Incidence of lung cancer is high in the male population of the German Democratic Republic: 0,005--4,63 per thousand annualy in the age groups 25 years and above. Therefore, efforts to improve early detection are mandatory. Possibilities and effectivity of screening for lung cancer are discussed. Only mass X-ray examination and exfoliative cytology have up to now gained practical importance. Most roentgenological studies performed so far show methodological weaknesses. Based upon recent studies of screening of high risk groups in the USA and in the GDR, it is suggested that this method applied in short intervals may be effective. Cytological screening of risk groups demands high costs and cannot be implemented on a broad base. Ways of optimization of cost-benefit ratio in roentgenological screening are discussed.
Report on results of a prospective study for earlier detection of peripheral and central bronchial carcinoma by fluorography performed for 6 years. In 1972 41,532 men of the age groups 1907 to 1937 were enrolled in the study group examined every 6 months. They were compared statistically and clinically to a control group of 102,348 persons of about the same sex and age distribution examined every two years by mass-x-ray. 1. By fluorographic screening the detection and resection rate in the study group was significantly increased. The percentage of resections was double as high as in the control group. 2. The higher detection rate especially in the younger age groups (40 to 54 years) of the study group caused an increase of the resection rate being three times higher than in the corresponding age group of the control population. 3. 67.5% of the persons with resection in the study group and 49.5% in the control group came to a life expectancy of more than three years. A 5 years healing after resection was attained by 23 of 42 resected patients of the study group and by 15 among 46 of the control group (55% to 32%). 4. Fluorography in 6 months intervals led to an increase of lower tumor stages. 5. At present fluorographic examinations showed to be the only mode of detection with good chances of resection as well in the study as in the control group, case-finding with clinical methods offering only small chances. 6. Among the patients resected in the study group the histological type of adenocarcinoma was rather frequent in 26.0%, parvicellular carcinoma amounting to 13.5%, on the other hand in the control group these types could be found with the same frequency in 16.8%. 7. The own results are reviewed with national and international investigations. Fluorographic examinations of selected risk groups (males between 40 and 70 years) in short intervals have proved to be at present the only method of finding bronchial carcinoma in time with some effectivity. 8. The effectivity of mass-x-ray-examinations must be improved a) by aimed examinations of risk groups, b) by improving the operational approach of fluorography using a special data bank of inhabitants, c) by reducing the medical protraction still high up to diagnosing bronchial cancer, d) by using the computer controlled risk aimed x-ray-examination for a complex screening programme.
e20546 Background: Significant progress has been made in improving progression-free survival in lung cancer through the combination of molecular biomarker testing and personalized therapeutics. Broadening access to national guideline recommended comprehensive molecular testing requires overcoming challenges of inadequate tissue biopsies, which can lead to the need for additional procedures and ultimately, delays in obtaining molecular testing. Additionally, there is growing evidence for the use of targeted therapies to treat early stage lung cancer and therefore a need for molecular testing across all stages of lung cancer. We show Percepta Genomic Atlas can identify key molecular alterations in early stage and advanced lung cancers and that it can successfully detect these alterations in surgical lung biopsy (SLB) specimens, transbronchial needle aspirates (TBNA) and bronchial brush specimens obtained during the initial bronchoscopy at the time of diagnosis. Methods: Percepta Genomic Atlas combines the whole exome TruSeq RNA Exome and targeted AmpliSeq Focus DNA assays (Illumina) for a comprehensive gene panel including ALK, RET, ROS1, NTRK1/3, MET, EGFR, BRAF, KRAS and HER2. TruSight Oncology 500 DNA and AmpliSeq Focus RNA assays (Illumina) were used as orthogonal assays. 92 fresh-frozen SLB samples were purchased from BioIVT and biopsies from 25 patients undergoing a diagnostic bronchoscopy during an IRB approved clinical study were collected into RNAprotect (Qiagen). DNA and RNA were extracted from both sample sets with the AllPrep Micro kit (Qiagen) and analyzed by Percepta Genomic Atlas and orthogonal assays. Results: The Percepta Genomic Atlas assay was used to profile small amounts of RNA and DNA from lung cancer SLB tissues, of which 60% were Stage I, 24% Stage II and 16% Stage III. Genomic alterations were observed in 65% of Stage I, 64% of Stage II and 73% of Stage III samples including single nucleotide variants (SNV) in KRAS, EGFR, and PIK3CA, indels in HER2 exon 20, multiple copy number variants, and RET and MET exon 14 skip rearrangements. Percepta Genomic Atlas was used to successfully profile TBNA and bronchial brush specimens providing molecular data from all 25 patients and identifying multiple alterations including KRAS, EGFR and PIK3CA SNVs. Conclusions: Percepta Genomic Atlas detects clinically actionable alterations in both SLB of early stage lung cancer tumors and in specimens collected at the time of diagnostic bronchoscopy or needle aspiration prior to surgery. The early detection of actionable alterations at the time of initial tissue acquisition could minimize need for additional diagnostic procedures and inform earlier treatment decisions with the expanding field of targeted adjuvant therapy.
The platelet collagen receptor glycoprotein VI (GPVI) and the fibrinogen receptor integrin αIIbβ3 trigger intracellular signalling cascades involving the tyrosine kinase Syk, the adapter SLP-76 and phospholipase Cγ2 (PLCγ2). Similar pathways are activated downstream of immune receptors in lymphocytes, where they have been localized in part to glycolipid-enriched membrane domains (GEMs). Here we provide several lines of evidence that GPVI-mediated tyrosine phosphorylation of PLCγ2 in platelets is dependent on GEM-organized signalling and utilizes the GEM resident adapter protein LAT (linker for activation of T cells). In sharp contrast, although fibrinogen binding to platelets stimulates αIIbβ3-dependent activation of Syk and tyrosine phosphorylation of SLP-76 and PLCγ2, it does not utilize GEMs to promote these responses or to support platelet aggregation. These results establish that GPVI and αIIbβ3 trigger distinct patterns of receptor signalling in platelets, leading to tyrosine phosphorylation of PLCγ2, and they highlight the role of GEMs in compartmentalizing signalling reactions involved in haemostasis.
Glycoproteins GPVI and GPIb-IX-V stimulate robust tyrosine phosphorylation of Syk and PLCγ2 (phospholipase Cγ2) in washed platelets, but only the former stimulates pronounced activation of phospholipase. Using phospho-specific antibodies, we demonstrate that GPVI, but not GPIb-IX-V, stimulates significant tyrosine phosphorylation of Syk at the autophosphorylation site pY525/526, a marker of Syk activity. In addition, GPVI stimulates tyrosine phosphorylation of PLCγ2 at Tyr753 and Tyr759, whereas GPIb-IX-V only induces significant phosphorylation at Tyr753. Both receptors stimulate tyrosine phosphorylation of Btk at the regulatory Tyr223 and Tyr551. Syk and Btk phosphorylate peptides from PLCγ2 containing Tyr753 and Tyr759 respectively, suggesting that they may stimulate phosphorylation at these sites in phospholipase. Studies using PLCγ2-deficient platelets demonstrated that phospholipase is not required for the activation of integrin αIIbβ3 by GPIb-IX-V. Our results demonstrate fundamental differences between GPVI and GPIb-IX-V in the regulation of tyrosine phosphorylation of Syk and PLCγ2 consistent with the functional impairment of phospholipase in signalling by GPIb-IX-V.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)
