| 1. |
- Tell, Roger, et al.
(författare)
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Multicentre Phase II Trial of Paclitaxel and Carboplatin with Concurrent Radiotherapy in Locally Advanced Non-small Cell Lung Cancer
- 2008
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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 28:5B, s. 2851-2857
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To evaluate weekly, induction chemotherapy followed by weekly concomitant chemoradiotherapy in a multicentre phase II study of patients with wiresectable stage III non-small cell lung cancer (NSCLC; stage wet IIIB excluded). Patients (aid Methods: Eligible patients received three weekly cycles of paclitaxel 100 mg/m(2) and carboplatin AUC2 followed by six weekly cycles of paclitaxel 60 mg/m(2) and carboplatin AUC2 in combination with thoracic radiotherapy (2 Gy per fraction and day to a total (lose of 60 Gy), Results: Sixty-four patients (40 males and 24 females) with a median age of 63 Years (range, 43-79 years) entered the study. T and N stage were distributed as follows: T1 2 patients (3.2%). T2 10 patients (15.6%), T3 15 patients (23.4%). T4 37 patients (57.8%), N0 10 patients (15.6%). N1 1 patient (1.6%), N2 26 patients (40.6%), N3 26 patients (40.6%), and N missing I patient (1.6%). Seven patients (10.9%) suffered from grade 314 oesophagitis. Grade 112 oesophagitis occurred in 36 patients (56.3%) and pneumonitis grade 112 occurred in 10 patients (15.6%). Sixty-three patients were evaluated on an intent-to-treat basis. The overall response rate was 74.6%. The median time to progression was 247 days and median overall survival was 461 days. According to subgroup analyses, no statistically signicant differences were noted according to gender, age (<65 vs. >= 65 years), perfromance status, histology, or study centre. Conclusion: Induction chemotherapy followed by concurrent chemoradiotherapy with weekly cycles of paclitaxel and carboplatin is feasible and generates moderate toxicity. Efficacy is comparable to other recently published regimens. However, prognosis remains, ill general, poor for this group of patients and further work to develop better therapy is required.
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| 2. |
- 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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| 3. |
- 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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| 4. |
- 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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| 5. |
- 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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| 6. |
- Brandén, Eva
(författare)
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A 20-year follow-up of a case with tracheobronchopathia osteochondroplastica
- 2013
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Ingår i: Journal of bronchology & interventional pulmonology. - 1948-8270. ; 20:1, s. 84-86
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Tidskriftsartikel (refereegranskat)abstract
- A 39-year-old woman underwent bronchoscopy because of shortness of breath and audible breathing upon exertion. An advanced tracheobronchopathia osteochondroplastica was diagnosed. Twenty years later, the woman's health status is stable, she has no cough or excessive mucous production, but she does suffer from effort dyspnea. Difficulties may arise if there is need for intubation in patients with tracheobronchopathia osteochondroplastica because of the nodules protruding inward from the cartilage rings.
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| 7. |
- Brandén, Eva
(författare)
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Chronic infection with chlamydia pneumoniae in COPD and lung cancer
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lung cancer and chronic obstructive pulmonary disease (COPD) are major causes of morbidity and mortality throughout the world. Smoking is the main cause for both diseases, but other factors seem to contribute. Chlamydia pneumoniae (Cpn) is an obligate intracellular bacterium with a unique biphasic replicative cycle associated with respiratory infections. The ability to cause chronic infections is characteristic for bacteria of the family Chlamydiacae. Persistent elevated IgA antibodies to Cpn is used as a marker for chronic Cpn infection. The aims of the thesis were to study the prevalence of chronic Cpn infection in patients with lung cancer (I), to study the prevalence of chronic Cpn infection in relation to lung function in patients without lung cancer (II), to study a new treatment regimen in patients with longstanding airway and/or pharyngeal symptoms and chronic Cpn infection (III), and to detect Cpn in cytospin preparations from bronchoalveolar lavage (BAL) fluid and in lung tissue from patients with COPD (IV). In studies I-II we investigated patients who underwent bronchoscopy due to longstanding airway symptoms andlor pathological chest X-rays. Study I: 136 men and 74 women with lung cancer (LC) were included. Currently smoking or ex-smoking consecutively collected blood donors and 70-year olds from a population study were used as control groups. Blood specimens for specific Cpn antibodies were analysed using the micro-immunofluorescence (MIF) technique. The prevalence of Cpn IgG antibody titres of >1/512 was 57% in male LC patients compared to 27% in male 70 year olds and 17% in male blood donors. The prevalence of Cpn lgA antibody titres >1/64 was 69% for male LC patients compared to 25% and 20% for respective control groups. The difference between male patients and controls was statistically significant. For female LC patients a statistically significant difference was found in prevalence only regarding lgA antibodies; 57% compared to 30% and 9% for the control groups. Study II: 199 patients for whom spirometry and paired scrum samples were available were included. Thirty patients fulfilled criteria for COPD. Antibodies in acute and convalescent sera were analysed by MIF. Chronic Cpn infection (defined as stable lgA titre >1/64) was present in 85 patients. lgA titres increased with age in both COPD and non-COPD patients, but were higher in the COPD group independent of age. Chronic infection was associated with smoking and higher age, but no difference was observed between genders. A statistically significant association was observed between chronic Cpn infection and COPD. This remained after correction for smoking. Study III: 103 patients were treated with azithromycin 500 mg daily for five days, repeated 3 times with a 23 days interval, or placebo. Patients were examined 4 months and one year after completed treatment. A general improvement of symptoms and less hawking was found in patients treated with azithromycin compared to placebo after 4 months, but there was no sustained difference one year after completed treatment. The antibody titres remained stable, and there was no influence on lung function. Study IV: Cytospin preparations of BAL fluid from 14 COPD patients, 10 healthy smokers and 7 nonsmokers were studied using a direct immunofluorescence technique for detection of Cpn. Lung tissue from 24 patients with emphysema were tested using immunohistochemistry (MC) for Cpn. Serum samples were available for all patients undergoing BAL and in 11 of the emphysema patients. Elementary body like structures were detected in cytospin slides from 29% of COPD patients, 10% of healthy smokers and 14% of non-smokers. Cpn was detected in lung tissue from 8% of patients with advanced emphysema. COPD patients demonstrated a tendency to have specific Cpn lgA > 1/64 to a larger extent than the control groups, but no correlation was found between detection of Cpn and antibody titres. Conclusions: An association was found between serological signs of chronic Cpn infection and COPD and lung cancer. Cpn was detected in the respiratory tract in a minority of the patients, but there was no correlation between the presence of organisms and antibodies. Azithromycin treatment resulted in transient effect on symptoms, without affecting the antibody titres or lung function.
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| 8. |
- 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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| 9. |
- Brandén Klang, Anders, et al.
(författare)
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Hållbar policy : utvärderingarav transportpolitiska styrmedel
- 2024
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Den här rapporten presenterar en kunskapssammanställning över ex-postutvärderingar av transportpolitiska styrmedel i en svensk kontext sedan de befintliga transportpolitiska målen antogs av riksdagen 2009. Baserat på denna kunskapssammanställning föreslås också några inriktningar för fortsatta analyser. En effektiv policy bör hamna tillräckligt högt utifrån kriterierna effekt, effektivitet och acceptans. För att en effektiv policy ska vara hållbar krävs även att styrmedlet är robust över tid, samtidigt som den är balanserad i relation till proportionalitet och andra politikområden. Att utvärdera styrmedel är viktigt för politikens legitimitet och för att säkerställa att begränsade resurser används på ett sätt som uppnår både effekt och effektivitet. Att genomföra en utvärdering är dock en komplex uppgift, då styrmedel inte låter sig studeras i laboratoriemiljö, utan alltid verkar i ett sammanhang där många andra faktorer också påverkar den utveckling som kan observeras. Med policy avser vi den politiska operationaliseringen som leder till åtgärder som påverkar utvecklingen av ett politikområde.
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| 10. |
- Brandén, Maria, et al.
(författare)
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Does similarity in work-family related attitudes improve relationship quality? Evidence from Sweden
- 2022
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Ingår i: Journal of Family Studies. - : Informa UK Limited. - 1322-9400 .- 1839-3543. ; 28:3, s. 822-840
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Tidskriftsartikel (refereegranskat)abstract
- This study examines how similarity in work-family related attitudes matter for relationship satisfaction and union dissolution among Swedish couples. It utilizes a data set from 2009 (the Young Adult Panel Study) containing information on 1055 opposite-sex couples (married or co-residential), and registered union dissolutions up to 2014. Results indicate that couples who have similar notions on the importance of being successful at work; on the importance of having children; or on the importance of having enough time for leisure activities are more likely to be satisfied with their partner relationship than couples who have dissimilar attitudes. However, there are no effects of similarity in attitudes regarding the importance of living in a good partner relationship or doing well economically on relationship satisfaction, and we do not find any impact of similarity in attitudes of any kind on actual breakups. We find no support for specialization theory, which would predict that dissimilarity in work orientation would increase relationship quality. The study concludes that having similar priorities regarding work, career, and family does seem to matter for relationship quality, at least when it comes to the partners' satisfaction with the relationship.
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| 11. |
- 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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| 12. |
- 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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| 13. |
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| 14. |
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| 15. |
- Drilon, Alexander, et al.
(författare)
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Clinicopathologic Features and Response to Therapy of NRG1 Fusion-Driven Lung Cancers : The eNRGy1 Global Multicenter Registry
- 2021
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Ingår i: Journal of Clinical Oncology. - : LIPPINCOTT WILLIAMS & WILKINS. - 0732-183X .- 1527-7755. ; 39:25, s. 2791-2802
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE Although NRG1 fusions are oncogenic drivers across multiple tumor types including lung cancers, these are difficult to study because of their rarity. The global eNRGy1 registry was thus established to characterize NRG1 fusion-positive lung cancers in the largest and most diverse series to date. METHODS From June 2018 to February 2020, a consortium of 22 centers from nine countries in Europe, Asia, and the United States contributed data from patients with pathologically confirmed NRG1 fusion-positive lung cancers. Profiling included DNA-based and/or RNA-based next-generation sequencing and fluorescence in situ hybridization. Anonymized clinical, pathologic, molecular, and response (RECIST v1.1) data were centrally curated and analyzed. RESULTS Although the typified never smoking (57%), mucinous adenocarcinoma (57%), and nonmetastatic (71%) phenotype predominated in 110 patients with NRG1 fusion-positive lung cancer, further diversity, including in smoking history (43%) and histology (43% nonmucinous and 6% nonadenocarcinoma), was elucidated. RNA-based testing identified most fusions (74%). Molecularly, six (of 18) novel 5 ' partners, 20 unique epidermal growth factor domain-inclusive chimeric events, and heterogeneous 5 '/3 ' breakpoints were found. Platinum-doublet and taxane-based (post-platinum-doublet) chemotherapy achieved low objective response rates (ORRs 13% and 14%, respectively) and modest progression-free survival medians (PFS 5.8 and 4.0 months, respectively). Consistent with a low programmed death ligand-1 expressing (28%) and low tumor mutational burden (median: 0.9 mutations/megabase) immunophenotype, the activity of chemoimmunotherapy and single-agent immunotherapy was poor (ORR 0%/PFS 3.3 months and ORR 20%/PFS 3.6 months, respectively). Afatinib achieved an ORR of 25%, not contingent on fusion type, and a 2.8-month median PFS. CONCLUSION NRG1 fusion-positive lung cancers were molecularly, pathologically, and clinically more heterogeneous than previously recognized. The activity of cytotoxic, immune, and targeted therapies was disappointing. Further research examining NRG1-rearranged tumor biology is needed to develop new therapeutic strategies.
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| 16. |
- 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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| 17. |
- Goldscheider, Frances, et al.
(författare)
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Domestic gender equality and childbearing in Sweden
- 2013
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Ingår i: Demographic Research. - : Max-Planck-Institut fuer Demografische Forschung. - 1435-9871. ; 29, s. 1097-1126
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Sweden, which is among the most gender-equal societies in the world, combines, modern. family patterns such as unmarried cohabitation, delayed parenthood, high maternal labor force participation, and high break-up rates - all usually linked with low birth rates - with relatively high fertility. Sweden also has a high level of shared parental responsibility for home and children. OBJECTIVE After decades of late 20th century research showing that increasing gender equality in the workplace was linked with lower fertility, might gender equality in the home increase fertility? METHODS Using data from the Swedish Young Adult Panel Study (YAPS), we use Cox regression to examine the effects on first, second, and third births of 1) holding attitudes about sharing equally in the care of the home and children, and 2) actual sharing in these domestic tasks. RESULTS Our analysis shows that, measuring attitudes before the transition to parenthood and actual practice four years later, it is inconsistency between sharing attitudes and the actual division of housework that reduces the likelihood of continued childbearing, especially on second births among women. CONCLUSIONS As women are most likely to confront an inconsistent situation, with egalitarian ideals in a household without equal sharing, it is clear that having a partner who does not share housework is depressing Swedish fertility.
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| 18. |
- 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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| 19. |
- 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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| 20. |
- 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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| 21. |
- 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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| 22. |
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| 23. |
- 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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| 24. |
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| 25. |
- 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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