| 21. |
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| 22. |
- Karlsson, Terese, 1979-, et al.
(author)
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LMO7 and LIMCH1 interact with LRIG proteins in lung cancer, with prognostic implications for early-stage disease
- 2018
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In: Lung Cancer. - : Elsevier BV. - 0169-5002 .- 1872-8332. ; 125, s. 174-184
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Journal article (peer-reviewed)abstract
- Objectives: The human leucine-rich repeats and immunoglobulin-like domains (LRIG) protein family comprises the integral membrane proteins LRIG1, LRIG2 and LRIG3. LRIG1 is frequently down-regulated in human cancer, and high levels of LRIG1 in tumor tissue are associated with favorable clinical outcomes in several tumor types including non-small cell lung cancer (NSCLC). Mechanistically, LRIG1 negatively regulates receptor tyrosine kinases and functions as a tumor suppressor. However, the details of the molecular mechanisms involved are poorly understood, and even less is known about the functions of LRIG2 and LRIG3. The aim of this study was to further elucidate the functions and molecular interactions of the LRIG proteins.Materials and methods: A yeast two-hybrid screen was performed using a cytosolic LRIG3 peptide as bait. In transfected human cells, co-immunoprecipitation and co-localization experiments were performed. Proximity ligation assay was performed to investigate interactions between endogenously expressed proteins. Expression levels of LMO7 and LIMCH1 in normal and malignant lung tissue were investigated using qRT-PCR and through in silico analyses of public data sets. Finally, a clinical cohort comprising 355 surgically treated NSCLC cases was immunostained for LMO7.Results: In the yeast two-hybrid screen, the two paralogous proteins LMO7 and LIMCH1 were identified as interaction partners to LRIG3. LMO7 and LIMCH1 co-localized and co-immunoprecipitated with both LRIG1 and LRIG3. Endogenously expressed LMO7 was in close proximity of both LRIG1 and LRIG3. LMO7 and LIMCH1 were highly expressed in normal lung tissue and down-regulated in malignant lung tissue. LMO7 immunoreactivity was shown to be a negative prognostic factor in LRIG1 positive tumors, predicting poor patient survival.Conclusion: These findings suggest that LMO7 and LIMCH1 physically interact with LRIG proteins and that expression of LMO7 is of clinical importance in NSCLC.
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| 23. |
- Kerr, Keith M., et al.
(author)
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The evolving landscape of biomarker testing for non-small cell lung cancer in Europe
- 2021
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In: Lung Cancer. - : Elsevier. - 0169-5002 .- 1872-8332. ; 154, s. 161-175
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Research review (peer-reviewed)abstract
- The discovery of oncogenic driver mutations rendering non-small cell lung cancer (NSCLC) targetable by small molecule inhibitors, and the development of immunotherapies, have revolutionised NSCLC treatment. Today, instead of non-selective chemotherapies, all patients with advanced NSCLC eligible for treatment (and increasing numbers with earlier, less extensive disease) require fast and comprehensive screening of biomarkers for first-line patient selection for targeted therapy, chemotherapy, or immunotherapy (with or without chemotherapy). To avoid unnecessary re-biopsies, biomarker screening before first-line treatment should also include markers that are actionable from second-line onwards; PD-L1 expression testing is also mandatory before initiating treatment.& nbsp; Population differences exist in the frequency of oncogenic driver mutations: EGFR mutations are more frequent in Asia than Europe, whereas the converse is true for KRAS mutations. In addition to approved first-line therapies, a number of emerging therapies are being investigated in clinical trials. Guidelines for biomarker testing vary by country, with the number of actionable targets and the requirement for extensive molecular screening strategies expected to increase. To meet diagnostic demands, rapid screening technologies for single driver mutations have been implemented. Improvements in DNA-and RNA-based next-generation sequencing & nbsp;technologies enable analysis of a group of genes in one assay; however, turnaround times remain relatively long. Consequently, rapid screening technologies are being implemented alongside next-generation sequencing.& nbsp; Further challenges in the evolving landscape of biomarker testing in NSCLC are actionable primary and secondary resistance mechanisms to targeted therapies. Therefore, comprehensive testing on re-biopsies, collected at the time of disease progression, in combination with testing of circulating tumour DNA may provide important information to guide second-or third-line therapies. Furthermore, longitudinal biomarker testing can provide insights into tumour evolution and heterogeneity during the course of the disease. We summarise best practice strategies for Europe in the changing landscape of biomarker testing at diagnosis and during treatment.
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| 24. |
- Killingberg, K. T., et al.
(author)
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Patient-reported health-related quality of life from a randomized phase II trial comparing standard-dose with high-dose twice daily thoracic radiotherapy in limited stage small-cell lung cancer
- 2022
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In: Lung Cancer. - : Elsevier BV. - 0169-5002 .- 1872-8332. ; 166, s. 49-57
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Journal article (peer-reviewed)abstract
- Objectives: In a randomized phase II trial, twice daily (BID) thoracic radiotherapy (TRT) of 60 Gy/40 frac-tions improved survival compared with 45 Gy/30 fractions in limited stage small-cell lung cancer (LS SCLC). Notably, the higher dose did not cause more toxicity. Here we present health related quality of life (HRQoL) reported by the trial participants during the first 2 years.& nbsp;Materials and methods: 170 patients were randomized 1:1 to TRT of 45 Gy or 60 Gy concurrently with cisplatin/etoposide chemotherapy. The 150 patients who commenced TRT and completed a minimum of one HRQoL-questionnaire were included in the present study. Patients reported HRQoL on the European Organization for Research and Treatment of Cancer Core 30 and Lung Cancer 13 Quality of Life Questionnaires. Questionnaires were completed weeks 0, 4 (before TRT), 8 (end of TRT), 12 (response evaluation after chemoradiotherapy) and 16 (end of prophylactic cranial irradiation), then every 10 weeks year one, and every 3 months year two. Primary HRQoL endpoints were dysphagia and dyspnea. A difference in mean score of >= 10 was defined as clinically significant.& nbsp;Results: Maximum dysphagia was reported on week 8, with no significant difference between treatment arms (mean scores 45 Gy: 44.2, 60 Gy: 51.1). The 60 Gy arm had more dysphagia in the convalescence period, but dysphagia scores returned to baseline levels at week 16 in both arms. For dyspnea there were no significant changes, or differences between treatment arms, at any timepoint. There were no significant differences between treatment arms for any other HRQoL-scales.& nbsp;Conclusion: TRT of 60 Gy did not cause significantly higher maximum dysphagia, though patients on the 60 Gy arm reported more dysphagia the first 8 weeks of convalescence. The higher dose was well tolerated and is an attractive alternative to current TRT schedules in LS SCLC.& nbsp;
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| 25. |
- Koukourakis, Michael I., et al.
(author)
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C2028T polymorphism in exon 12 and dinucleotide repeat polymorphism in intron 13 of the HIF-1 alpha gene define HIF-1 alpha protein expression in non-small cell lung cancer
- 2006
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In: Lung Cancer. - : Elsevier BV. - 1872-8332 .- 0169-5002. ; 53:3, s. 257-262
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Journal article (peer-reviewed)abstract
- Objectives: In this study, we investigated whether polymorphisms of the HIF-1 alpha gene may account for the patterns of HIF-1 alpha protein expression in non-small cell lung carcinomas (NSCLC) and the expression of HIF-1 alpha down-stream proteins. Methods: Specific HIF-1 alpha polymorphisms were assessed in a series of patients with NSCLC: (a) the C to T transition at nucleotide 1744 (position 2028 according to sequence with accession number NM_001530, which gives rise to Pro/Ser variation at codon 582), (b) the G to A nucleotide substitution at point 1790 (position 2046 according to sequence with accession number NM_001530, which gives rise to Ala/Thr variation at codon 588), and (c) the dinucleotide GT repeat polymorphism in intron 13. Immunohistochemistry for HIF-1 alpha and down-stream proteins (VEGF, LDH-5, GLUT-1) was also performed in tumor material. Results: A strong association of the P582S polymorphism and of GT repeat polymorphism higher than 14/14 with increased HIF-1 alpha expression was noted. HIF-1 alpha polymorphism did not relate to the expression of the HIF-1 alpha downstream proteins analysed, but significant association of HIF-1 alpha expression with LDH-5 was confirmed (p=0.008). Conclusions: HIF-1 alpha polymorphisms may have an important impact on HIF-protein stability and, eventually, function. (C) 2006 Elsevier Ireland Ltd. All rights reserved.
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| 26. |
- Kuemmel, Andreas, et al.
(author)
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TA-MUC1 epitope in non-small cell lung cancer
- 2009
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In: Lung Cancer. - : Elsevier BV. - 0169-5002 .- 1872-8332. ; 63:1, s. 98-105
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Journal article (peer-reviewed)abstract
- MUC1 (CD227), an established tumor marker, is expressed on glandular epithelia and on epithelial tumors. Tumor MUC1 differs from normal MUC1 by modified glycan side chains. Recently, a novel carbohydrate-induced conformational tumor-associated MUC1 epitope (TA-MUC1) was described, whose clinical relevance in lung cancer is not known. Eighty-five paraffin embedded tissue sections of non-small cell lung cancer (NSCLC) patients (73% male; mean age 64+/-9 years) were stained with the monoclonal antibody PankoMab (against TA-MUC1) and compared with the established antibodies E29 and 214D4 regarding prognostic relevance. TA-MUC1 is virtually absent in bronchial epithelium. As shown by multivariate analysis, only staining with PankoMab, but not with E29 or 214D4, was correlated with patients' survival (p=0.029). Moreover, when regarding interactions of MUC1 antibody staining results and clinico-pathological parameters, patients with lymph node metastasis lacking PankoMab staining were attributed the highest risk by far (Hazard ratio=4.6, 95% CI: 2.1-9.7, p=0.000). In summary, the presence of TA-MUC1 is a favorable prognostic factor in this cohort of NSCLC patients, in particular if lymph node metastases are present. This is in contrast to the results for E29 and 214D4, which recognize less or not glycosylation dependent epitopes. As this is the first report on a well-defined MUC1 epitope associated with improved survival in NSCLC, a more differentiated view on MUC1 may be mandatory.
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| 27. |
- La Fleur, Linnea, et al.
(author)
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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
-
In: Lung Cancer. - : Elsevier BV. - 0169-5002 .- 1872-8332. ; 130, s. 50-58
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Journal article (peer-reviewed)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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| 28. |
- Lal, R., et al.
(author)
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Feasibility of home delivery of pemetrexed in patients with advanced non-squamous non-small cell lung cancer
- 2015
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In: Lung Cancer. - : Elsevier. - 0169-5002 .- 1872-8332. ; 89:2, s. 154-160
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Journal article (peer-reviewed)abstract
- Objectives: To evaluate the feasibility and adherence to home delivery (HD) of pemetrexed maintenance treatment in patients with advanced non-squamous non-small cell lung cancer (nsqNSCLC). Materials and methods: Exploratory, prospective, single-arm, Phase II study in advanced nsqNSCLC patients, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0/1 that did not progress after 4 first-line induction cycles of a platinum doublet. The first cycle of pemetrexed (500 mg/m(2)) was hospital administered, further cycles were HD until progressive disease or discontinuation. Feasibility was assessed by the adherence rate to HD (probability of reversion to hospital administration or treatment discontinuation due to HD) as primary endpoint, and by health-related quality-of-life (HRQoL: EQ-5D, lung cancer symptom scale [LCSS]), satisfaction with HD, overall survival (OS), and safety. Results: 52 patients (UK and Sweden) received a median of 4 (range 1-19) pemetrexed maintenance cycles. Adherence rate up to Cycle 6 was 98.0% (95% confidence interval [CI]: 86.4%, 99.7%). All but 2 patients remained on HD. 1 patient discontinued after Cycle 1 (patient decision), and 1 after Cycle 6 (noncompliance with oral dexamethasone). 87% (33/38) of the patients preferred home to hospital treatment and in 90% (28/31) of cases, physicians were satisfied with distant management of patients. During HD Cycles 2-4 mean change from baseline ranged from 3.0 to 7.7 for EQ-5D visual analog scale. The 6-month OS rate was 73% (95% CI: 58%, 83%). 1 patient had an HD-related adverse event (device-related infection, Grade 2) and 1 patient died after Cycle 1, before HD, due to a possibly drug-related atypical pneumonia. Conclusion: HD of pemetrexed maintenance treatment in patients with advanced nsqNSCLC was feasible, safe, and preferred by patients, while maintaining HRQoL. Physicians were satisfied with distant patient management. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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| 29. |
- Lindqvist, Jonatan, et al.
(author)
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Effect of adherence to treatment guidelines on overall survival in elderly non-small-cell lung cancer patients
- 2022
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In: Lung Cancer. - : Elsevier. - 0169-5002 .- 1872-8332. ; 171, s. 9-17
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Journal article (peer-reviewed)abstract
- Objectives: Mean age at diagnosis of lung cancer is increasing with increasing age in Western populations. The present study was designed to evaluate the effect of adherence to first-line treatment guidelines on overall survival (OS) in elderly patients with non-small-cell lung cancer (NSCLC) and reasons for non-adherence to treatment guidelines.Materials and methods: All patients aged ≥ 65 years diagnosed with NSCLC in Ostrobothnia, Finland, during the years 2016 to 2020 were identified from hospital registries. Adherence of first-line treatment to contemporary treatment guidelines was analysed based on diagnosis, tumour stage and performance status (PS), as was the effect of adherence on OS.Results: A review of hospital registries identified 238 NSCLC patients aged ≥ 65 years. Guideline adherence by stage decreased significantly with age, with 66.4% of patients aged 65 to 74 years, but only 33.3% of those aged > 80 years treated according to guidelines (p < 0.001). Other factors associated with non-adherence to guidelines included poor PS, frailty, and limited lung function. Of the patients with PS 0–2, 26.9% were under-treated according to guidelines. Reasons for under-treatment included comorbidities, decreased lung function, physician decision to reduce treatment intensity or recommend best supportive care, patient choice and PS decline before treatment initiation. Guideline adherence increased overall OS of elderly NSCLC patients in all stages. Elderly PS 2 patients appear to benefit from guideline adherence and active treatment. In contrast, active treatment did not benefit patients with PS 3–4.Conclusions: Guideline adherence was associated with increased OS in elderly NSCLC patients. Almost 10% of elderly and otherwise fit NSCLC patients were not treated according to guidelines and could have benefitted from more intensive treatment.
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| 30. |
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