| 1. |
- Ahmed, Hytham, et al.
(författare)
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Determination and Pharmacokinetics of Omeprazole Enantiomers in Human Plasma and Oral Fluid Utilizing Microextraction by Packed Sorbent and Liquid Chromatography-Tandem Mass Spectrometry
- 2021
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Ingår i: International Journal of Analytical Chemistry. - : Hindawi Publishing Corporation. - 1687-8760 .- 1687-8779. ; 2021
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Tidskriftsartikel (refereegranskat)abstract
- In the present work, the determination of omeprazole (OME) enantiomers in oral fluid and plasma samples was carried out utilizing microextraction by packed sorbent (MEPS) and liquid chromatography-tandem mass spectrometry. A chiral column with cellulose-SB phase was used for the first time for enantiomeric separation of OME with an isocratic elution system using 0.2% ammonium hydroxide in hexane-ethanol mixture (70 : 30, v/v) as the mobile phase. OME enantiomers were determined utilizing a triple quadrupole tandem mass spectrometer in positive ion mode (ESI+) monitoring mass transitions: m/z 346.3 -> 198.0 for OME and m/z 369.98 -> 252.0 for internal standard. The limits of detection and quantification of the present method for both enantiomers were 0.1 and 0.4 ng/mL, respectively. The method validation provided good accuracy and precision. The matrix effect factor was less than 5%, and no interfering peaks were observed. The interday precision values ranged from 2.2 to 7.5 (%RSD), and the accuracy of determinations varied from -9.9% to 8.3%. In addition, the pharmacokinetics (PK) of omeprazole enantiomers in healthy subjects after a single oral dose was investigated. (S)-Enantiomers showed higher levels than (R)-enantiomers throughout 24 h. It was found that the mean maximum concentrations of (R)- and (S)-omeprazole in plasma samples were about two times higher than in oral fluid.
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| 2. |
- Björn, Niclas, et al.
(författare)
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Genes and variants in hematopoiesis-related pathways are associated with gemcitabine/carboplatin-induced thrombocytopenia
- 2020
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Ingår i: The Pharmacogenomics Journal. - : Nature Publishing Group. - 1470-269X .- 1473-1150. ; 20:2, s. 179-191
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Tidskriftsartikel (refereegranskat)abstract
- Chemotherapy-induced myelosuppression, including thrombocytopenia, is a recurrent problem during cancer treatments that may require dose alterations or cessations that could affect the antitumor effect of the treatment. To identify genetic markers associated with treatment-induced thrombocytopenia, we whole-exome sequenced 215 non-small cell lung cancer patients homogeneously treated with gemcitabine/carboplatin. The decrease in platelets (defined as nadir/baseline) was used to assess treatment-induced thrombocytopenia. Association between germline genetic variants and thrombocytopenia was analyzed at single-nucleotide variant (SNV) (based on the optimal false discovery rate, the severity of predicted consequence, and effect), gene, and pathway levels. These analyses identified 130 SNVs/INDELs and 25 genes associated with thrombocytopenia (P-value < 0.002). Twenty-three SNVs were validated in an independent genome-wide association study (GWAS). The top associations include rs34491125 in JMJD1C (P-value = 9.07 × 10−5), the validated variants rs10491684 in DOCK8 (P-value = 1.95 × 10−4), rs6118 in SERPINA5 (P-value = 5.83 × 10−4), and rs5877 in SERPINC1 (P-value = 1.07 × 10−3), and the genes CAPZA2 (P-value = 4.03 × 10−4) and SERPINC1 (P-value = 1.55 × 10−3). The SNVs in the top-scoring pathway “Factors involved in megakaryocyte development and platelet production” (P-value = 3.34 × 10−4) were used to construct weighted genetic risk score (wGRS) and logistic regression models that predict thrombocytopenia. The wGRS predict which patients are at high or low toxicity risk levels, for CTCAE (odds ratio (OR) = 22.35, P-value = 1.55 × 10−8), and decrease (OR = 66.82, P-value = 5.92 × 10−9). The logistic regression models predict CTCAE grades 3–4 (receiver operator characteristics (ROC) area under the curve (AUC) = 0.79), and large decrease (ROC AUC = 0.86). We identified and validated genetic variations within hematopoiesis-related pathways that provide a solid foundation for future studies using genetic markers for predicting chemotherapy-induced thrombocytopenia and personalizing treatments.
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| 3. |
- Björn, Niclas, et al.
(författare)
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The association of four genetic variants with myelosuppression in gemcitabine-treated Japanese is not evident in gemcitabine/carboplatin-treated Swedes
- 2022
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - : John Wiley & Sons. - 1742-7835 .- 1742-7843. ; 130:4, s. 513-521
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Tidskriftsartikel (refereegranskat)abstract
- Gemcitabine/carboplatin-induced myelosuppressive adverse drug reactions (ADRs) are clinical problems leading to patient suffering and dose alterations. There is a need for personalised medicine to improve treatment effects and patients' well-being. We tested four genetic variants, rs11141915, rs1901440, rs12046844 and rs11719165, previously suggested as potential biomarkers for gemcitabine-induced leukopenia/neutropenia in Japanese patients, in 213 Swedish gemcitabine/carboplatin-treated non-small cell lung cancer (NSCLC) patients. DNA was genotyped using TaqMan probes and real-time PCR. The relationships between the risk alleles and low toxicity (non-ADR: Common Terminology Criteria for Adverse Events [CTCAE] grades 0) or high toxicity (ADR: CTCAE grades 3-4) of platelets, leukocytes and neutrophils were evaluated using Fisher's exact test. The risk alleles did not correlate with myelosuppression, and the strongest borderline significance (not withstanding adjustment for multiple testing) was for rs1901440 (neutropenia, p = 0.043) and rs11719165 (leukopenia, p = 0.049) where the risk alleles trended towards lower toxicity, contrasting with previous study findings. Risk alleles and higher risk scores were more common among our patients. We conclude that the genetic variants do not apply to Swedish patients treated with gemcitabine/carboplatin. However, they can still be important in other populations and cohorts, especially in a gemcitabine monotherapy setting, where the causal genetic variation might influence myelosuppressive ADRs.
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| 4. |
- Björn, Niclas, 1990-, et al.
(författare)
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Whole-genome sequencing and gene network modules predict gemcitabine/carboplatin-induced myelosuppression in non-small cell lung cancer patients
- 2020
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Ingår i: npj Systems Biology and Applications. - : Nature Publishing Group. - 2056-7189. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Gemcitabine/carboplatin chemotherapy commonly induces myelosuppression, including neutropenia, leukopenia, and thrombocytopenia. Predicting patients at risk of these adverse drug reactions (ADRs) and adjusting treatments accordingly is a long-term goal of personalized medicine. This study used whole-genome sequencing (WGS) of blood samples from 96 gemcitabine/carboplatin-treated non-small cell lung cancer (NSCLC) patients and gene network modules for predicting myelosuppression. Association of genetic variants in PLINK found 4594, 5019, and 5066 autosomal SNVs/INDELs with p ≤ 1 × 10−3 for neutropenia, leukopenia, and thrombocytopenia, respectively. Based on the SNVs/INDELs we identified the toxicity module, consisting of 215 unique overlapping genes inferred from MCODE-generated gene network modules of 350, 345, and 313 genes, respectively. These module genes showed enrichment for differentially expressed genes in rat bone marrow, human bone marrow, and human cell lines exposed to carboplatin and gemcitabine (p < 0.05). Then using 80% of the patients as training data, random LASSO reduced the number of SNVs/INDELs in the toxicity module into a feasible prediction model consisting of 62 SNVs/INDELs that accurately predict both the training and the test (remaining 20%) data with high (CTCAE 3–4) and low (CTCAE 0–1) maximal myelosuppressive toxicity completely, with the receiver-operating characteristic (ROC) area under the curve (AUC) of 100%. The present study shows how WGS, gene network modules, and random LASSO can be used to develop a feasible and tested model for predicting myelosuppressive toxicity. Although the proposed model predicts myelosuppression in this study, further evaluation in other studies is required to determine its reproducibility, usability, and clinical effect.
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| 5. |
- Brandén, Eva, et al.
(författare)
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Computer tomography-guided core biopsies in a county hospital in Sweden : Complication rate and diagnostic yield
- 2014
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Ingår i: Annals of Thoracic Medicine. - : Medknow. - 1817-1737 .- 1998-3557. ; 9:3, s. 149-153
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Core biopsies are valuable in obtaining sufficient tissue to ensure diagnosis of diseases in the thorax. OBJECTIVE: To evaluate the complication rate and the diagnostic yield in computer tomography (CT)-guided core biopsies performed in a county hospital in Sweden. METHODS: Medical journals, spirometry results, pathology reports and CT scans were reviewed in 463 consecutive cases, where a transthoracic core biopsy was performed between January 2005 and December 2010. Of these 380 (82%) were lung lesions, 48 (10%) were mediastinal lesions and 35 (8%) were pleural lesions. RESULTS: All patients underwent a chest X-ray 4 hours post-biopsy and pneumothorax was seen in 156/463 (34%) patients: 137 after lung biopsy and 17 after mediastinal biopsy. Chest tube insertion was required for 27 (17%) of these patients (6% of all core biopsies). Small intraparenchymal hemorrhages and hemoptysis were observed with subjective difficulty in one case. The diagnostic yield for the 463 patients was 212 (46%) cases of lung cancer, 188 (41%) benign lesions and 39 (8%) pulmonary metastases. CONCLUSIONS: A transthoracic core biopsy ensures diagnosis with a low complication rate and is suitable as an outpatient procedure. An increased risk for pneumothorax was observed when the biopsied lesion was small or when emphysema was in the path of the biopsy needle. Reduced lung function pre-biopsy or emphysema in the path of the biopsy needle increased the need for chest tube treatment of pneumothorax. A CT-guided core biopsy is safe and applicable in a county hospital.
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| 6. |
- De Petris, Luigi, et al.
(författare)
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Diagnostic and prognostic role of plasma levels of two forms of cytokeratin 18 in patients with non-small-cell lung cancer
- 2011
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 47:1, s. 131-137
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE:Cytokeratin 18 (CK18) can be used as a serum biomarker for carcinoma cell death, whereas caspase-cleaved (ccCK18) fragments reflect tumour apoptosis. We explored the potential diagnostic and prognostic role of circulating CK18 and ccCK18 in patients with non-small-cell lung cancer (NSCLC) in comparison with Cyfra 21.1, a fragment of cytokeratin 19.METHODS:Subject cohorts consisted of 200 healthy blood donors (HBD), 113 patients with benign lung diseases (BLD) and 179 NSCLC cases. Plasma levels of ccCK18, total CK18 and Cyfra 21.1 were determined with ELISA assays.RESULTS:Plasma levels of ccCK18 and total CK18 were higher in the NSCLC group compared to the HBD and BLD cohorts (p<0.0001). Using a cut-off of 104 U/L for ccCK18 and 302 U/L for total CK18 (95% specificity in the HBD group) the diagnostic accuracy of both CK18 forms to distinguish between NSCLC and BLD cases was 56%, whereas it was 94% for Cyfra 21.1. Multivariate survival analysis showed that total CK18 was a stronger prognostic factor than both ccCK18 and Cyfra 21.1 (HR 0.64 for low versus high total CK18 levels, 95% confidence interval (CI) 0.50-0.82; p=0.0004) in the entire NSCLC cohort and in 78 patients with locally advanced or metastatic disease treated with chemoradiotherapy or first-line chemotherapy (HR 0.70 95% CI 0.52-0.94; p=0.018).CONCLUSIONS:Cyfra 21.1 is a useful diagnostic biomarker for NSCLC. Total CK18 shows a promising potential as prognostic marker in NSCLC patients, independently of the therapeutical intervention. In contrast, ccCK18 was not of prognostic value in NSCLC, suggesting that tumour necrosis is of particular importance in this disease.
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| 7. |
- Djureinovic, Dijana, et al.
(författare)
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Profiling cancer testis antigens in non-small-cell lung cancer
- 2016
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Ingår i: JCI INSIGHT. - : American Society for Clinical Investigation. - 2379-3708. ; 1:10
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Tidskriftsartikel (refereegranskat)abstract
- Cancer testis antigens (CTAs) are of clinical interest as biomarkers and present valuable targets for immunotherapy. To comprehensively characterize the CTA landscape of non-small-cell lung cancer (NSCLC), we compared RNAseq data from 199 NSCLC tissues to the normal transcriptome of 142 samples from 32 different normal organs. Of 232 CTAs currently annotated in the Caner Testis Database (CTdatabase), 96 were confirmed in NSCLC. To obtain an unbiased CTA profile of NSCLC, we applied stringent criteria on our RNAseq data set and defined 90 genes as CTAs, of which 55 genes were not annotated in the CTdatabase, thus representing potential new CTAs. Cluster analysis revealed that CTA expression is histology dependent and concurrent expression is common. IHC confirmed tissue-specific protein expression of selected new CTAs (TKTL1, TGIF2LX, VCX, and CXORF67). Furthermore, methylation was identified as a regulatory mechanism of CTA expression based on independent data from The Cancer Genome Atlas. The proposed prognostic impact of CTAs in lung cancer was not confirmed, neither in our RNAseq cohort nor in an independent meta-analysis of 1,117 NSCLC cases. In summary, we defined a set of 90 reliable CTAs, including information on protein expression, methylation, and survival association. The detailed RNAseq catalog can guide biomarker studies and efforts to identify targets for immunotherapeutic strategies.
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| 8. |
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| 9. |
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| 10. |
- Edlund, Karolina, et al.
(författare)
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Prognostic Impact of Tumor Cell Programmed Death Ligand 1 Expression and Immune Cell Infiltration in NSCLC
- 2019
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Ingår i: Journal of Thoracic Oncology. - : Elsevier BV. - 1556-0864 .- 1556-1380. ; 14:4, s. 628-640
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Infiltration of T and B/plasma cells has been linked to NSCLC prognosis, but this has not been thoroughly investigated in relation to the expression of programmed death ligand 1 (PD-L1). Here, we determine the association of lymphocytes and PD-L1 with overall survival (OS) in two retrospective cohorts of operated NSCLC patients who were not treated with checkpoint inhibitors targeting the programmed death 1/PD-L1 axis. Moreover, we evaluate how PD-L1 positivity and clinicopathologic factors affect the prognostic association of lymphocytes.Methods: Cluster of differentiation (CD) 3 (CD3)-, CD8-, CD4-, forkhead box P3 (FOXP3)-, CD20-, CD79A-, and immunoglobulin kappa constant (IGKC)-positive immune cells, and tumor PD-L1 positivity, were determined by immunohistochemistry on tissue microarrays (n = 705). Affymetrix data was analyzed for a patient subset, and supplemented with publicly available transcriptomics data (N = 1724). Associations with OS were assessed by Kaplan-Meier plots and uni- and multivariate Cox regression.Results: Higher levels of T and B plasma cells were associated with longer OS (p = 0.004 and p < 0.001, for CD8 and IGKC, respectively). Highly proliferative tumors with few lymphocytes had the worst outcome. No association of PD-L1 positivity with OS was observed in a nonstratified patient population; however, a significant association with shorter OS was observed in never-smokers (p = 0.009 and p = 0.002, 5% and 50% cutoff). Lymphocyte infiltration was not associated with OS in PD-L1–positive tumors (50% cutoff). The prognostic association of lymphocyte infiltration also depended on the patients’ smoking history and histologic subtype.Conclusions: Proliferation, PD-L1 status, smoking history, and histology should be considered if lymphocyte infiltration is to be used as a prognostic biomarker.
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| 11. |
- Elmongy, Hatem, et al.
(författare)
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Online post-column solvent assisted and direct solvent-assisted electrospray ionization for chiral analysis of propranolol enantiomers in plasma samples
- 2015
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Ingår i: Journal of Chromatography A. - : Elsevier BV. - 0021-9673 .- 1873-3778. ; 1418, s. 110-118
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Tidskriftsartikel (refereegranskat)abstract
- An Online post-column solvent-assisted ionization (OPSAI) method was developed for enhancing the ionization of the beta-blocker propranolol utilizing normal phase LC-MS/MS. Solvent-assisted electrospray ionization (SAESI) was studied by the introduction of the assistant solvents A: 0.5% Formic acid in Isopropanolol, B: 0.5% Formic acid in lsopropanolol-Water (1:1), and C: 0.5% Formic acid in water into the electrospray ionization chamber using a spray needle. Analyte molecules can be directly ionized by the aid of the assistant solvent spray. Both methods were applied to the chiral separation of propranolol enantiomers using normal phase analysis on cellulose-based chiral column. Interestingly, both methods are easy to handle and offer a wide range of assistant solvents that can be used in order to gain the optimum ionization of the analyte molecules. The both methods considerably improved the analyte signal and the peak area greatly increased. The propranolol average signal-to-noise (S/N) ratio was enhanced from 26 +/- 1 and 42 +/- 1 to 2341 +/- 61 and 1725 +/- 29 for R-propranolol and S-propranolol, respectively, when the post-column solvent method (OPSAI) was used with isopropanol-assistant solvent (A). While in case of solvent-assisted electrospray ionization method (SAESI) signal was enhanced from 26 +/- 1 and 42 +/- 1 to 2223 +/- 72 and 2155 +/- 58 for R-propranolol and S-propranolol, respectively, with water as an assistant solvent. The limit of detection was 10 ng/mL and the method was linear in the range 50-2000 ng/mL. The NPLC-MS method was applied for the determination of propranolol enantiomers in human plasma after microextraction by packed C18 sorbent.
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| 12. |
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| 13. |
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| 14. |
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| 15. |
- Gonzalez Lindh, Margareta, 1965-, et al.
(författare)
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Prevalence of swallowing dysfunction screened in Swedish cohort of COPD patients
- 2017
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Ingår i: The International Journal of Chronic Obstructive Pulmonary Disease. - 1176-9106 .- 1178-2005. ; 12, s. 331-337
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Tidskriftsartikel (refereegranskat)abstract
- Background: COPD is a common problem associated with morbidity and mortality. COPD may also affect the dynamics and coordination of functions such as swallowing. A misdirected swallow may, in turn, result in the bolus entering the airway. A growing body of evidence suggests that a subgroup of people with COPD is prone to oropharyngeal dysphagia. The aim of this study was to evaluate swallowing dysfunction in patients with stable COPD and to determine the relation between signs and symptoms of swallowing dysfunction and lung function (forced expiratory volume in 1 second percent predicted). Methods: Fifty-one patients with COPD in a stable phase participated in a questionnaire survey, swallowing tests, and spirometry. A post-bronchodilator ratio of the forced expiratory volume in 1 second/best of forced vital capacity and vital capacity,0.7 was used to define COPD. Swallowing function was assessed by a questionnaire and two swallowing tests (water and cookie swallow tests). Results: Sixty-five percent of the patients reported subjective signs and symptoms of swallowing dysfunction in the questionnaire and 49% showed measurable ones in the swallowing tests. For the combined subjective and objective findings, 78% had a coexisting swallowing dysfunction. No significant difference was found between male and female patients. Conclusion: Swallowing function is affected in COPD patients with moderate to severe airflow limitation, and the signs and symptoms of this swallowing dysfunction were subjective, objective, or both.
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| 16. |
- Gonzalez Lindh, Margareta, 1965-, et al.
(författare)
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Subjective swallowing symptoms and related risk factors in COPD
- 2019
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Ingår i: ERJ Open Research. - : European Respiratory Society. - 2312-0541. ; 5:3
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: This study aimed to investigate the prevalence of subjective (i.e. self-reported) swallowing symptoms in a large cohort of patients with stable chronic obstructive pulmonary disease (COPD) and to identify potential related risk factors.Methods: A total of 571 patients with COPD, investigated in a stable phase, participated in this multicentre study (335 females, 236 males; mean age: 68.6 years (sd 7.7)). Data were derived from spirometry, a questionnaire and a 30-metre walking test.Results: In total, 33% (n=186) patients reported at least some degree of swallowing problem. The most frequently reported symptom was food lodging in the throat (23%). A significant relationship was found between swallowing symptoms and dyspnoea, assessed as modified Medical Research Council (mMRC) ≥2 compared with <2 (46% versus 22%; p<0.001) and health-related quality of life, assessed as the COPD Assessment Test (CAT) ≥10 (40% versus 19%; p<0.001). Swallowing problems were also related to lower physical capacity (p=0.02) but not to lung function (p>0.28).Conclusion: Subjective swallowing symptoms seem to be a common problem in patients with stable COPD. This problem is seen in all stages of the disease, but is more common in symptomatic patients and in patients with lower physical capacity.
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| 17. |
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| 18. |
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| 19. |
- Gonzalez Lindh, Margareta, 1965-, et al.
(författare)
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Swallowing dysfunction in patients hospitalised due to a COPD exacerbation
- 2021
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Ingår i: ERJ Open Research. - : European Respiratory Society. - 2312-0541. ; 7:2, s. 00173-2021-
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: This cross-sectional study aimed to investigate the prevalence of self-reported and clinically screened swallowing dysfunction (dysphagia) in COPD patients with severe exacerbations and to identify any associated factors. Findings were then compared to a control group.Methods: Participants included 30 patients hospitalised due to a COPD exacerbation. The control group consisted of 30 adults hospitalised with acute cardiac symptoms. Data were derived from spirometry, the 150 mL timed water swallow test, a cookie swallow test and a dyspnoea questionnaire (modified Medical Research Council (mMRC)). Scores from the 10-item Eating Assessment Tool (EAT-10) were calculated to assess patient perception of swallowing dysfunction.Results: Self-reported swallowing dysfunction and clinical signs thereof were more common in COPD patients than in the control group (67% versus 23% and 80% versus 37%, respectively; p <= 0.001). Clinical signs of swallowing dysfunction in the group with acute exacerbation of COPD were associated with self-reported swallowing dysfunction (p=0.02) and xerostomia (p=0.04). Dyspnoea (mMRC >= 2) was more common among the COPD patients (90% versus 47%, p<0.001). There was a significant negative correlation between lung function and self-reported dysphagia (r=-0.39, p=0.03), but not between lung function and clinically screened dysphagia (r=-0.23, p=0.21).Conclusion: COPD patients hospitalised with an acute exacerbation experienced significantly more self-reported and clinically screened swallowing dysfunction compared to a control group of patients with cardiac symptoms. Both patient groups experienced dyspnoea, but it was twice as common in the group with acute exacerbation of COPD. Both groups also experienced xerostomia.
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| 20. |
- Gonzalez Lindh, Margareta, 1965-
(författare)
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Swallowing Dysfunction in Respiratory Diseases : Prevalence and risk factors in COPD and COVID-19
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Objective: Swallowing dysfunction, dysphagia, is a common, sometimes dangerous, and often neglected problem that affects many people. The prevalence is estimated to be approximately 8% in the general population which makes it as common as e.g. diabetes or asthma. Dysphagia can cause serious complications like malnutrition, aspiration pneumonia and even death. The aims of this thesis were to gain further knowledge and a broader understanding of the prevalence, characteristics and risk factors of swallowing dysfunction in patients with respiratory diseases. Specifically Chronic Obstructive Pulmonary Disease, COPD, and COVID-19 after invasive mechanical ventilation.Study I is a prospective explorative study of 51 COPD patients in stable phase. Swallowing function was evaluated through a questionnaire and through two swallowing tests (water and a cookie) and lung function was measured through a spirometry. The prevalence of self- reported swallowing dysfunction was 65% and the screened prevalence was 49%. There was a negative correlation between lung function and both measurements of swallowing function, i.e. the poorer the lung function the more dysphagia symptoms.Study II is a cross-sectional multi-centre study where we examined the prevalence of self-reported swallowing dysfunction in 571 COPD patients. Additional tests were: spirometry, physical capacity, mMRC and CAT. Subjective swallowing symptoms were found in 33% of the patients. More prevalent in symptomatic patients and patients with lower physical capacity. A high score on the mMRC or CAT and a classification in GOLD groups B and D may be predictive of a swallowing dysfunction and should be addressed by the COPD nurse or physician.Study III is a cross-sectional study of 30 COPD patients hospitalized with a severe exacerbation. Their swallowing function was compared to a control group. The main results of this study were that the prevalence of swallowing dysfunction, both patient-reported and screened in patients hospitalised with a COPD exacerbation, was high. In addition, the AECOPD group was almost three times more likely to suffer from self-reported dysphagia compared to the control group.Study IV is a longitudinal cohort study of swallowing function in 28 COVID-19 patients post invasive mechanical ventilation. Dysphagia was found in 71% of the patients at baseline and it was associated with number of days in the hospital and in the ICU. At discharge from the hospital swallowing function and tolerance of oral intake had improved significantly.Conclusion: Swallowing dysfunction is prevalent both in COPD and in COVID-19 patients post invasive mechanical ventilation.
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| 21. |
- Gonzalez Lindh, Margareta, 1965-, et al.
(författare)
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Swallowing function in COVID-19 patients after invasive mechanical ventilation
- 2022
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Ingår i: Archives of Rehabilitation Research and Clinical Translation. - : Elsevier. - 2590-1095. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To explore swallowing function and risk factors associated with delayed recovery of swallowing in patients with COVID-19 post–invasive mechanical ventilation using the Functional Oral Intake Scale (FOIS).Design: Longitudinal cohort study.Setting: Three secondary-level hospitals.Participants: Invasively ventilated patients (N=28) who were hospitalized with severe COVID-19 and referred to the hospitals’ speech and language pathology (SLP) departments after mechanical ventilation between March 5 and July 5, 2020 for an evaluation of swallowing function before commencing oral diet.Interventions: SLP assessment, advice, and therapy for dysphagia.Main Outcome Measures: Oral intake levels at baseline and hospital discharge according to the FOIS. Patients were stratified according to FOIS (1-5, dysphagia; 6-7, functional oral intake). Data regarding comorbidities, frailty, intubation and tracheostomy, proning, and SLP evaluation were collected.Results: Dysphagia was found in 71% of the patients at baseline (79% men; age, 61±12y; body mass index, 30±8 kg/m2). The median FOIS score at baseline was 2 (interquartile range [IQR], 1) vs 5 (IQR, 2.5) at hospital discharge. Patients with dysphagia were older (64±8.5y vs 53±16y; P=.019), had a higher incidence of hypertension (70% vs 12%; P=.006), and were ventilated invasively longer (16±7d vs 10±2d; P=.017) or had a tracheostomy (9±9d vs 1±2d; P=.03) longer. A negative association was found between swallowing dysfunction at bedside and days hospitalized (r=–0.471, P=.01), and number of days in the intensive care unit (ICU) (r=–0.48, P=.01).Conclusion: Dysphagia is prevalent in COVID-19 patients after invasive mechanical ventilation and is associated with number of days in hospital and number of days in the ICU. Swallowing function and tolerance of oral diet improved at discharge (P<.001).
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| 22. |
- Green, Henrik, et al.
(författare)
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Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities
- 2016
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Ingår i: Clinical Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 1078-0432 .- 1557-3265. ; 22:2, s. 366-373
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Chemotherapies are associated with significant interindividual variability in therapeutic effect and adverse drug reactions. In lung cancer, the use of gemcitabine and carboplatin induces grade 3 or 4 myelosuppression in about a quarter of the patients, while an equal fraction of patients is basically unaffected in terms of myelosuppressive side effects. We therefore set out to identify genetic markers for gemcitabine/carboplatin-induced myelosuppression. Experimental Design: We exome sequenced 32 patients that suffered extremely high neutropenia and thrombocytopenia (grade 3 or 4 after first chemotherapy cycle) or were virtually unaffected (grade 0 or 1). The genetic differences/polymorphism between the groups were compared using six different bioinformatics strategies: (i) whole-exome nonsynonymous single-nucleotide variants association analysis, (ii) deviation from Hardy-Weinberg equilibrium, (iii) analysis of genes selected by a priori biologic knowledge, (iv) analysis of genes selected from gene expression meta-analysis of toxicity datasets, (v) Ingenuity Pathway Analysis, and (vi) FunCoup network enrichment analysis. Results: A total of 53 genetic variants that differed among these groups were validated in an additional 291 patients and were correlated to the patients myelosuppression. In the validation, we identified rs1453542 in OR4D6 (P = 0.0008; OR, 5.2; 95% CI, 1.8-18) as a marker for gemcitabine/carboplatin-induced neutropenia and rs5925720 in DDX53 (P = 0.0015; OR, 0.36; 95% CI, 0.17-0.71) as a marker for thrombocytopenia. Patients homozygous for the minor allele of rs1453542 had a higher risk of neutropenia, and for rs5925720 the minor allele was associated with a lower risk for thrombocytopenia. Conclusions: We have identified two new genetic markers with the potential to predict myelosuppression induced by gemcitabine/ carboplatin chemotherapy. (C)2015 AACR.
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| 23. |
- Grinberg, Marianna, et al.
(författare)
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Reaching the limits of prognostication in non-small cell lung cancer : an optimized biomarker panel fails to outperform clinical parameters.
- 2017
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Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952 .- 1530-0285. ; 30:7, s. 964-977
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Tidskriftsartikel (refereegranskat)abstract
- Numerous protein biomarkers have been analyzed to improve prognostication in non-small cell lung cancer, but have not yet demonstrated sufficient value to be introduced into clinical practice. Here, we aimed to develop and validate a prognostic model for surgically resected non-small cell lung cancer. A biomarker panel was selected based on (1) prognostic association in published literature, (2) prognostic association in gene expression data sets, (3) availability of reliable antibodies, and (4) representation of diverse biological processes. The five selected proteins (MKI67, EZH2, SLC2A1, CADM1, and NKX2-1 alias TTF1) were analyzed by immunohistochemistry on tissue microarrays including tissue from 326 non-small cell lung cancer patients. One score was obtained for each tumor and each protein. The scores were combined, with or without the inclusion of clinical parameters, and the best prognostic model was defined according to the corresponding concordance index (C-index). The best-performing model was subsequently validated in an independent cohort consisting of tissue from 345 non-small cell lung cancer patients. The model based only on protein expression did not perform better compared to clinicopathological parameters, whereas combining protein expression with clinicopathological data resulted in a slightly better prognostic performance (C-index: all non-small cell lung cancer 0.63 vs 0.64; adenocarcinoma: 0.66 vs 0.70, squamous cell carcinoma: 0.57 vs 0.56). However, this modest effect did not translate into a significantly improved accuracy of survival prediction. The combination of a prognostic biomarker panel with clinicopathological parameters did not improve survival prediction in non-small cell lung cancer, questioning the potential of immunohistochemistry-based assessment of protein biomarkers for prognostication in clinical practice.Modern Pathology advance online publication, 10 March 2017; doi:10.1038/modpathol.2017.14.
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| 24. |
- Hasmats, Johanna, et al.
(författare)
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Using whole exome sequencing to identify genetic candidates for carboplatin and gemcitabine induced toxicities
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Chemotherapies are associated with significant inter-individual variability in therapeutic effect and adverse drug reactions. In lung cancer the use of gemcitabine and carboplatin induces grade 3-4 myelosuppression in about ¼ of the patients while an equal fraction of patients are basically unaffected in terms of myelosuppressive side effects. We therefore set out to try to identify genetic markers for gemcitabine / carboplatin induced myelosuppression. We selected 32 patients that suffered extremely high neutropenia and thrombocytopenia (grade 3 or 4 after first chemotherapy cycle) or were virtually unaffected (grade 0-1 after the first chemotherapy cycle) by the chemotherapy out of 243 lung cancer patients treated with gemcitabine / carboplatin. These patients were exome sequenced and their genetic differences compared using six different bioinformatic strategies; whole exome non-synonymous SNV association analysis, deviation from Hardy-Weinberg equilibrium, analysis of genes selected by a priori biological knowledge, analysis of genes selected from gene expression meta-analysis of toxicity data sets, Ingenuity pathway analysis and FunCoup network enrichment analysis. All patients were successfully sequenced and 5000-7000 non-synonymous single nucleotide variants were identified in each patient. PI3 (elastase specific inhibitor in neutrophils) showed the strongest association in the single SNV analysis (nominal p=0.0005). Further, variants within IL37, an inhibitor of the innate immune system, and CSAG1, a tumor antigen, differed among the two patient groups and appeared among the top hits in several of the performed analysis, indicating that the approach identifies genetic variants associated with the immune system and tumor differentiation, which might be important for the sensitivity to chemotherapeutic agents. However, the associations reported here are in a need of replication before clinical interpretations can be made.
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| 25. |
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| 26. |
- Hillerdal, Gunnar, et al.
(författare)
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Intrabronchial stents in heterogenous emphysema : a highly selected material followed 5 years
- 2020
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Ingår i: Journal of Thoracic Disease. - : AME Publishing Company. - 2072-1439 .- 2077-6624. ; 12:7, s. 3524-3528
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Tidskriftsartikel (refereegranskat)abstract
- Background: Endobronchial lung volume reduction (EBVR) with one-way valves introduced into the most diseased lobe of the lung is a non-invasive method to improve lung function in patients with severe heterogenous emphysema. The problem is to select the right patients for the procedure. Furthermore, the long-term effects have not been reported in most studies.Methods: EBVR was performed in 35 patients with severely handicapping emphysema and with one radiologically clearly enlarged (at least 125%) target lung lobe and clearly visible and complete interlobar fissures on CT. Most of the successful survivors have then been followed for five years.Results: Five (14%) were primary failures (defined as less than 15% increase of FEV1sec) and 10 (28%) were secondary failures (the valves were coughed up or removed for some reason). In the 21 successful 1 patients, the improvement of FEV1sec was in the mean 59%. Over the years, FEV1sec gradually decreased but was still higher 5 years later than initially. Of the successful group, 76% were still alive after 5 years, while only 50% were in the refused or failed groups.Conclusions: With careful selection of patients remarkably good results in lung function can be achieved, and these improvements will last for years though slowly decrease. In addition, the results indicate an improvement in survival with successful EBVR procedure.
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| 27. |
- Holgersson, Georg, et al.
(författare)
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A phase I pilot study of the insulin-like growth factor 1 receptor pathway modulator AXL1717 in combination with gemcitabine HCl and carboplatin in previously untreated, locally advanced, or metastatic non-small cell lung cancer
- 2015
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Ingår i: Medical Oncology. - : Springer Science and Business Media LLC. - 1357-0560 .- 1559-131X. ; 32:4
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Tidskriftsartikel (refereegranskat)abstract
- AXL1717 is an orally bioavailable IGF-1R pathway modulator that has been shown to have anti-tumoral effects. The objectives of the present study were to define maximum tolerated dose and the recommended phase II dose (RPTD) of AXL1717 in combination with gemcitabine HCl and carboplatin in non-small cell lung cancer (NSCLC). Patients with previously untreated, locally advanced, or metastatic NSCLC (squamous cell cancer or adenocarcinoma) in good performance status and with preserved major organ functions were enrolled in the study. The study was an open-label phase I study with planned cohorts of three patients per dose level of AXL1717 (215, 290, and 390 mg BID). In total, 12 patients were enrolled in the study, and of these, two were prematurely excluded. AXL1717 was administered at one dose level, 215 mg BID. A total number of 81 unique adverse events were reported. Bone marrow toxicity was reported in 10 out of 12 patients, and this organ class showed the largest number of related events. AXL1717 in combination with gemcitabine HCl and carboplatin is a possible treatment approach in previously untreated, locally advanced, or metastatic non-small cell lung cancer. However, due to the bone marrow toxicity profile shown in the present study, further dose increases of AXL1717 above 215 mg BID will probably not be feasible. Therefore, 215 mg BID constitutes maximum tolerated dose and RPTD.
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| 28. |
- Holgersson, Georg, et al.
(författare)
-
[In Process Citation].
- 2015
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Ingår i: Läkartidningen. - 0023-7205 .- 1652-7518. ; 112
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Tidskriftsartikel (refereegranskat)abstract
- The work-up process for lung cancer patients consists of several steps from suspicion of malignant disease to start of treatment. Delays between these steps should be minimized. Data in the Swedish National Lung Cancer Register show that the work-up times for lung cancer patients vary greatly between different counties in central Sweden. In order to reduce delays, a trial of implementing patient guides (Sw: patientlotsar) for patients referred to the hospital was conducted. When comparing the work-up times before and after implementation of patient guides the median waiting time from suspicion of lung cancer to start of treatment in the region was reduced from 71 to 45 days. Furthermore, the duration of most of the steps in the work-up process were shortened despite more complex investigation procedures, e.g. increased use of PET/CT in the guided patient group.
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| 29. |
- Iadaresta, Francesco, et al.
(författare)
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Application of graphitic sorbent for online microextraction of drugs in human plasma samples
- 2015
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Ingår i: Journal of Chromatography A. - : Elsevier BV. - 0021-9673 .- 1873-3778. ; 1422, s. 34-42
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Tidskriftsartikel (refereegranskat)abstract
- In the present work a new sorbent based on graphitized carbon (CarbonX (R) COA) was evaluated in microextraction by packed sorbent (MEPS) for extraction of lidocaine and ropivacaine from human plasma samples. The new graphitic sorbent showed high recoveries of lidocaine and ropivacaine compared to C18 sorbent In the present study the G-MEPS (syringe packed with graphitic sorbent) was connect online with liquid chromatography tandem mass spectrometry (LC-MS/MS). In order to obtain a fast and reliable method different factors affecting MEPS performance were investigated. The extraction efficiency of the graphitic sorbent was compared with silica-based sorbents used in MEPS. The G-MEPS was also evaluated for reuse (50-100 times). The recoveries of lidocaine and ropivacaine from plasma samples were 79% and 82%; respectively. The method was validated according to FDA (Food and Drug Administration) guideline for bioanalytical method validation. Linearity was assessed in the range 5-2000 nmol/L, with coefficient of determination r(2) > 0,995 (n=3) for lidocaine and r(2) > 0.997 (n=3) for ropivacaine. The lower limit of quantification (LLOQ) was 5 nmol/L and the limit of detection (LOD) was 1 nmol/L for studied analytes in plasma samples. For both analytes considered in this study the accuracy values in plasma samples were ranged from 86% to 113%. The Inter-day precisions, expressed as relative standard deviation (%RSD), at three different concentrations (QC-samples) ranged from 8% to 9% for lidocaine, and from 4% to 11% for ropivacaine.
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| 30. |
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| 31. |
- Isaksson, Johan, et al.
(författare)
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Highly elevated systemic inflammation is a strong independent predictor of early mortality in advanced non-small cell lung cancer
- 2022
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Ingår i: Cancer Treatment and Research Communications. - : Elsevier. - 2468-2942. ; 31
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAmple evidence support inflammation as a marker of outcome in non-small cell lung cancer (NSCLC). Here we explore the outcome for a subgroup of patients with advanced disease and substantially elevated systemic inflammatory activity.MethodsThe source cohort included consecutive patients diagnosed with NSCLC between January 2016 – May 2017 (n = 155). Patients with active infection were excluded. Blood parameters were examined individually, and cut-offs (ESR > 60 mm, CRP > 20 mg/L, WBC > 10 × 109, PLT > 400 × 109) were set to define the group of hyperinflamed patients. A score was developed by assigning one point for each parameter above cut-off (0–4 points).ResultsHigh systemic inflammation was associated with advanced stage and was seldom present in limited NSCLC. However, the one year survival of patients in stage IIIB-IV (n = 93) with an inflammation score of ≥2 was 0% compared to 33% and 50% among patients with a score of 1 and 0 respectively. The effect of a high inflammation score on overall survival remained significant in multi-variate analysis adjusted for confounding factors. The independent hazard ratio of an inflammation score ≥ 2 in multi-variate analysis (HR 3.43, CI 1.76–6.71) was comparable to a change in ECOG PS from 0 to 2 (HR 2.42, CI 1.13–5.18).ConclusionOur results show that high level systemic inflammation is a strong independent predictor of poor survival in advanced stage NSCLC. This observation may indicate a need to use hyperinflammation as an additional clinical parameter for stratification of patients in clinical studies and warrants further research on underlying mechanisms linked to tumor progression.
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| 32. |
- Isaksson, Johan
(författare)
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The Molecular Epidemiology of Non-Small Cell Lung Cancer
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to explore the role of a spectrum of biomarkers, for disease classification or predictors of treatment outcomes in non-small cell lung cancer (NSCLC).Paper I examined the impact of systemic inflammation on the clinical outcome of NSCLC patients.Paper II evaluated if plasma protein markers are able to predict immunotherapy response and if they are associated with patient survival. Paper III examined outcomes and relapse patterns in NSCLC patients treated with chemoradiotherapy with curative intent.In Paper IV we identified patients with tumors harboring a KRAS G12C mutation and determined the clinical characteristics in comparison to patients with other KRAS mutations and without KRAS mutations. Results in Paper I showed that systemic inflammation is pronounced in NSCLC and has a substantial effect on overall survival in advanced stage NSCLC. In Paper III, inflammation was linked to worse overall survival in patients treated with curative chemoradiotherapy and mOS was drastically higher in patients without signs of systemic inflammation. Moreover, in Paper II, we used a multiplex proteomic assay to investigate expression levels of various proteins involved in immune cell activation and could show an association between T-cell activation markers and response to immunotherapy.In Paper III, relapse patterns were influenced by the presence of driver mutation alterations. This indicates that fundamental biological mechanisms behind local relapse and metastatic dissemination are regulated by early mutational events such as classical lung adenocarcinoma driver mutations. Likewise, in Paper IV, unlike other KRAS variants, patients with the specific KRAS G12C mutation subtype had a large fraction of CNS metastasis at diagnosis, normally with the CNS as the only metastatic site. These findings indicate a need for CNS monitoring as a routine in curative treatment settings and suggests that KRAS G12C patients should be evaluated with CT-scans of the brain during initial diagnostic procedures.In conclusion, available but underutilized parameters from routine diagnostics have prognostic utility and impact on patient stratification. These biomarkers provide guidance for the evaluation of treatment efficacy and disease monitoring and deserve more attention during diagnostic work-up of lung cancer patients. However, the mechanics behind this impact is less well understood and offers avenues for further research.
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| 33. |
- Karlsson, Anna, et al.
(författare)
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A combined gene expression tool for parallel histological prediction and gene fusion detection in non-small cell lung cancer
- 2019
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 9
-
Tidskriftsartikel (refereegranskat)abstract
- Accurate histological classification and identification of fusion genes represent two cornerstones of clinical diagnostics in non-small cell lung cancer (NSCLC). Here, we present a NanoString gene expression platform and a novel platform-independent, single sample predictor (SSP) of NSCLC histology for combined, simultaneous, histological classification and fusion gene detection in minimal formalin fixed paraffin embedded (FFPE) tissue. The SSP was developed in 68 NSCLC tumors of adenocarcinoma (AC), squamous cell carcinoma (SqCC) and large-cell neuroendocrine carcinoma (LCNEC) histology, based on NanoString expression of 11 (CHGA, SYP, CD56, SFTPG, NAPSA, TTF-1, TP73L, KRT6A, KRT5, KRT40, KRT16) relevant genes for IHC-based NSCLC histology classification. The SSP was combined with a gene fusion detection module (analyzing ALK, RET, ROS1, MET, NRG1, and NTRK1) into a multicomponent NanoString assay. The histological SSP was validated in six cohorts varying in size (n = 11-199), tissue origin (early or advanced disease), histological composition (including undifferentiated cancer), and gene expression platform. Fusion gene detection revealed five EML4-ALK fusions, four KIF5B-RET fusions, two CD74-NRG1 fusion and three MET exon 14 skipping events among 131 tested cases. The histological SSP was successfully trained and tested in the development cohort (mean AUC = 0.96 in iterated test sets). The SSP proved successful in predicting histology of NSCLC tumors of well-defined subgroups and difficult undifferentiated morphology irrespective of gene expression data platform. Discrepancies between gene expression prediction and histologic diagnosis included cases with mixed histologies, true large cell carcinomas, or poorly differentiated adenocarcinomas with mucin expression. In summary, we present a proof-of-concept multicomponent assay for parallel histological classification and multiplexed fusion gene detection in archival tissue, including a novel platform-independent histological SSP classifier. The assay and SSP could serve as a promising complement in the routine evaluation of diagnostic lung cancer biopsies.
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| 34. |
- Koyi, Hirsh, et al.
(författare)
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A prospective study of a total material of lung cancer from a county in Sweden 1997-1999 : gender, symptoms, type, stage and smoking habits
- 2002
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Ingår i: Lung Cancer. - 0169-5002 .- 1872-8332. ; 36:1, s. 9-14
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Recension (övrigt vetenskapligt/konstnärligt)abstract
- The epidemiology of lung cancer is changing in many parts of the world. In the industrialized countries, there is a trend that the incidence in men is declining, while it is increasing for women. Also, adenocarcinomas are becoming relatively more common, especially among men. The purpose of this study was to investigate whether such trends also occur in Sweden and also to describe other aspects of an unselected lung cancer material today, such as symptoms, stage and smoking habits. In the county of Gaevleborg, Sweden, practically all patients with lung cancer are referred to the lung department, and thus a total material of lung cancer patients with only a minimal selection bias can be studied. All patients with lung cancer in the county from January 1, 1997 to December 31, 1999, were investigated prospectively regarding stage, type of cancer, and symptoms. In all, there were 364 patients, 237 (65.1%) men and 127 (34.9%) women. The mean age for men was 69.8 and for women, 68.1 years. 91.9% of the men and 78.6% of the women were smokers or ex-smokers. In general the men were heavier smokers than were the women (P<0.0001). Adenocarcinoma was the most common subtype found in women and squamous cell carcinoma in men. The excess of adenocarcinoma in women was due to never-smoking women; for smoking and ex-smoking men and women, the proportion of adenocarcinomas was the same. In all, 240 patients (68.0%) were diagnosed at Stage IIIb (27.2%) or IV (40.8%), with no significant differences between the sexes. The most common first symptom was cough. Only 7.0% of patients were asymptomatic. In conclusion, the trend of an increasing proportion of adenocarcinoma in lung cancer is seen also in Sweden. A depressingly high percentage of patients present in late stages and are thus inoperable.
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| 35. |
- Koyi, Hirsh, et al.
(författare)
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Biopsy testing in an inoperable, non-small cell lung cancer population : a retrospective, real-life study in Sweden
- 2015
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Ingår i: Journal of Thoracic Disease. - 2072-1439 .- 2077-6624. ; 7:12, s. 2226-2233
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Tidskriftsartikel (refereegranskat)abstract
- Background: Correct diagnosis and staging are required for optimal treatment choice in lung cancer patients. This retrospective, patient medical records study investigated the clinical practice of lung cancer biopsy procedures and testing in Sweden. Methods: Consecutive patients with a recorded inoperable, malignant tumour of bronchus and lung were retrospectively identified at geographically widespread pulmonology clinics (NCT01139619). Data, including diagnostic sampling methodology [bronchoscopy, biopsy by pulmonologist and computed tomography (CT)-guided biopsy], were collected for patients diagnosed between 1 June 2009-31 May 2010, and analysed using descriptive statistics. A study-predefined algorithm, including six criteria on tumour localization and size, forced expiratory volume in one second (FEV1), blood saturation and risk of bleeding theoretically categorizing patient suitability for CT-guided biopsy, was used. Results: In total, 132 patients (mean age 68 years, 48% women, 61% adenocarcinoma, 86% current/former smokers, 96% performance status <= 2, mean FEV1 volume >= 2 L) were included. The majority were examined by > 1 diagnostic procedure (29% by CT-guided biopsy). Median overall time from first hospital contact to established diagnosis was 12.0 days (10.0 and 28.0 days for bronchoscopy and CT-guided biopsy, respectively). No major differences in lung function, age, performance status or predefined algorithm criteria were noted for patients examined by CT-guided biopsy versus bronchoscopy or biopsy. Complications were reported for 11 patients, including pneumothorax in six patients. Histopathology was used most frequently to diagnose and subtype (70%), although 66% of patients examined solely by bronchoscopy were diagnosed by cytology. For 26.5% of patients, epidermal growth factor receptor (EGFR) mutation testing was recorded. Conclusions: No limitations regarding patient suitability or methodological complications were noted in this real-life, observational study. The CT-guided biopsy is a relatively safe and well-established method, and may need to be utilized further to fulfil current and future demands for faster diagnosis and high quality tissue as new tumour markers and targeted therapies become available.
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| 36. |
- Koyi, Hirsh, et al.
(författare)
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Chemotherapy Treatment of Elderly Patients (≥70 Years) with Non-Small Cell Lung Cancer : A Seven-Year Retrospective Study of Real-Life Clinical Practice at Karolinska University Hospital, Sweden.
- 2015
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Ingår i: Lung cancer international. - : Hindawi Limited. - 2090-3197 .- 2090-3200. ; 2015
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Tidskriftsartikel (refereegranskat)abstract
- An increasing proportion of cancer patients are aged >65 years and many are aged >70 years. Treatment of the elderly with lung cancer has, therefore, become an important issue; so we performed a retrospective study of our patients to demonstrate how elderly patients with NSCLC are treated in real-life, clinical practice. All patients aged ≥70 years with NSCLC at our department were reviewed retrospectively. In total, 1059 patients (50.8% of all NSCLC patients). Of these patients, 243 (22.9%) received chemotherapy, 164 (70.4%) of whom were treated with a platinum doublet using carboplatin. Second- and third-line chemotherapy were given to 31.4% and 13.9% of patients, respectively. Median overall survival was 289 and 320 days for male and female patients, respectively. Patients with performance status (PS) 0 experienced significantly better survival than patients with PS1 or PS 2: 410, 314, and 204 days, respectively. Age was of less importance, with patients aged 70-79 years versus those aged ≥80 years. Treatment of elderly NSCLC patients with chemotherapy is feasible if they have a good PS and appears to prolong survival. In this study, we found no significant differences in survival either between age groups or genders.
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| 37. |
- Koyi, Hirsh, et al.
(författare)
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Co-localisation of Glandular and Squamous Cell Markers in Non-small Cell Lung Cancer
- 2018
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Ingår i: Anticancer Research. - : Anticancer Research USA Inc.. - 0250-7005 .- 1791-7530. ; 38:6, s. 3341-3346
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Accurate classification of lung carcinomas is crucial for selecting appropriate and adequate chemotherapy treatment. In this study, glandular (adenocarcinoma), and squamous cell differentiation were examined in non-small cell lung carcinoma (NSCLC) without obvious light-microscopic signs of squamous and glandular differentiation. Materials and Methods: All lung tumours diagnosed as NSCLC (n=61), without obvious squamous or glandular features, were obtained by bronchial biopsy or core biopsy supported by computed tomography. They were diagnosed during 1996-2009, at the Department of Pathology, Gavle Hospital, Sweden. The tumours were examined immunohistochemically with antibodies against CK5/6, p63 (squamous cell markers) and carcinoembryonic antigen (CEA) (adenocarcinoma cell marker). Double immunostaining (p63/CEA) was also performed on individual tumours. Results: The tumours originated from 36 males and 25 females, aged 54-83 years. Pure squamous cell differentiation (CK5/6 positive only) occurred in 34.4% (n=21) tumours and pure adenocarcinoma cell differentiation (CEA positive only) was present in 14.9% (n=9). Tumours with both squamous and adenocarcinoma features (CK5/6 and CEA positive) were most prevalent (47.5%, n=29). Two tumours (3.3%) were negative with both stains (and also synaptophysin negative). Double immunostaining (p63/CEA) revealed that squamous and adenocarcinoma markers were co-localised in cells in certain tumours. Conclusion: Co-localisation of squamous and adenocarcinoma markers in the same tumour cell suggests that additional analyses for novel biomarkers of specific lung cancer types may subsequently lead to a refined treatment choice for patients with the goal of improving clinical outcomes.
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| 38. |
- Koyi, Hirsh, et al.
(författare)
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Lung cancer among native and foreign-born Swedes : histopathology, treatment, and survival
- 2016
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Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 55:11, s. 1344-1348
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lung cancer (LC) is the leading cause of cancer-related death worldwide, including Sweden. Several studies have shown that socioeconomic status affects the risk, treatment, and survival of LC. Due to immigration after Second World War, foreign-born people constitute 12.5% of the Swedish population. We wanted to investigate if there were any differences in LC management, treatment and survival among the foreign-born Swedes (FBS) compared to the native Swedish population (NatS) in Stockholm.Material and methods: A retrospective analysis of all patients diagnosed with non-small cell lung cancer (NSCLC) at the Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Solna from 1 January 2003 to 31 December 2008 was made. In all, 2041 cases of LC were diagnosed, thereof 1803 with NSCLC. Of these, 211 (11.7%) were FBS.Results: The mean age of NatS and FBS patients was 69.9 years, median 70 (range 26-96) and 66.0 years, median 66 (range 38-94), respectively (p<0.001). In all, 89.8% of NatS and 90.0% of FBS were either smokers or former smokers. Adenocarcinoma was the most common subtype in both groups (NatS 54.7%, FBS 48.3%). In 140 (8.8%) of the NatS and 17 (8.1%) of the FBS the diagnosis was clinical only. There were no significant differences in stage at diagnosis, nor in performance status (PS) or different therapies between the groups. The median overall survival time for the NatS was 272 days and for FBS 328 days, again no significant difference. However, the median overall survival time for female NatS was 318 days and for female FBS 681 days (p=0.002).Conclusion: FBS patients were significantly younger than NatS at diagnosis, and female FBS lived longer than female NatS, but otherwise there were no significant differences between NatS and FBS patients with LC regarding diagnosis, treatment, and survival.
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| 39. |
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| 40. |
- Koyi, Hirsh
(författare)
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Lung cancer in the county of Gaevleborg : epidemiology and importance of infection with Chlamydia pneumoniae
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- At the beginning of the 20th century lung cancer was a rare malignancy. It is in Sweden the second most common cause of cancer death in both men and women. The purpose of the studies was to investigate whether chronic infection with C pneumoniae can contribute to cancer development; to describe a complete material of lung cancer in a geographically limited area; to try to find the "hidden cases", i.e. all those cases which would "normally" never be diagnosed or reported; and to investigate the delays in diagnosis, both from the patient and from the doctors. In the county of GaevIeborg, Sweden, with a population 290 000, practically all cases of lung cancer will be seen by the lung department. Beginning in 1998, meetings with all the general practitioners of the county were organized, asking them to refer all suspected cases of lung carcinoma as early as possible to the lung department, also including those with a dismal prognosis. Study I and II. the aim was to investigate the occurrence of chronic Chlamydia pneumoniae infection in patients with lung cancer. In study 1, sera from 33 women and 64 men were compared to healthy civil servants and a group who underwent coronary angiography. In Study II, 136 men and 74 women with lung cancer were included. Consecutive blood donors and currently smoking or ex-smoking 70-year-olds were used as controls. Blood was obtained and a swab was taken from the posterior part of the retropharyngeal mucosa for detection of C. pneumoniae by PCR. The prevalence of specific C. pneumoniae IgG antibody titer of> 512 was 57 % in male lung cancer patients compared to 27 % in male 70-year-olds and 17 % in male blood donors. The prevalence figures for specific C. pneumoniae IgA antibody titers > 64 were 69 % for lung cancer patients compared to 25 and 20 % for the respective control groups. The difference between patients and controls was highly significant (p < 0.000001). The throat specimens had a low sensitivity. Study III. patient's and doctors' delays in an unselected material of patients with lung cancer were investigated. A questionnaire recorded symptoms and when they first occurred. All dates for visits to doctors and investigations were recorded. The mean delay of the patients was 43 days (median 21) days. The GP delay was a mean of 56 days, median 33, and the specialist doctor's delay was a mean of 33 days (median 9). The time from first symptom until treatment or decision not to treat was in the mean 203 days (median 189). Study IV. is a descriptive analysis of cancer type, stage, symptoms, smoking habits etc. The first symptoms were cough and dyspnea. 60 % were smokers, 27 % ex-smokers. Only 12.8 % had never smoked. Of the men, 91.9 % were smokers or ex-smokers, and of the women, 78.4 %. The difference between the sexes were statistically highly significant (p< 0.0001). Squamous cell carcinoma was seen in 30.4 % of the men but only 19.8 of the women. Adenocarcinoma was seen in one third of the women but only 19 % of the men. 18 % were stage I, 2 % II, 10 % IIIa, 28 % IIIb and 42 % IV. Study V was made to study how big the proportion of all lung cancer patients which "normally" never are diagnosed or reported to official cancer registries is, in other words try to find "the hidden cases of lung cancer". The incidence of lung cancer, as published by the official cancer registries from the County of GaevIeborg and four neighbouring counties from 1985 to 1998, were compared. For the four neighbouring counties there was an average of 86 new cases per year and county prior to 1997 and an average of 96 new cases per year during 1997 and 1998, thus a slight increase (p <0.045). Comparable figures for the county of GaevIeborg were 87 new cases per year prior to 1997 and 124 cases for 1997 and 1998. After 1997 the incidence in the county remained high and in year 2000, 140 new cases were diagnosed. The number of cases in the county of GaevIeborg from 1997 onwards is significantly higher both compared to the number of cases in the four neighbouring counties during the same period of time (p < 0.000) and compared to the number of cases prior to 1997 in the county of GaevIeborg (p < 0.000). Thus, the implementation of the new routines in the county of GaevIeborg in 1997 caused a considerable increase in the incidence of lung cancer. One can thus conclude that around 20 % of all lung cancers were never registered earlier. The figures are probably similar for most Sweden. Conclusions: There is a correlation between antibodies to C. Pneumoniae and lung cancer. There can be a considerable number of patients with lung cancer who are never "normally" diagnosed. Both patients' and doctors' delays are in most instances fairly long. Adenocarcinoma incidence is increasing. A distressingly large proportion of patients is diagnosed in high stages.
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| 41. |
- Koyi, Hirsh, et al.
(författare)
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Non-small Cell Lung Cancer (NSCLC) in Octogenarians in Clinical Practice
- 2016
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Ingår i: Anticancer Research. - : Anticancer Research USA Inc.. - 0250-7005 .- 1791-7530. ; 36:10, s. 5397-5402
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aim: Globally, an increasing proportion of cancer patients are aged >65 years and many are aged >70 years. Treatment of the elderly with lung cancer has, therefore, become an important issue. We performed a retrospective study of our patients to demonstrate how octogenarians with non-small cell lung cancer (NSCLC) are treated in real-life clinical practice. Patients and Methods: This was a retrospective observational study of all elderly (>= 80 years) patients with NSCLC referred to the Department of Respiratory Medicine and Allergy, Karolinska Hospital, Sweden, 2003-2010, and followed until June, 2016. Results: In total, 452 patients, 216 (47.8%) men and 236 (52.2%) women, were included. The mean and median age was 83 years; 28 (6.2%) were aged 90 years or more. Current or former smokers constituted 91.1%, with men having smoked more (p<0.001). There was no difference in performance status (PS) between genders with PS 0-1 in 45.4%, PS 2 in 25.6% and PS3-4 in 29%. About a third each was diagnosed in stages 1-II, III and IV. Adenocarcinoma was most common (45.6%), 18.1% had squamous cell carcinoma, while histological diagnosis was unavailable in 23.2%. Best supportive care (BSC) was given only to 209 patients (46.2%). Potentially curative therapy was administered to 16.5% of men and 20.3% of the women with surgery performed in 35 patients (7.8%) and stereotactic body radiation therapy (SBRT) in 48 patients (10.6%). Chemotherapy was given to 51 patients (11.2%) and palliative radiotherapy to 77 (17.0%). Second-line chemotherapy was given in 4% and third-line in 1.5%. Only one patient received fourth-line. Male patients who received chemotherapy survived a mean of 281 days and for female patients it was 332 days (not significant). Median overall survival (OS) was 115 days in patients receiving BSC and 362 days in patients given any therapy. Patients who underwent surgery for stage I-II had a median OS of 5.6 years compared to 3.5 years for patients given SBRT. Conclusion: Treatment of NSCLC patients 80 years and older with any modality is feasible with a good PS. Survival is fairly good with surgery or SBRT.
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- Koyi, Hirsh, et al.
(författare)
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Refined Diagnosis of Pleural Effusions by Immunocytochemistry of Cell Blocks
- 2023
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Ingår i: Anticancer Research. - : International Institute of Anticancer Research. - 0250-7005 .- 1791-7530. ; 43:2, s. 669-673
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aim: The main objective of microscopic examination of pleural effusions is to ascertain the presence of malignant cells. Effusions prepared routinely using May-Grunwald-Giemsa (MGG)-and Papanicolaou (PAP)-staining can, in a number of cases, provide inconclusive cytological results regarding malignancy.Patients and Methods: This report describes the refined diagnosis of such cases based on immunocytochemical analysis of pleural effusion cell blocks. Of the 340 pleural effusions obtained during 2019 at the Department of Clinical Cytology, Gavle Hospital, Sweden, 63 (18.5%) contained atypical cells of undetermined significance or potentially malignant cells.Results: This diagnosis could be refined using Epithelial Cell Adhesion Molecule/EPCAM (BEREP4) immunocytochemical analysis of effusion cell blocks, allowing previously inconclusive effusions to be classified as clearly benign 42/63 (66.7%) or malignant 21/63 (33.3%). Effusions initially diagnosed as clearly malignant (27/340; 7.9%) were all 27 (100%) BEREP4-immuno-stained. Most BEREP4-positive effusions (37/48; 77.1%) were also carcinoembryonic antigen (CEA) positive. The number of BEREP4-positive cells, however, tended to exceed that of CEA-positive cells. The BEREP4 positive effusions were further examined using different monoclonal antibodies, such as Thyroid transcription factor 1 (TTF-1) for primary pulmonary adenocarcinoma, to determine the original site of the primary tumour.Conclusion: Immunohistochemical staining of pleural effusion cell blocks significantly refines the diagnosis of serous pleural effusions, especially in cases where the preliminary diagnosis was atypical cells of undetermined significance or potentially malignant cells. Furthermore, in the cases of malignancy, the origin of the primary tumour could most often be determined.
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| 45. |
- Koyi, Hirsh, et al.
(författare)
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The 'reservoir' of undetected bronchial carcinomas in the generalpopulation
- 2002
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Ingår i: Lung Cancer. - 0169-5002 .- 1872-8332. ; 37:2, s. 137-142
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Tidskriftsartikel (refereegranskat)abstract
- Study objectives: Autopsy studies have shown that a sizeable portion of lung cancers are never diagnosed and thus not entered into any cancer registry.Design: In 1997, we decided to make all available efforts to find all patients with lung cancer who had not been registered previously.Setting: The local hospitals in the county of Gävleborg, Sweden.Patients: All patients with lung cancer diagnosed in the county from 1997 to 2000.Interventions: In meetings with all the general practitioners of the county, these were asked to refer all suspected cases as early as possible, including those with a seemingly dismal prognosis. This initiative was also covered by the newspapers and the local television station.Measurements and results: From 1997 onwards, the incidence of lung cancer in the county was found to be 40–50 per 100 000 inhabitants compared with an incidence of about 30 during the ten preceding years. This difference is significant in time (P<0.0001) and is compared with the incidence of lung cancers in four neighboring counties (P=0.002). Conclusions: There can be a considerable number of patients with lung cancer who are never diagnosed. This can explain differences in survival between various countries and this will also affect the results of screening programs, since the control groups will also include a number of lung cancer cases which will never be recognized.
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| 48. |
- La Fleur, Linnea, et al.
(författare)
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Expression of scavenger receptor MARCO defines a targetable tumor-associated macrophage subset in non-small cell lung cancer
- 2018
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Ingår i: International Journal of Cancer. - : WILEY. - 0020-7136 .- 1097-0215. ; 143:7, s. 1741-1752
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Tidskriftsartikel (refereegranskat)abstract
- Tumor-associated macrophages (TAMs) are attractive targets for immunotherapy. Recently, studies in animal models showed that treatment with an anti-TAM antibody directed against the scavenger receptor MARCO resulted in suppression of tumor growth and metastatic dissemination. Here we investigated the expression of MARCO in relation to other macrophage markers and immune pathways in a non-small cell lung cancer (NSCLC) cohort (n=352). MARCO, CD68, CD163, MSR1 and programmed death ligand-1 (PD-L1) were analyzed by immunohistochemistry and immunofluorescence, and associations to other immune cells and regulatory pathways were studied in a subset of cases (n=199) with available RNA-seq data. We observed a large variation in macrophage density between cases and a strong correlation between CD68 and CD163, suggesting that the majority of TAMs present in NSCLC exhibit a protumor phenotype. Correlation to clinical data only showed a weak trend toward worse survival for patients with high macrophage infiltration. Interestingly, MARCO was expressed on a distinct subpopulation of TAMs, which tended to aggregate in close proximity to tumor cell nests. On the transcriptomic level, we found a positive association between MARCO gene expression and general immune response pathways including strong links to immunosuppressive TAMs, T-cell infiltration and immune checkpoint molecules. Indeed, a higher macrophage infiltration was seen in tumors expressing PD-L1, and macrophages residing within tumor cell nests co-expressed MARCO and PD-L1. Thus, MARCO is a potential new immune target for anti-TAM treatment in a subset of NSCLC patients, possibly in combination with available immune checkpoint inhibitors.
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| 49. |
- La Fleur, Linnea, et al.
(författare)
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Mutation patterns in a population-based non-small cell lung cancer cohort and prognostic impact of concomitant mutations in KRAS and TP53 or STK11
- 2019
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Ingår i: Lung Cancer. - : Elsevier BV. - 0169-5002 .- 1872-8332. ; 130, s. 50-58
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Non-small cell lung cancer (NSCLC) is a heterogeneous disease with unique combinations of somatic molecular alterations in individual patients, as well as significant differences in populations across the world with regard to mutation spectra and mutation frequencies. Here we aim to describe mutational patterns and linked clinical parameters in a population-based NSCLC cohort.MATERIALS AND METHODS: Using targeted resequencing the mutational status of 82 genes was evaluated in a consecutive Swedish surgical NSCLC cohort, consisting of 352 patient samples from either fresh frozen or formalin fixed paraffin embedded (FFPE) tissues. The panel covers all exons of the 82 genes and utilizes reduced target fragment length and two-strand capture making it compatible with degraded FFPE samples.RESULTS: We obtained a uniform sequencing coverage and mutation load across the fresh frozen and FFPE samples by adaption of sequencing depth and bioinformatic pipeline, thereby avoiding a technical bias between these two sample types. At large, the mutation frequencies resembled the frequencies seen in other western populations, except for a high frequency of KRAS hotspot mutations (43%) in adenocarcinoma patients. Worse overall survival was observed for adenocarcinoma patients with a mutation in either TP53, STK11 or SMARCA4. In the adenocarcinoma KRAS-mutated group poor survival appeared to be linked to concomitant TP53 or STK11 mutations, and not to KRAS mutation as a single aberration. Similar results were seen in the analysis of publicly available data from the cBioPortal. In squamous cell carcinoma a worse prognosis could be observed for patients with MLL2 mutations, while CSMD3 mutations were linked to a better prognosis.CONCLUSION: Here we have evaluated the mutational status of a NSCLC cohort. We could not confirm any survival impact of isolated driver mutations. Instead, concurrent mutations in TP53 and STK11 were shown to confer poor survival in the KRAS-positive adenocarcinoma subgroup.
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