcitabine in Pancreatic Cancer but Only with Low CDA mRNA
- 2021
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In: Cancers. - : MDPI. - 2072-6694. ; 13:22
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Journal article (peer-reviewed)abstract
- Gemcitabine or 5-fluorouracil (5-FU) based treatments can be selected for pancreatic cancer. Equilibrative nucleoside transporter 1 (hENT1) predicts adjuvant gemcitabine treatment benefit over 5-FU. Cytidine deaminase (CDA), inside or outside of the cancer cell, will deaminate gemcitabine, altering transporter affinity. ESPAC-3(v2) was a pancreatic cancer trial comparing adjuvant gemcitabine and 5-FU. Tissue microarray sections underwent in situ hybridization and immunohistochemistry. Analysis of both CDA and hENT1 was possible with 277 patients. The transcript did not correlate with protein levels for either marker. High hENT1 protein was prognostic with gemcitabine; median overall survival was 26.0 v 16.8 months (p = 0.006). Low CDA transcript was prognostic regardless of arm; 24.8 v 21.2 months with gemcitabine (p = 0.02) and 26.4 v 14.6 months with 5-FU (p = 0.02). Patients with low hENT1 protein did better with 5-FU, but only if the CDA transcript was low (median survival of 5-FU v gemcitabine; 29.3 v 18.3 months, compared with 14.2 v 14.6 with high CDA). CDA mRNA is an independent prognostic biomarker. When added to hENT1 protein status, it may also provide treatment-specific predictive information and, within the frame of a personalized treatment strategy, guide to either gemcitabine or 5FU for the individual patient.Simple Summary:Recent clinical trials suggest that combination therapies that include either gemcitabine or 5-fluorouracil (5-FU) both give significant survival benefits for pancreatic cancer patients. The tumor level of the nucleoside transporter hENT1 is prognostic in patients treated with adjuvant gemcitabine but not adjuvant 5-FU. This work shows for the first time that hENT1 is only predictive of benefit from gemcitabine over 5-FU in patients with low levels of CDA transcript. A choice between adjuvant 5-FU based combination therapies (such as FOLFIRINOX) and gemcitabine-based therapy (e.g., GemCap) could be made based on a combination of hENT1 protein and CDA mRNA measured in a resected tumor.
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| 4. |
- Björnsson, Bergthor, et al.
(author)
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Digital twins to personalize medicine
- 2020
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In: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 12:1
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Research review (peer-reviewed)abstract
- Personalized medicine requires the integration and processing of vast amounts of data. Here, we propose a solution to this challenge that is based on constructing Digital Twins. These are high-resolution models of individual patients that are computationally treated with thousands of drugs to find the drug that is optimal for the patient.
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| 5. |
- Blomstrand, Hakon, et al.
(author)
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Clinical characteristics and blood/serum bound prognostic biomarkers in advanced pancreatic cancer treated with gemcitabine and nab-paclitaxel
- 2020
-
In: BMC Cancer. - : BioMed Central. - 1471-2407. ; 20:1
-
Journal article (peer-reviewed)abstract
- BackgroundIn recent years treatment options for advanced pancreatic cancer have markedly improved, and a combination regimen of gemcitabine and nab-paclitaxel is now considered standard of care in Sweden and elsewhere. Nevertheless, a majority of patients do not respond to treatment. In order to guide the individual patient to the most beneficial therapeutic strategy, simple and easily available prognostic and predictive markers are needed.MethodsThe potential prognostic value of a range of blood/serum parameters, patient-, and tumour characteristics was explored in a retrospective cohort of 75 patients treated with gemcitabine/nab-paclitaxel (Gem/NabP) for advanced pancreatic ductal adenocarcinoma (PDAC) in the South Eastern Region of Sweden. Primary outcome was overall survival (OS) while progression free survival (PFS) was the key secondary outcome.ResultUnivariable Cox regression analysis revealed that high baseline serum albumin (> 37 g/L) and older age (> 65) were positive prognostic markers for OS, and in multivariable regression analysis both parameters were confirmed to be independent prognostic variables (HR 0.48, p = 0.023 and HR = 0.47, p = 0.039,). Thrombocytopenia at any time during the treatment was an independent predictor for improved progression free survival (PFS) but not for OS (HR 0.49, p = 0.029, 0.54, p = 0.073), whereas thrombocytopenia developed under cycle 1 was neither related with OS nor PFS (HR 0.87, p = 0.384, HR 1.04, p = 0.771). Other parameters assessed (gender, tumour stage, ECOG performance status, myelosuppression, baseline serum CA19–9, and baseline serum bilirubin levels) were not significantly associated with survival.ConclusionSerum albumin at baseline is a prognostic factor with palliative Gem/NabP in advanced PDAC, and should be further assessed as a tool for risk stratification. Older age was associated with improved survival, which encourages further studies on the use of Gem/NabP in the elderly.
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| 6. |
- Blomstrand, Hakon, et al.
(author)
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Impact of resection margins and para-aortic lymph node metastases on recurrence patterns and prognosis in resectable pancreatic cancer - a long-term population-based cohort study
- 2023
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In: HPB. - : ELSEVIER SCI LTD. - 1365-182X .- 1477-2574. ; 25:12, s. 1531-1544
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Journal article (peer-reviewed)abstract
- Background: Pancreatic cancer remains a leading cause of cancer-related death. To individualise management and improve survival, more accurate prognostic models are needed.Methods: All patients resected for pancreatic ductal adenocarcinoma in a tertiary Swedish centre during 2009-2019 were thoroughly analysed with regards to pathological and clinical parameters including tumour grade, resection margin status, para-aortic lymph node engagement (node station 16), and systemic treatment.Results: The study cohort included 275 patients. Overall median survival was 21.2 months (95% CI 17.5-24.8). Year of resection, margin status (R1 subdivided into R1(1mm)/R1(ink)), perineural invasion, differentiation grade, TNM stage, and adjuvant therapy were independent factors with significant impact on survival. Margin status also significantly affected recurrence-free survival and relapse patterns, with local and peritoneal relapses being associated with R1-status (p < 0.001 and p = 0.007). Presence of paraaortic lymph node metastases was associated with shorter recurrence-free survival as compared to N1 status only.Conclusion: Survival in resected pancreatic cancer is improving over time. Resection margin status is a key factor affecting recurrence patterns and prognosis. Given the poor recurrence-free survival in node station 16 metastasised patients, the rational for resection remains in doubt, and improved treatment strategies for this patient group is necessary.
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| 7. |
- Blomstrand, Hakon, et al.
(author)
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Real-world evidence on first- and second-line palliative chemotherapy in advanced pancreatic cancer
- 2021
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In: World Journal of Clinical Oncology. - : Baishideng Publishing Group Inc. - 2218-4333. ; 12:9, s. 787-799
-
Research review (peer-reviewed)abstract
- In spite of recent diagnostic and therapeutic advances, the prognosis of pancreatic ductal adenocarcinoma (PDAC) remains very poor. As most patients are not amenable to curative intent treatments, optimized palliative management is highly needed. One key question is to what extent promising results produced by randomized controlled trials (RCTs) correspond to clinically meaningful outcomes in patients treated outside the strict frames of a clinical trial. To answer such questions, real-world evidence is necessary. The present paper reviews and discusses the current literature on first- and second-line palliative chemotherapy in PDAC. Notably, a growing number of studies report that the outcomes of the two predominant first-line multidrug regimens, i.e. gemcitabine plus nab-paclitaxel (GnP) and folfirinox (FFX), is similar in RCTs and real-life populations. Outcomes of second-line therapy following failure of first-line regimens are still dismal, and considerable uncertainty of the optimal management remains. Additional RCTs and real-world evidence studies focusing on the optimal treatment sequence, such as FFX followed by GnP or vice versa, are urgently needed. Finally, the review highlights the need for prognostic and predictive biomarkers to inform clinical decision making and enable personalized management in advanced PDAC.
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| 8. |
- Blomstrand, Hakon, et al.
(author)
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Real world evidence on gemcitabine and nab-paclitaxel combination chemotherapy in advanced pancreatic cancer
- 2019
-
In: BMC Cancer. - : BMC. - 1471-2407. ; 19
-
Journal article (peer-reviewed)abstract
- BackgroundIn the recent phase III trial MPACT the combination of gemcitabine and nab-paclitaxel (Gem/NabP) showed increased overall survival compared to gemcitabine alone in the treatment of advanced pancreatic ductal adenocarcinoma (aPDA). Until now there has been limited information on the clinical benefit and toxicity of the combination regimen in a real world setting. In addition the value for patients with locally advanced rather than metastatic aPDA has been unclear, since the former category of patients was not included in the MPACT trial.MethodsA multicentre retrospective observational study in the South Eastern Region of Sweden was performed, with the first 75 consecutive patients diagnosed with aPDA (both locally advanced and metastatic disease) who received first-line treatment with Gem/NabP.ResultsIn the overall population median progression free survival (PFS) and overall survival (OS) were 5.2 (3.4-7.0 95% CI) and 10.9 (7.8-14.0 95% CI) months, respectively. Patients with metastatic disease displayed a median OS of 9.4 (4.9-13.9) and a median PFS of 4.5 (3.3-5.7) months whereas the same parameters in the locally advanced subgroup were 17.1 (7.6-26.6) and 6.8 (5.2-8.4) months, respectively. Grade 3-4 hematologic toxicity was recorded: Neutropenia, leukopenia, thrombocytopenia, and anaemia were observed in 23, 20, 5, and 4% of patients, respectively. Dose reductions were performed in 80% of the patients.ConclusionThis study confirms the effectiveness and safety of first-line Gem/NabP in both locally advanced and metastatic PDA in a real world setting.
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| 9. |
- Elander, Nils, et al.
(author)
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Association Between Adenomatosis Polyposis Coli Functional Status and Microsomal Prostaglandin E Synthase-1 Expression in Colorectal Cancer
- 2009
-
In: Molecular Carcinogenesis. - : Wiley. - 0899-1987 .- 1098-2744. ; 48:5, s. 401-407
-
Journal article (peer-reviewed)abstract
- Bioactive metabolites downstream of cyclooxygenase-2 (COX-2) generated prostaglandin H-2 (PGH(2)), in particular prostaglandin E-2 (PGE(2)), are thought to play critical roles during the development of colorectal tumors. Previous reports reveal that defects of the tumor suppressor adenomatosis polyposis coli (APC) contribute to COX-2 upregulation in colon tumor cells. We investigated whether a similar relation was present between APC functional status and the expression of microsomal prostaglandin E synthase-1 (mPGES-1), which acts downstream of COX-2 and catalyses the terminal conversion of PGH(2) into PGE(2). Surprisingly, mPGES-1 mRNA and protein levels were upregulated upon induction of a wild type-APC carrying vector in HT29 colon cancer cells, and downregulated following siRNA silencing of APC in HCT-116 cells. mPGES-1 was overall enhanced in human colorectal tumor specimens versus corresponding non-tumor mucosa and, in accordance with data on HT29 and HCT116 cells, higher levels of mPGES-1 were observed among tumors carrying wild type versus mutant APC. RNAi silencing of beta-catenin and luciferase assays regarding the mPGES-1 promoter region did not reveal a role for APC or beta-catenin/Tcf in controlling mPGES-1 gene transcription. However, RNA degradation assays in HT29 cells revealed a suppressed degradation of mPGES-1 in the presence of wild type APC, implying that mPGES-1 mRNA is stabilized in the APC wild type state. Collectively, we demonstrate a novel association between APC functional status and mPGFS-1 expression in colorectal tumor cells, being most likely related to reduced mPGES-1 mRNA degradation rate in the APC wild type state.
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| 10. |
- Elander, Nils, et al.
(author)
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Complex scaling and self adjoint dilations
- 1993
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In: International Journal of Quantum Chemistry. - : Wiley. - 0020-7608 .- 1097-461X. ; 46:3, s. 415-418
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Journal article (peer-reviewed)abstract
- Complex scaling of the Schrodinger equation on the halfaxis with a nontrivial boundary condition at the origin is investigated. A self-adjoint dilation of the corresponding dissipative operator is constructed. The relations between the scattering problems for the operator and it's dilation are clarified
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| 11. |
- Elander, Nils, et al.
(author)
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Convergence and Quantum Number Assignment Studies of Rovibrational Eigenstates in a Model of Predissociating NeICI van der Waals Complex
- 2009
-
In: International Journal of Quantum Chemistry. - : Wiley. - 0020-7608 .- 1097-461X. ; 109:3, s. 459-468
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Journal article (peer-reviewed)abstract
- This report details extensions and further analysis of the results presented in an earlier study (Elander et al., Phys Rev A 2001, 64, 012505). Rovibrational resonances in a model of the triatomic van der Waals complex NeICI were studied with a full quantum mechanical, smooth exterior dilation technique realized in a three-dimensional finite element code. Both exact and approximate results, where Coriolis effects are neglected, are presented, and their structures are discussed. Although the helicity is a good quantum number in a one-equation approximation, it is here demonstrated that this is not in the case when including Coriolis coupling, that is, couplings to other helicity components. The behavior of the resonance widths and the positions together with the structure of the resonance wave functions and their dependence on the total angular momentum and its projection have been studied. The dependence of the width of a given resonance oil the total angular momentum was found to be weak while the dependence on the helicity is stronger.
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| 12. |
- Elander, Nils, 1980-, et al.
(author)
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Genetic deletion of mPGES-1 accelerates intestinal tumorigenesis in APCMin/+ mice
- 2008
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In: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 372:1, s. 249-253
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Journal article (peer-reviewed)abstract
- The induced synthesis of bioactive prostanoids downstream of cyclooxygenase-2 (COX-2) and prostaglandin H2 (PGH2) exerts a critical event in colorectal carcinogenesis. Here we demonstrate that APCMin/+ mice with genetic deletion of microsomal prostaglandin E synthase-1 (mPGES-1), which catalyses the terminal conversion of PGH2 into PGE2, surprisingly develop more and generally larger intestinal tumors than do mPGES-1 wild type littermates (mean number of tumors/intestine 80 vs. 38, p < 0.0005, mean tumor diameter 1.64 vs. 1.12 mm, p < 0.0005). No deviation regarding the expression of other PGE2 related enzymes (COX-1, COX-2, mPGES-2, cPGES, and 15-PGDH) or receptors (EP1-4) was obvious among the mPGES-1 deficient mice. PGE2 levels were suppressed in tumors of mPGES-1 deficient animals, but the concentrations of other PGH2 derived prostanoids were generally enhanced, being most prominent for TxA2 and PGD2. Thus, we hypothesise that a redirected synthesis towards other lipid mediators might (over)compensate for loss of mPGES-1/PGE2 during intestinal tumorigenesis. Nevertheless, our results question the suitability for mPGES-1 targeting therapy in the treatment or prevention of colorectal cancer. © 2008 Elsevier Inc. All rights reserved.
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| 13. |
- Elander, Nils
(author)
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Inflammation-associated genes and genetic variations in colorectal cancer
- 2009
-
Doctoral thesis (other academic/artistic)abstract
- Colorectal cancer is a major cause of morbidity and mortality around the world, each year affecting about one million individuals worldwide. The disease is characterized by an accumulation of genetic alterations, and a sequence of events leading to the development of an invasive and metastasising tumour. Chronic or dysregulated inflammation may contribute to tumour initiation and progression via the release and activity of various mediators – e.g. cytokines, prostaglandins, inducible nitric oxide synthase (NOS2), matrix metalloproteinases (MMPs), and vascular endothelial growth factors (VEGF). In the present thesis, genes and genetic alterations controlling these events were analysed and discussed within the context of colorectal cancer.Prostaglandins, being generated from arachidonic acid in reactions dependent on cyclooxygenases (COX-1, COX-2), have been implicated in carcinogenesis of many organs. Since the quite recent characterization of the terminal and specific prostaglandin synthases, which act downstream of COX enzymes, the search for molecular targets which selectively suppress individual prostanoids has been intensified. In papers I-II, the role and regulation of inducible prostaglandin E2 (PGE2) synthase - mPGES-1 - were explored within the context of intestinal cancer. mPGES-1 was genetically deleted in the ApcMin/+ mouse - yielding marked suppression of PGE2 generation in intestinal and tumour tissue. However, a shift towards enhanced generation of non-PGE2 prostanoids was observed in mPGES-1 knock out mice, and these mice developed more and larger instestinal tumours. These results therefore indicate that targeting mPGES-1 may paradoxically promote tumourigenesis, most likely by secondary effects on other potentially pro-tumoural mediators. We also explored the relation of the commonly mutated APC gene and mPGES-1 in colon tumour cells, and found that high expression of mPGES-1 was associated with the presence of wild type APC. Rather than by regulating putative β-catenin/Tcf binding sites of the mPGES-1 promoter, APC seems to influence the stabilisation of mPGES-1 mRNA.In papers III-V, the possible contribution of variations in regulatory regions of genes encoding NOS2, MMPs, and VEGF, was assessed in populations of colorectal cancer patients and healthy control individuals. A single nucleotide insertion (1G/2G) at -1607 upstream the transcription start site of the MMP-1 gene was identified to be a susceptibility factor for colorectal cancer development, although no relation with disease characteristics was observed. Except for a rather uncommon combination of two individual polymorphisms of the VEGF gene, investigated genetic variations of VEGF, other MMPs, and NOS2, were not associated with colorectal cancer susceptibility or clinicopathological characteristics. We therefore suggest that other molecular events play more significant roles for the dysregulation of these genes in colorectal tumours.In summary, accumulating evidence, including the results here presented, suggest significant albeit complex roles of inflammation-induced genes and mediators in colorectal tumourigenesis. The present results may aid in identifying or excluding potential biomarkers and drug targets within cancer-related inflammation.
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| 14. |
- Elander, Nils, 1980-, et al.
(author)
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Matrix metalloproteinase (MMP) -1, -2, -3 and -9 promoter polymorphisms in colorectal cancer
- 2006
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In: Anticancer Research. - : International Institute of Anticancer Research. - 0250-7005 .- 1791-7530. ; 26:1B, s. 791-795
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Journal article (peer-reviewed)abstract
- Background: Matrix metalloproteinases (MMPs) are a group of matrix-degrading proteins implicated in several pathological processes, e.g., invasion and metastasis in malignant diseases such as colorectal cancer (CRC). Materials and methods: One hundred and twenty-seven CRC patients and 208 controls were genotyped for MMP-1, -2, -3 and -9 promoter polymorphisms. The genotyping was performed with PCR/primer-extension/DHPLC or PCR/RFLP. Results: The MMP-1 2G allele was significantly associated with CRC (p=0.037). No significant association between CRC and MMP-2, -3 or -9 polymorphisms was evident. The analysis of polymorphisms in the clinicopathological subgroups displayed no significant associations. Conclusion: The MMP-1 promoter polymorphism seems to affect the susceptibility to CRC, while MMP-2, -3 and -9 polymorphisms appear less likely to have any impact on CRC.
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| 15. |
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| 16. |
- Elander, Nils O, et al.
(author)
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Resonances and Their Relations to Spectral Densities and Scattering Cross Sections in the Schrodinger Formulation
- 2013
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In: Few-body systems. - : Springer Science and Business Media LLC. - 0177-7963 .- 1432-5411. ; 54:5-6, s. 685-695
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Journal article (peer-reviewed)abstract
- The concept of resonances for a two-body single and many channel Schrodinger problem is discussed with respect to the Titchmarsh-Weyl theory. It is argued that the contributions from the entire set of resonances together with the free particle spectral density build the entire spectrum. The implication of this statement on the influence of resonances on a two-body scattering cross section is discussed. It is described how the residues of the S-matrix at a complex resonance energy, i.e. two complex numbers, is used to define its contribution to the cross section. The limitations of the Breit-Wigner approximation is discussed.
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| 17. |
- Elander, Nils, et al.
(author)
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Quantum Scattering with the Driven Schrödinger Approachand Complex Scaling
- 2009
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In: Few-body systems. - Heidelberg : Springer Verlag. - 0177-7963 .- 1432-5411. ; 45:2-4, s. 197-201
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Journal article (peer-reviewed)abstract
- Quantum scattering calculations of two and three-body systems with Coulomb interaction using thedriven Schrödinger equation combined with exterior complex scaling are discussed. A rigorous formulationfor two-body scattering is reported, and its generalization to three-body scattering is considered.
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| 18. |
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| 19. |
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| 20. |
- Ellegård, Sander, et al.
(author)
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ERBB2 and PTPN2 gene copy numbers as prognostic factors in HER2-positive metastatic breast cancer treated with trastuzumab
- 2019
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In: Oncology Letters. - Athens, Greece : Spandidos Publications. - 1792-1074 .- 1792-1082. ; 17:3, s. 3371-3381
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Journal article (peer-reviewed)abstract
- Trastuzumab has markedly improved the treatment and long-term prognosis of patients with HER2-positive breast cancer. A frequent clinical challenge in patients with relapsing and/or metastatic disease is de novo or acquired trastuzumab resistance, and to date no predictive biomarkers for palliative trastuzumab have been established. In the present study, the prognostic values of factors involved in the HER2-associated PI3K/Akt signalling pathway were explored. The first 46 consecutive patients treated at the Department of Oncology, Linkoping University Hospital between 2000 and 2007 with trastuzumab for HER2-positive metastatic breast cancer were retrospectively included. The gene copy number variation and protein expression of several components of the PI3K/Akt pathway were assessed in the tumour tissue and biopsy samples using droplet digital polymerase chain reaction and immunohistochemistry. Patients with tumours displaying a high-grade ERBB2 (HER2) amplification level of amp;gt;= 6 copies had a significantly improved overall survival hazard ratio [(HR)=0.4; 95%, confidence interval (CI): 0.2-0.9] and progression-free survival (HR=0.3; 95% CI: 0.1-0.7) compared with patients with tumours harbouring fewer ERBB2 copies. High-grade ERBB2 amplification was significantly associated with the development of central nervous system metastases during palliative treatment. Copy gain (amp;gt;= 3 copies) of the gene encoding the tyrosine phosphatase PTPN2 was associated with a shorter overall survival (HR=2.0; 95% CI: 1.0-4.0) and shorter progression-free survival (HR=2.1; 95% CI: 1.0-4.1). In conclusion, high ERBB2 amplification level is a potential positive prognostic factor in trastuzumab-treated HER2-positive metastatic breast cancer, whereas PTPN2 gain is a potential negative prognostic factor. Further studies are warranted on the role of PTPN2 in HER2 signalling.
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| 21. |
- Ellegård, Sander, 1985-
(author)
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HER2-positive breast cancer : Clinical and molecular aspects
- 2024
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Doctoral thesis (other academic/artistic)abstract
- BackgroundHuman Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer is notable for its aggressive behavior, however with the introduction of trastuzumab in the early 2000’s, prognosis has improved. This thesis investigates the efficacy of trastuzumab in real-world settings after its introduction and evaluates the prognostic value of molecular biomarkers, aiming to optimize treatment approaches and improve patient outcomes.Material and MethodsHER2-positive patients treated in the advanced and early stages of breast cancer were retrospectively identified using Swedish patient registries and through the review of medical records.Study I included 46 patients with advanced breast cancer treated with trastuzumab between 2000 and 2007. Immunohistochemical analysis of several proteins hypothesized to be involved in trastuzumab resistance were evaluated. Additionally, gene copy number variations were analyzed using droplet digital PCR.Study II include 599 patients who received adjuvant trastuzumab between 2006 and 2014 in the Southeastern health care region, in order to evaluate the implementation of trastuzumab after its approval and to evaluate patient outcomes with regard to clinicopathological variables.Study III conducted quantitative analyses of stromal tumor-infiltrating lymphocytes (sTILs) in patients with available tumor material from the same cohort identified in study II. Additionally, a case-control study of 21 cases with 21 matched controls treated with trastuzumab were analyzed with RNA-sequencing in order to identify important differentially expressed genes.ResultsStudy I demonstrated that trastuzumab treatment in a real-world setting had similar survival as in pivotal clinical trials. Additionally, high amplification of HER2 correlated with improved progression-free survival (PFS) and overall survival (OS) in advanced breast cancer patients and PTPN2 gain was correlated with reduced PFS and OS.Study II confirmed trastuzumab's efficacy in a large real-world cohort. Trastuzumab treatment, estrogen receptor (ER) status and number of metastatic lymph nodes were the most important prognostic factors for breast cancer-specific survival and distant recurrence-free survival.Study III identified a significant association between high levels of sTILs and improved overall survival. Additionally, several G-protein coupled receptors (GPCRs) involved in EGFR and Wnt signaling were found to be upregulated in cases vs controls.ConclusionsTrastuzumab maintains its efficacy in clinical practice, affirming its role in current treatment regimens for HER2-positive breast cancer. The findings support the prognostic significance of sTILs and suggest HER2-amplification levels as a relevant prognostic factor. We propose PTPN2 and several GPCRs as areas for future research.
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| 22. |
- Ellegård, Sander, et al.
(author)
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Long-term follow-up of early stage HER2-positive breast cancer patients treated with trastuzumab: A population-based real world multicenter cohort study
- 2022
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In: Frontiers in Oncology. - : FRONTIERS MEDIA SA. - 2234-943X. ; 12
-
Journal article (peer-reviewed)abstract
- IntroductionSince its introduction in standard of care, trastuzumab has revolutionized the treatment of patients with early and late stages of HER2-positive breast cancer. While the initial clinical trials were convincing and lead to major changes in practice, more knowledge on the long-term outcome and tolerability is needed. The present study was designed to assess the survival, prognostic factors and relapse patterns after the implementation of trastuzumab in a real-world cohort. MethodsAll cases of HER2-positive breast cancer diagnosed between 2006 and 2014 in the Southeast Healthcare Region of Sweden were retrospectively identified. Medical records were thoroughly reviewed with regard to clinicopathological parameters, treatments, relapse pattern and adverse events. Results643 patients were identified and 599 were eligible for analysis. Breast cancer specific survival, distant recurrence free survival and local recurrence free survival were 93.4%, 89.7% and 98.0% for trastuzumab treated patients and 87.4%, 81.6% and 87.4% in patients not treated with trastuzumab, respectively. ER status, nodal status and trastuzumab treatment were all independent prognostic factors in multivariable analysis. No new safety concerns were discovered. ConclusionThe real-world outcome of trastuzumab-treated patients with early HER2-positive breast cancer is similar to what has been previously reported in long-term follow up of prospective clinical trials. ER status, nodal status and trastuzumab treatment are independent prognostic factors for breast cancer specific mortality rate, distant recurrence rate and locoregional recurrence rate in HER2-positive patients in the trastuzumab era.
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| 23. |
- Fransén, Karin, 1973-, et al.
(author)
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Nitric oxide synthase 2 (NOS2) promoter polymorphisms in colorectal cancer
- 2005
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In: Cancer Letters. - : Elsevier. - 0304-3835 .- 1872-7980. ; 225:1, s. 99-103
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Journal article (peer-reviewed)abstract
- Previously, increased expression of nitric oxide synthase 2 (NOS2) in colorectal cancer (CRC) has been identified. The NOS2 gene is transcriptionally regulated, which suggests that polymorphisms in the NOS2 promoter may have a role for CRC development and progression. The genotyping was performed with PCR/RFLP, single strand conformation analysis or MegaBACE genotyping of normal blood DNA from CRC patients and normal healthy controls. However, no significant association between NOS2 polymorphisms and CRC onset or clinical outcome was evident. In conclusion, these results, therefore, suggest that NOS2 promoter polymorphisms have a limited effect on the onset or progression of CRC.
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| 24. |
- Gagin, Anton, et al.
(author)
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Eigen Energies and the Statistical Distributions of the Rovibrational Levels of the Bosonic van der Waals Argon Trimer
- 2009
-
In: Journal of Physical Chemistry A. - : American Chemical Society (ACS). - 1089-5639 .- 1520-5215. ; 113:52, s. 14979-14986
-
Journal article (peer-reviewed)abstract
- The eigen energies and the statistical distributions of the rovibrational levels (J = 0-2) of the bosonic van der Waals argon trimer were calculated using a full angular momentum three-dimensional finite element method. The influence of interatomic potentials on the vibrational levels and statistical properties of the trimer was discussed.
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| 25. |
- Gränsmark, Emma, et al.
(author)
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Real World Evidence on Second-Line Palliative Chemotherapy in Advanced Pancreatic Cancer
- 2020
-
In: Frontiers in Oncology. - : Frontiers Media S.A.. - 2234-943X. ; 10
-
Journal article (peer-reviewed)abstract
- Background: The outcome and tolerability of palliative second line chemotherapy for advanced pancreatic cancer (APC) in real life patients are largely unknown. Prognostic parameters for risk stratification and treatment guidance are lacking.Materials and Methods: A population based multicenter retrospective cohort study was conducted, covering all APC patients who received palliative second-line chemotherapy between 2011 and 2018 at any cancer center in the South East Region of Sweden. Primary outcome was overall survival after second-line therapy (OS2). Time to treatment failure after second-line therapy (TTF2), hematological toxicity, and unplanned hospitalizations were key secondary outcomes. A number of baseline potentially prognostic parameters were assessed.Results: A total of 509 patients received first-line palliative chemotherapy, and of these 167 (33%) received at least one dose of second-line therapy and formed the final study population. Median OS2 was 5.2 months (95% CI = 4.7–5.7) and median TTF2 was 1.9 months (1.5–2.2). OS2 and TTF2 were similar regardless regimen, including comparison of the two most common regimens (fluoropyrimidine monotherapy vs. fluoropyrimidine/oxaliplatin doublet). Multivariate analysis revealed that normal plasma albumin (≥35) and serum CA-19-9 above median (>1,550) were independent predictors for OS2 (HR = 0.21, p < 0.001 and HR = 2.03, p = 0.009) and TTF2 (HR = 0.22, p < 0.001 and HR = 2.03, p = 0.01), while ECOG performance status >1 was predictive for TTF2 (HR = 2.05, p = 0.032). Grade 3–4 hematological toxicity was registered in 17 patients (10%). 50 (30%) had at least one event of hospitalization.Conclusion: The real world outcome of second line palliative chemotherapy for refractory APC remains dismal. Baseline plasma albumin, serum CA-19-9, and performance status emerge as key prognostic factors, and should be further studied as tools for individualized treatment decisions.
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| 26. |
- Hedvall, Patrik, et al.
(author)
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Treatment of asymptotic non-adiabatic couplings with higher order reprojection method in the diabatic representation
-
Other publication (other academic/artistic)abstract
- The problem of asymptotic non-adiabatic couplings in heavy particle collisions is treated using the reprojection method. The mixing matrix that mix the asymptotic solutions of the coupled states to obtain appropriate boundary conditions, is here derived to second order yielding a faster convergence of the cross section. Additionally, the reprojection method is implemented in a diabatic representation and applied to inelastic scattering of Li+Na, H+H and to mutual neutralization in H++H- collisions.
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| 27. |
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| 28. |
- Isaksson, Jenny, et al.
(author)
-
Real-world evaluation of upfront docetaxel in metastatic castration-sensitive prostate cancer
- 2021
-
In: World Journal of Clinical Oncology. - : Baishideng Publishing Group Inc. - 2218-4333. ; 12:11, s. 1009-1022
-
Journal article (peer-reviewed)abstract
- BACKGROUNDThe majority of patients with newly diagnosed metastatic prostate cancer (PC) initially respond to androgen deprivation therapy (ADT) and are classified as metastatic castration-sensitive PC (mCSPC). Following months to years of ADT, the disease tends to become resistant to ADT. Recent randomized phase-III trials demonstrated a survival benefit with the addition of upfront docetaxel to ADT in mCSPC. Following its implementation in routine care, this combined treatment strategy requires more detailed evaluation in a real-world setting.AIMTo assess the real-world outcome and safety of upfront docetaxel treatment in mCSPC.METHODSA multicenter retrospective cohort study in the Southeast Health Care Region of Sweden was performed. This region includes approximately 1.1 million citizens and the oncology departments of Linkoping, Jonkoping, and Kalmar. All patients given upfront docetaxel for mCSPC from July 2015 until December 2017 were included. The primary endpoint was progression-free survival (PFS) at 12 mo, and the secondary endpoints were PFS at 24 mo, overall survival (OS), treatment intensity, adverse events, and unplanned hospitalizations. Exploratory analyses on potential prognostic parameters were performed.RESULTSNinety-four patients were eligible and formed the study cohort. PFS at 12 and 24 mo was 75% (95%CI: 66-84) and 58% (46-70), respectively. OS at 12 and 24 mo was 93% (87-99) and 86% (76-96). A total of 91% of patients (n = 86) were given docetaxel according to the standard protocol of 75 mg/m(2) every 3 wk (6 cycles), while 9% (n = 8) received a modified protocol of 50 mg/m(2) every 2 wk (9 cycles). The average overall dose intensity for those commencing standard treatment was 91%. Univariate Cox regression analyses show that baseline PSA > 180 vs < 180 and the presence of distant metastases vs locoregional lymph node metastases were only negative prognostic factors (HR 2.86, 95%CI: 1.39-5.87, P = 0.0041 and 3.36, 95%CI: 1.03-10.96, P = 0.045). Following multivariate analysis, statistical significance remained for PSA (2.51, 95%CI: 1.21-5.19, P = 0.013) but not for metastatic status (2.60, 95%CI: 0.78-8.65, P = 0.12). Febrile neutropenia was recorded in 21% (n = 20) of patients, and 26% (n = 24) had at least one episode of unplanned hospitalization under and up to 30 d after the treatment course.CONCLUSIONResults from this study support the implementation of upfront docetaxel plus ADT as part of the standard of care treatment strategy in mCSPC.
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| 29. |
- Kapshai, Valery, et al.
(author)
-
Integral equations and complex resonance energies for analytical potentials
- 2007
-
In: International Journal of Quantum Chemistry. - : Wiley. - 0020-7608 .- 1097-461X. ; 107:5, s. 1029-1039
-
Journal article (peer-reviewed)abstract
- It is shown that the Volterra integral equation in combination with complex scaling gives a formalism capable to solve Schrodinger-type problems concerning bound states and resonances. The regular solution of the Schrodinger equation presented at the Volterra integral equation allows us to define the explicit form of the Jost function analytically continued into the lower half complex momentum plane. The resulting formalism is used to develop a numerical method for finding resonances defined as zeros of the Jost function. The numerical method is tested on several analytical potentials; it gives good results for arbitrary orbital momentum l.
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| 30. |
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| 31. |
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| 32. |
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| 33. |
- Kurasov, Pavel, et al.
(author)
-
Resonances and irreversibility for Schroedinger evolution
- 1993
-
In: International Journal of Quantum Chemistry. - : Wiley. - 0020-7608 .- 1097-461X. ; 46:3, s. 401-413
-
Journal article (peer-reviewed)abstract
- The relations between the Schrödinger and wave evolutions are investigated. A generalization of the Lax-Phillips scattering theory for the case of the Schrödinger equation is constructed. An analog of the wave decay operator is obtained. The general ideas are illustrated by an explicitly solvable model of multichannel scattering on the halfaxis. A Lax-Phillips scattering theory is developed for the model operator obtained by a self-adjoint perturbation of the background operator
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| 34. |
- Kurasov, Pavel, et al.
(author)
-
δ' potential arising in exterior complex scaling
- 1994
-
In: Physical Review A (Atomic, Molecular and Optical Physics). - 1050-2947. ; 49:6, s. 5095-5097
-
Journal article (peer-reviewed)abstract
- In the method of exterior complex scaling the coordinates of the Hamilton operator are scaled by a constant factor starting at a radius R≠0. We show that this procedure induces a singularity in the kinetic-energy term which must be interpreted as the derivative of a δ function.
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| 35. |
- Labori, Knut Jørgen, et al.
(author)
-
Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1) : a multicentre, randomised, phase 2 trial
- 2024
-
In: The Lancet Gastroenterology & Hepatology. - : The Lancet Group. - 2468-1253. ; 9:3, s. 205-217
-
Journal article (peer-reviewed)abstract
- BackgroundIn patients undergoing resection for pancreatic cancer, adjuvant modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improves overall survival compared with alternative chemotherapy regimens. We aimed to compare the efficacy and safety of neoadjuvant FOLFIRINOX with the standard strategy of upfront surgery in patients with resectable pancreatic ductal adenocarcinoma.MethodsNORPACT-1 was a multicentre, randomised, phase 2 trial done in 12 hospitals in Denmark, Finland, Norway, and Sweden. Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, and had a resectable tumour of the pancreatic head radiologically strongly suspected to be pancreatic adenocarcinoma. Participants were randomly assigned (3:2 before October, 2018, and 1:1 after) to the neoadjuvant FOLFIRINOX group or upfront surgery group. Patients in the neoadjuvant FOLFIRINOX group received four neoadjuvant cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h on day 1 of each 14-day cycle), followed by surgery and adjuvant chemotherapy. Patients in the upfront surgery group underwent surgery and then received adjuvant chemotherapy. Initially, adjuvant chemotherapy was gemcitabine plus capecitabine (gemcitabine 1000 mg/m2 over 30 min on days 1, 8, and 15 of each 28-day cycle and capecitabine 830 mg/m2 twice daily for 3 weeks with 1 week of rest in each 28-day cycle; four cycles in the neoadjuvant FOLFIRINOX group, six cycles in the upfront surgery group). A protocol amendment was subsequently made to permit use of adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 over 46 h on day 1 of each 14-day cycle; eight cycles in the neoadjuvant FOLFIRINOX group, 12 cycles in the upfront surgery group). Randomisation was performed with a computerised algorithm that stratified for each participating centre and used a concealed block size of two to six. Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was overall survival at 18 months. Analyses were done in the intention-to-treat (ITT) and per-protocol populations. Safety was assessed in all patients who were randomly assigned and received at least one cycle of neoadjuvant or adjuvant therapy. This trial is registered with ClinicalTrials.gov, NCT02919787, and EudraCT, 2015-001635-21, and is ongoing.FindingsBetween Feb 8, 2017, and April 21, 2021, 77 patients were randomly assigned to receive neoadjuvant FOLFIRINOX and 63 to undergo upfront surgery. All patients were included in the ITT analysis. For the per-protocol analysis, 17 (22%) patients were excluded from the neoadjuvant FOLFIRINOX group (ten did not receive neoadjuvant therapy, four did not have pancreatic ductal adenocarcinoma, and three received another neoadjuvant regimen), and eight (13%) were excluded from the upfront surgery group (seven did not have pancreatic ductal adenocarcinoma and one did not undergo surgical exploration). 61 (79%) of 77 patients in the neoadjuvant FOLFIRINOX group received neoadjuvant therapy. The proportion of patients alive at 18 months by ITT was 60% (95% CI 49–71) in the neoadjuvant FOLFIRINOX group versus 73% (62–84) in the upfront surgery group (p=0·032), and median overall survival by ITT was 25·1 months (95% CI 17·2–34·9) versus 38·5 months (27·6–not reached; hazard ratio [HR] 1·52 [95% CI 1·00–2·33], log-rank p=0·050). The proportion of patients alive at 18 months in per-protocol analysis was 57% (95% CI 46–67) in the neoadjuvant FOLFIRINOX group versus 70% (55–83) in the upfront surgery group (p=0·14), and median overall survival in per-protocol population was 23·0 months (95% CI 16·2–34·9) versus 34·4 months (19·4–not reached; HR 1·46 [95% CI 0·99–2·17], log-rank p=0·058). In the safety population, 42 (58%) of 73 patients in the neoadjuvant FOLFIRINOX group and 19 (40%) of 47 patients in the upfront surgery group had at least one grade 3 or worse adverse event. 63 (82%) of 77 patients in the neoadjuvant group and 56 (89%) of 63 patients in the upfront surgery group had resection (p=0·24). One sudden death of unknown cause and one COVID-19-related death occurred after the first cycle of neoadjuvant FOLFIRINOX. Adjuvant chemotherapy was initiated in 51 (86%) of 59 patients with resected pancreatic ductal adenocarcinoma in the neoadjuvant FOLFIRINOX group and 44 (90%) of 49 patients with resected pancreatic ductal adenocarcinoma in the upfront surgery group (p=0·56). Adjuvant modified FOLFIRINOX was given to 13 (25%) patients in the neoadjuvant FOLFIRINOX group and 19 (43%) patients in the upfront surgery group. During adjuvant chemotherapy, neutropenia (11 [22%] patients in the neoadjuvant FOLFIRINOX group and five [11%] in the upfront surgery group) was the most common grade 3 or worse adverse event.InterpretationThis phase 2 trial did not show a survival benefit from neoadjuvant FOLFIRINOX in resectable pancreatic ductal adenocarcinoma compared with upfront surgery. Implementation of neoadjuvant FOLFIRINOX was challenging. Future trials on treatment sequencing in resectable pancreatic ductal adenocarcinoma should be biomarker driven.
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| 36. |
- Labori, Knut Jørgen, et al.
(author)
-
Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1) : a multicentre, randomised, phase 2 trial
- 2024
-
In: The Lancet Gastroenterology & Hepatology. - : Elsevier. - 2468-1253. ; 9:3, s. 205-217
-
Journal article (peer-reviewed)abstract
- Background: In patients undergoing resection for pancreatic cancer, adjuvant modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improves overall survival compared with alternative chemotherapy regimens. We aimed to compare the efficacy and safety of neoadjuvant FOLFIRINOX with the standard strategy of upfront surgery in patients with resectable pancreatic ductal adenocarcinoma.Methods: NORPACT-1 was a multicentre, randomised, phase 2 trial done in 12 hospitals in Denmark, Finland, Norway, and Sweden. Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, and had a resectable tumour of the pancreatic head radiologically strongly suspected to be pancreatic adenocarcinoma. Participants were randomly assigned (3:2 before October, 2018, and 1:1 after) to the neoadjuvant FOLFIRINOX group or upfront surgery group. Patients in the neoadjuvant FOLFIRINOX group received four neoadjuvant cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h on day 1 of each 14-day cycle), followed by surgery and adjuvant chemotherapy. Patients in the upfront surgery group underwent surgery and then received adjuvant chemotherapy. Initially, adjuvant chemotherapy was gemcitabine plus capecitabine (gemcitabine 1000 mg/m2 over 30 min on days 1, 8, and 15 of each 28-day cycle and capecitabine 830 mg/m2 twice daily for 3 weeks with 1 week of rest in each 28-day cycle; four cycles in the neoadjuvant FOLFIRINOX group, six cycles in the upfront surgery group). A protocol amendment was subsequently made to permit use of adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 over 46 h on day 1 of each 14-day cycle; eight cycles in the neoadjuvant FOLFIRINOX group, 12 cycles in the upfront surgery group). Randomisation was performed with a computerised algorithm that stratified for each participating centre and used a concealed block size of two to six. Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was overall survival at 18 months. Analyses were done in the intention-to-treat (ITT) and per-protocol populations. Safety was assessed in all patients who were randomly assigned and received at least one cycle of neoadjuvant or adjuvant therapy. This trial is registered with ClinicalTrials.gov, NCT02919787, and EudraCT, 2015-001635-21, and is ongoing.Findings: Between Feb 8, 2017, and April 21, 2021, 77 patients were randomly assigned to receive neoadjuvant FOLFIRINOX and 63 to undergo upfront surgery. All patients were included in the ITT analysis. For the per-protocol analysis, 17 (22%) patients were excluded from the neoadjuvant FOLFIRINOX group (ten did not receive neoadjuvant therapy, four did not have pancreatic ductal adenocarcinoma, and three received another neoadjuvant regimen), and eight (13%) were excluded from the upfront surgery group (seven did not have pancreatic ductal adenocarcinoma and one did not undergo surgical exploration). 61 (79%) of 77 patients in the neoadjuvant FOLFIRINOX group received neoadjuvant therapy. The proportion of patients alive at 18 months by ITT was 60% (95% CI 49–71) in the neoadjuvant FOLFIRINOX group versus 73% (62–84) in the upfront surgery group (p=0·032), and median overall survival by ITT was 25·1 months (95% CI 17·2–34·9) versus 38·5 months (27·6–not reached; hazard ratio [HR] 1·52 [95% CI 1·00–2·33], log-rank p=0·050). The proportion of patients alive at 18 months in per-protocol analysis was 57% (95% CI 46–67) in the neoadjuvant FOLFIRINOX group versus 70% (55–83) in the upfront surgery group (p=0·14), and median overall survival in per-protocol population was 23·0 months (95% CI 16·2–34·9) versus 34·4 months (19·4–not reached; HR 1·46 [95% CI 0·99–2·17], log-rank p=0·058). In the safety population, 42 (58%) of 73 patients in the neoadjuvant FOLFIRINOX group and 19 (40%) of 47 patients in the upfront surgery group had at least one grade 3 or worse adverse event. 63 (82%) of 77 patients in the neoadjuvant group and 56 (89%) of 63 patients in the upfront surgery group had resection (p=0·24). One sudden death of unknown cause and one COVID-19-related death occurred after the first cycle of neoadjuvant FOLFIRINOX. Adjuvant chemotherapy was initiated in 51 (86%) of 59 patients with resected pancreatic ductal adenocarcinoma in the neoadjuvant FOLFIRINOX group and 44 (90%) of 49 patients with resected pancreatic ductal adenocarcinoma in the upfront surgery group (p=0·56). Adjuvant modified FOLFIRINOX was given to 13 (25%) patients in the neoadjuvant FOLFIRINOX group and 19 (43%) patients in the upfront surgery group. During adjuvant chemotherapy, neutropenia (11 [22%] patients in the neoadjuvant FOLFIRINOX group and five [11%] in the upfront surgery group) was the most common grade 3 or worse adverse event.Interpretation: This phase 2 trial did not show a survival benefit from neoadjuvant FOLFIRINOX in resectable pancreatic ductal adenocarcinoma compared with upfront surgery. Implementation of neoadjuvant FOLFIRINOX was challenging. Future trials on treatment sequencing in resectable pancreatic ductal adenocarcinoma should be biomarker driven.
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| 37. |
- Lagenfelt, Hanna, et al.
(author)
-
Real-World Evidence on Palliative Gemcitabine and Oxaliplatin (GemOx) Combination Chemotherapy in Advanced Biliary Tract Cancer
- 2021
-
In: Cancers. - : MDPI. - 2072-6694. ; 13:14
-
Journal article (peer-reviewed)abstract
- Simple Summary Cancers of the biliary tract are rare but severe with high mortality rates. Randomised controlled trials suggest that chemotherapies such as gemcitabine and oxaliplatin (GemOx) may relieve symptoms and prolong life, but less is known on the efficacy and safety of such regimens in real life. The current paper assessed the real-world outcome of GemOx in all patients with advanced biliary tract cancer treated at any cancer centre in the South East Region of Sweden over a period of nine years. The median overall survival was nine months and time to disease progression five months. Prognostic factors such as performance status and gall bladder (rather than bile duct) localisation of the primary tumour were identified. Most patients received a lower dose of oxaliplatin than proposed by previous studies, which seemed feasible as few patients had severe adverse events. This study supports further use of GemOx as standard of care. Background: Gemcitabine and oxaliplatin (GemOx) is a standard combination regimen in advanced biliary tract cancer (BTC). There is limited evidence on its efficacy and safety in real life. Methods: A retrospective multicentre cohort study in the South East Region of Sweden, covering nine years (2011-2020) and three hospitals where GemOx was treatment of choice, was designed. Clinicopathological prognostic parameters were explored. Results: One hundred and twenty-one patients with advanced BTC were identified. Median overall and progression-free survival (OS and PFS) were 8.9 (95% CI = 7.2-10.6) and 5.3 (95% CI = 3.8-6.7) months. Performance status according to Eastern Cooperative Oncology Group (PS according to ECOG) 1-2 and primary gallbladder carcinoma were independent predictors for poor OS. PS and derived neutrophil/lymphocyte ratio were predictive for PFS. The most common severe type of myelosuppresion was grade 3 neutropenia that was recorded in 8%. Fifty-three (43.8%) experienced at least one episode of unplanned hospitalisation. One hundred and seventeen (97%) received oxaliplatin with lower dosage than was utilized in previous phase III trials (80-85 vs. 100 mg/m(2)) and a majority received further dose reductions of oxaliplatin and/or gemcitabine. Conclusion: The outcome of GemOx in advanced BTC appears comparable in controlled trials and real-world contexts. A lower dose of oxaliplatin seems more tolerable without compromising the outcome.
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| 38. |
- Mezei, J. Z., et al.
(author)
-
Mutual neutralization in low-energy H(+) + F(-) collisions
- 2011
-
In: Physical Review A. Atomic, Molecular, and Optical Physics. - 1050-2947 .- 1094-1622. ; 84:1, s. 012703-
-
Journal article (peer-reviewed)abstract
- The cross section for mutual neutralization in collisions between H(+) and F(-) ions at low energies ( E <= 10 eV) is calculated using a molecular close-coupling approach. Two different representations of the quasidiabatic potentials and couplings of HF are used. The effect of autoionization on the cross section is investigated. The coupled Schrodinger equation for the nuclear motion is solved using a numerical integration of the corresponding matrix Riccati equation and the cross section for mutual neutralization is computed from the asymptotic value of the logarithmic derivative of the radial wave function. The magnitude of the cross section for mutual neutralization in this reaction is small compared to other systems. This can be understood by the lack of avoided crossings at large internuclear distances. Resonant structures are found in the cross section and these are assigned with dominant angular momentum quantum number. The cross section for mutual neutralization in collisions of D(+) and F(-) ions is also calculated.
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| 39. |
- Mezei, Zsolt, et al.
(author)
-
Double charge transfer in low-energy H+ + H- collisions
- 2010
-
In: Physical Review A. Atomic, Molecular, and Optical Physics. - 1050-2947 .- 1094-1622. ; 82:1, s. 14701-
-
Journal article (peer-reviewed)abstract
- The cross section for double charge transfer between H+ and H- at low collision energies (E <= 90 eV) is calculated using a many-state molecular close-coupling model. The wave function is expanded in a diabatic representation of the seven lowest (1)Sigma(+)(g) and the six lowest (1)Sigma(+)(u) states of the hydrogen molecule. The calculated cross section shows clear oscillations as a function of the collision energy, similar to those observed experimentally. However, the magnitude of the calculated cross section is larger than found in experiments. Also, the cross section for double charge transfer in collisions between D+ and H- is calculated.
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| 40. |
- Naeser, Ylva, et al.
(author)
-
Quality of Life in the First Year of Follow-Up in a Randomized Multicenter Trial Assessing the Role of Imaging after Radical Surgery of Stage IIB-C and III Cutaneous Melanoma (TRIM Study)
- 2022
-
In: Cancers. - : MDPI. - 2072-6694. ; 14:4
-
Journal article (peer-reviewed)abstract
- Simple Summary After surgery of high-risk melanoma, patients are usually followed up by physical examinations. Recommendations regarding imaging vary due to insufficient evidence of the benefit of regular scans. It might also be stressful for patients to undergo imaging. In an ongoing Swedish study, half of the patients are randomized to whole-body imaging in addition to physical examinations. Three imaging procedures are performed during the first year. The main aim of our study was to investigate if imaging during the first year of follow-up affected the patients' well-being. Validated self-reporting questionnaires regarding symptoms of anxiety and depression and quality of life were answered at study start and at 1 year. Questionnaires from 204 recurrence-free patients were analyzed. No differences in either level of anxiety/depression or quality of life were found at 1 year follow-up between the imaging and non-imaging group. These findings can be considered in the formulation of future follow-up programs. The benefit of imaging in the follow-up setting for high-risk melanoma patients is uncertain, and even less is known about the impact of intensive follow-up on the patient ' s quality of life. In 2017, a Swedish prospective randomized multicenter study started, in which high-risk melanoma patients are randomly assigned 1:1 to follow-up by physical examinations +/- whole-body imaging. The first-year examinations are scheduled at 0, 6 and 12 months. The aim of this study was to investigate whether the patients ' health-related quality of life (HRQoL) and levels of anxiety and depression were affected at 1 year by imaging. Anxiety/depression and HRQoL were assessed at 0 and 12 months by the questionnaires Hospital Anxiety and Depression (HAD) scale and EORTC QLQ-C30 version 3. Expected baseline QLQ-C30 values for the patients were calculated using data from the general population. In total, 204 patients were analyzed. Mean differences in subscale scores at 1 year were not statistically significant either for HRQoL or for anxiety/depression. Baseline HRQoL did not differ from expected values in the general Swedish population. In conclusion, the patients in general coped well with the situation, and adding whole-body imaging to physical examinations did not affect the melanoma patients' HRQoL or levels of anxiety or depression.
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| 41. |
- Naeser, Ylva, et al.
(author)
-
TRIM study protocol - a prospective randomized multicenter Trial to assess the Role of Imaging during follow-up after radical surgery of stage IIB-C and III cutaneous malignant Melanoma
- 2020
-
In: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 20:1
-
Journal article (peer-reviewed)abstract
- BackgroundThe incidence of cutaneous malignant melanoma (CMM) is increasing worldwide. In Sweden, over 4600 cases were diagnosed in 2018. The prognosis after radical surgery varies considerably with tumor stage. In recent years, new treatment options have become available for metastatic CMM. Early onset of treatment seems to improve outcome, which suggests that early detection of recurrent disease should be beneficial. Consequently, in several countries imaging is a part of the routine follow-up program after surgery of high risk CMM. However, imaging has drawbacks, including resources required (costs, personnel, equipment) and the radiation exposure. Furthermore, many patients experience anxiety in waiting for the imaging results and investigations of irrelevant findings is another factor that also could cause worry and lead to decreased quality of life. Hence, the impact of imaging in this setting is important to address and no randomized study has previously been conducted. The Swedish national guidelines stipulate follow-up for 3years by clinical examinations only.MethodsThe TRIM study is a prospective randomized multicenter trial evaluating the potential benefit of imaging and blood tests during follow-up after radical surgery for high-risk CMM, compared to clinical examinations only. Primary endpoint is overall survival (OS) at 5years. Secondary endpoints are survival from diagnosis of relapse and health-related quality of life (HRQoL). Eligible for inclusion are patients radically operated for CMM stage IIB-C or III with sufficient renal function for iv contrast-enhanced CT and who are expected to be fit for treatment in case of recurrence. The planned number of patients is >1300. Patients are randomized to clinical examinations for 3years +/- whole-body imaging with CT or FDG-PET/CT and laboratory tests including S100B protein and LDH. This academic study is supported by the Swedish Melanoma Study Group.DiscussionThis is the first randomized prospective trial on the potential benefit of imaging as a part of the follow-up scheme after radical surgery for high-risk CMM.ResultsThe first patient was recruited in June 2017 and as of April 2020, almost 500 patients had been included at 19 centers in Sweden.Trial registrationClinicalTrials.gov, NCT 03116412. Registered 17 April 2017, https://clinicaltrials.gov/ct2/show/study/NCT03116412
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| 42. |
- Nkambule, Sifiso M., et al.
(author)
-
Differential and total cross sections of mutual neutralization in low-energy collisions of isotopes of H+ + H-
- 2016
-
In: Physical Review A: covering atomic, molecular, and optical physics and quantum information. - 2469-9926 .- 2469-9934. ; 93:3
-
Journal article (peer-reviewed)abstract
- Mutual neutralization in the collisions of H+ and H- is studied both theoretically and experimentally. The quantum-mechanical ab initio model includes covalent states associated with the H(1)+H(n <= 3) limits and the collision energy ranges from 1 meV to 100 eV. The reaction is theoretically studied for collisions between different isotopes of the hydrogen ions. From the partial wave scattering amplitude, the differential and total cross sections are computed. The differential cross section is analyzed in terms of forward- and backward-scattering events, showing a dominance of backward scattering which can be understood by examining the phase of the scattering amplitudes for the gerade and ungerade set of states. The isotope dependence of the total cross section is compared with the one obtained using a semiclassical multistate Landau-Zener model. The final state distribution analysis emphasizes the dominance of the n = 3 channel for collisions below 10 eV, while at higher collision energies, the n = 2 channel starts to become important. For collisions of ions forming a molecular system with a larger reduced mass, the n = 2 channel starts to dominate at lower energies. Using a merged ion-beam apparatus, the branching ratios for mutual neutralization in H+ and H- collisions in the energy range from 11 to 185 eV are measured with position- and time-sensitive particle detectors. The measured and calculated branching ratios satisfactorily agree with respect to state contributions.
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| 43. |
- Olofsson Bagge, Roger, et al.
(author)
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Isolated Hepatic Perfusion With Melphalan for Patients With Isolated Uveal Melanoma Liver Metastases : A Multicenter, Randomized, Open-Label, Phase III Trial (the SCANDIUM Trial)
- 2023
-
In: Journal of Clinical Oncology. - : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 41:16, s. 3042-3050
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Journal article (peer-reviewed)abstract
- PURPOSE: About half of patients with metastatic uveal melanoma present with isolated liver metastasis, in whom the median survival is 6-12 months. The few systemic treatment options available only moderately prolong survival. Isolated hepatic perfusion (IHP) with melphalan is a regional treatment option, but prospective efficacy and safety data are lacking.METHODS: In this multicenter, randomized, open-label, phase III trial, patients with previously untreated isolated liver metastases from uveal melanoma were randomly assigned to receive a one-time treatment with IHP with melphalan or best alternative care (control group). The primary end point was overall survival at 24 months. Here, we report the secondary outcomes of response according to RECIST 1.1 criteria, progression-free survival (PFS), hepatic PFS (hPFS), and safety.RESULTS: Ninety-three patients were randomly assigned, and 87 patients were assigned to either IHP (n = 43) or a control group receiving the investigator's choice of treatment (n = 44). In the control group, 49% received chemotherapy, 39% immune checkpoint inhibitors, and 9% locoregional treatment other than IHP. In an intention-to-treat analysis, the overall response rates (ORRs) were 40% versus 4.5% in the IHP and control groups, respectively (P < .0001). The median PFS was 7.4 months versus 3.3 months (P < .0001), with a hazard ratio of 0.21 (95% CI, 0.12 to 0.36), and the median hPFS was 9.1 months versus 3.3 months (P < .0001), both favoring the IHP arm. There were 11 treatment-related serious adverse events in the IHP group compared with seven in the control group. There was one treatment-related death in the IHP group.CONCLUSION: IHP treatment resulted in superior ORR, hPFS, and PFS compared with best alternative care in previously untreated patients with isolated liver metastases from primary uveal melanoma.
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| 44. |
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| 45. |
- Rakityansky, S. A., et al.
(author)
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A METHOD FOR EXTRACTING THE RESONANCE PARAMETERS FROM EXPERIMENTAL CROSS-SECTIONS
- 2013
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In: International Journal of Modern Physics E. - 0218-3013. ; 22:5, s. UNSP 1350032-
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Journal article (peer-reviewed)abstract
- Within the proposed method, a set of experimental data points are fitted using a multi-channel S-matrix. Then the resonance parameters are located as its poles on an appropriate sheet of the Riemann surface of the energy. The main advantage of the method is that the S-matrix is constructed in such a way that it has proper analytic structure, i.e. for any number of two-body channels, the branching at all the channel thresholds is represented via exact analytic expressions in terms of the channel momenta. The way the S-matrix is constructed makes it possible not only to locate multi-channel resonances but also to extract their partial widths as well as to obtain the scattering cross-section in the channels for which no data are available. The efficiency of the method is demonstrated by two model examples of a single-channel and a two-channel problems, where known resonance parameters are rather accurately reproduced by fitting the pseudo-data artificially generated using the corresponding potentials.
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| 46. |
- Rakityansky, S. A., et al.
(author)
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Analytic structure and power series expansion of the Jost function for the two-dimensional problem
- 2012
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In: Journal of Physics A. - : IOP Publishing. - 1751-8113 .- 1751-8121. ; 45:13, s. 135209-
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Journal article (peer-reviewed)abstract
- For a two-dimensional quantum-mechanical problem, we obtain a generalized power series expansion of the S-matrix that can be done near an arbitrary point on the Riemann surface of the energy, similar to the standard effective-range expansion. In order to do this, we consider the Jost function and analytically factorize its momentum dependence that causes the Jost function to be a multi-valued function. The remaining single-valued function of the energy is then expanded in the power series near an arbitrary point in the complex energy plane. A systematic and accurate procedure has been developed for calculating the expansion coefficients. This makes it possible to obtain a semi-analytic expression for the Jost function (and therefore for the S-matrix) near an arbitrary point on the Riemann surface and use it, for example, to locate the spectral points (bound and resonant states) as the S-matrix poles. The method is applied to a model similar to those used in the theory of quantum dots.
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| 47. |
- Rakityansky, S. A., et al.
(author)
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Analytic Structure and Power-Series Expansion of the Jost Matrix
- 2013
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In: Few-body systems. - : Springer Science and Business Media LLC. - 0177-7963 .- 1432-5411. ; 54:5-6, s. 673-683
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Journal article (peer-reviewed)abstract
- For the Jost-matrix that describes the multi-channel scattering, the momentum dependencies at all the branching points on the Riemann surface are factorized analytically. The remaining single-valued matrix functions of the energy are expanded in the power-series near an arbitrary point in the complex energy plane. A systematic and accurate procedure has been developed for calculating the expansion coefficients. This makes it possible to obtain an analytic expression for the Jost-matrix (and therefore for the S-matrix) near an arbitrary point on the Riemann surface (within the domain of its analyticity) and thus to locate the resonant states as the S-matrix poles. This approach generalizes the standard effective-range expansion that now can be done not only near the threshold, but practically near an arbitrary point on the Riemann surface of the energy. Alternatively, The semi-analytic (power-series) expression of the Jost matrix can be used for extracting the resonance parameters from experimental data. In doing this, the expansion coefficients can be treated as fitting parameters to reproduce experimental data on the real axis (near a chosen center of expansion E (0)) and then the resulting semi-analytic matrix S(E) can be used at the nearby complex energies for locating the resonances. Similarly to the expansion procedure in the three-dimensional space, we obtain the expansion for the Jost function describing a quantum system in the space of two dimensions (motion on a plane), where the logarithmic branching point is present.
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| 48. |
- Rakityansky, S. A., et al.
(author)
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Generalized effective-range expansion
- 2009
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In: Journal of Physics A. - : IOP Publishing. - 1751-8113 .- 1751-8121. ; 42:22, s. 225302-
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Journal article (peer-reviewed)abstract
- A systematic and accurate procedure has been developed for calculating the coefficients phi((in/out))(ln) of the series expansion f(l)((in/out))(k) = Sigma(infinity)(n=0)(k-k(0))(n) phi((in/out))(ln) of the Jost functions in the vicinity of an arbitrary point k(0) in the complex momentum plane. This makes it possible to obtain an analytic expression for the S-matrix s(l)(k) = f(l)((out))(k)/f(l)((in))(k) around k(0) and locate its possible poles. In the particular case of l = 0 and k(0) = 0, any number of the parameters of the standard effective-range expansion k cot delta(0) = -1/a + r(0)k(2)/2 - ... are easily obtained using the corresponding coefficients phi((in/out))(ln). Numerical examples demonstrate the stability and accuracy of the proposed method.
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| 49. |
- Rakityansky, S. A., et al.
(author)
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Multi-channel analog of the effective-range expansion
- 2011
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In: Journal of Physics A. - : IOP Publishing. - 1751-8113 .- 1751-8121. ; 44:11, s. 115303-
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Journal article (peer-reviewed)abstract
- Similar to the standard effective-range expansion that is done near the threshold energy, we obtain a generalized power-series expansion of the multi-channel Jost-matrix that can be done near an arbitrary point on the Riemann surface of the energy within the domain of its analyticity. In order to do this, we analytically factorize its momentum dependences at all the branching points on the Riemann surface. The remaining single-valued matrix functions of the energy are then expanded in the power series near an arbitrary point in the domain of the complex energy plane where it is analytic. A systematic and accurate procedure has been developed for calculating the expansion coefficients. This means that near an arbitrary point in the domain of physically interesting complex energies it is possible to obtain a semi-analytic expression for the Jost-matrix (and therefore for the S-matrix) and use it, for example, to locate the spectral points (bound and resonant states) as the S-matrix poles.
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| 50. |
- Salci, Moses, 1977-
(author)
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A Theoretical Study of Atomic Trimers in the Critical Stability Region
- 2006
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Doctoral thesis (other academic/artistic)abstract
- When studying the structure formation and fragmentation of complex atomic and nuclear systems it is preferable to start with simple systems where all details can be explored. Some of the knowledge gained from studies of atomic dimers can be generalised to more complex systems. Adding a third atom to an atomic dimer gives a first chance to study how the binding between two atoms is affected by a third. Few-body physics is an intermediate area which helps us to understand some but not all phenomena in many-body physics.Very weakly bound, spatially very extended quantum systems with a wave function reaching far beyond the classical forbidden region and with low angular momentum are characterized as halo systems. These unusual quantum systems, first discovered in nuclear physics may also exist in systems of neutral atoms.Since the first clear theoretical prediction in 1977, of a halo system possessing an Efimov state, manifested in the excited state of the bosonic van der Waals helium trimer 42He3, small helium and different spin-polarised halo hydrogen clusters and their corresponding isotopologues have been intensively studied the last three decades.In the work presented here, the existence of the spin-polarized tritium trimer ground state, 31H3, is demonstrated, verifying earlier predictions, and the system's properties elucidated. Detailed analysis has found no found evidence for other bound states and shape resonances in this system. The properties of the halo helium trimers, 42He3 and 42He2-32He have been investigated. Earlier predictions concerning the ground state energies and structural properties of these systems are validated using our three-dimensional finite element method. In the last part of this work we present results on the bound states and structural properties of the van der Waals bosonic atomic trimers Ne3 and Ar3. We believe to be the first to find evidence of a possible shape resonance just above the three-body dissociation limit of the neon trimer.
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