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By By By By Dr: HODA ASAAD EARLY DIAGNOSIS OF LUNG CANCER

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2 By By By By Dr: HODA ASAAD EARLY DIAGNOSIS OF LUNG CANCER
Lecturer of Chest diseases Al-Azhar University forGirls

3 Lung cancer continues to be the leading cause of cancer-related deaths worldwide.
5-year survival for lung cancer has remained relatively poor ( only 15%) despite many advances in imaging techniques and oncological care over because by the time a diagnosis is made, lung cancer is often well advanced and treatment options are limited.

4 Globally, lung cancer has been the most common cancer diagnosed each year since 1985.
Lung cancer had a higher incidence among males worldwide than any other cancer, followed by prostate cancer (more common in developed countries) and stomach cancer (particularly in developing countries). Among females, lung cancer was the fourth most diagnosed cancer, behind breast cancer, cervical cancer (mostly in developing countries), and colorectal cancer.

5 only 19% of lung cancers are localized at the time of diagnosis
The However, only 19% of lung cancers are localised at the time of diagnosis 2. The largest gain in life expectancy in lung cancer patients has been among those with localized disease versus those with regional or distant metastasis. only 19% of lung cancers are localized at the time of diagnosis

6 Early Detection/Screening
Screening for cancer means looking for cancer BEFORE there are symptoms Screening may identify early cases of cancer that never have become clinically apparent.

7 Goals early diagnosis of the disease or identification of truly high-risk populations may provide us opportunity to successfully cure or prevent the disease

8 Early Symptoms of Lung Cancer
What are the early symptoms of lung cancer that you should be on the lookout for? Early Symptoms of Lung Cancer What are the early symptoms of lung cancer that you should be on the lookout for? Symptoms

9 Keep in mind that understanding the early symptoms of lung cancer is important for non-smokers as well as smokers. At present, 50% of people who develop lung cancer are former smokers, and 15% have never smoked The 60% to 80% 5-year survival rate with stage 1 lung cancer drops to 10% with stage 4 disease nearly half of people have progressed to this advanced stage at the time of diagnosis About.com Guide Updated February 17, 2012

10 Early Symptoms of Lung Cancer
A) Cough That Doesn’t Go Away Many people dismiss or adapt to a chronic cough, . But a cough that lasts more than a few weeks can be a sign of something else. If you experience a persistent cough, check with your doctor, and ask for a second opinion if you don’t get a clear answer If you experience a persistent cough check with your doctor, and ask for a second opinion if you don’t get a clear answer If you experience a persistent cough check with your doctor, and ask for a second opinion if you don’t get a clear answer

11 Early Symptoms of Lung Cancer con,t
Wheezing chest People should pay attention to wheezing if it occurs with persistent coughing and other symptoms

12 Early Symptoms of Lung Cancer
Shortness of Breath With Activity Repeated Infections Such as Bronchitis and Pneumonia Pain or Aching in Shoulder, Back, Chest, or Arm Up to 50% of people with lung cancer have some chest or shoulder pain at the time of diagnosis, especially pain that increases with coughing and breathing. shoulder pain is sometimes the first symptom of lung cancer

13 Non Invasive early diagnosis of Lung Cancer
DETECTION OF EARLY PROXIMAL LUNG CANCER

14 Sputum cytology Sputum cytology
Sputum contains exfoliated airway epithelial cells and morphological analysis of sputum by cytology has been used for the early diagnosis of lung cancer, particularly central airway tumor Induced sputum has found to be better than spontaneous sputum

15 Limitation of sputum cytology
As the structure of the airway each sputum sample may contain only cells derived from part of the airway and therefore is not representative. the association was stronger for samples collected within 5 months of the diagnosis of lung cancer the skill required for identifying subtle morphological abnormalities in cells this results in significant variation in intra- and inter observer agreement in determining cancer cells

16 Sputum cytometry Sputum cytometry
Malignancy-associated change (MAC) is the change in the distribution of DNA in the nuclei of cytologically normal cells Sputum cytometry Computer-assisted sputum DNA analysis is the method used to detect (MAC) in exfoliated cells in sputum It is a powerful alternate to conventional cytology.

17 Sputum cytometry (con)
. Lung Sign is an image cytometry system analysis of sputum slides The system automatically scans slides and images thousands of cell nuclei per slide . It measures cell nuclear features and generates a single score for each specimen.

18 Sputum cytometry measuring the DNA content of cells (ploidy), detects large-scale chromosomal abnormalities associated with malignancy. Normal epithelial cells in sputum consist mostly of resting (diploid) cells. The observation of a significant fraction of hyper diploid cells in sputum is atypical and may represent the presence of a DNA aneuploid cell line. The detection of DNA aneuploidy has diagnostic and prognostic significance in lung cancer

19 the molecular diagnosis of lung cancer

20 the molecular diagnosis of lung cancer
Development of lung cancer requires repeated insult of carcinogens, mainly from tobacco smoke over a long period of time. The process so called carcinogenesis takes a few decades and results in accumulation of multiple molecular abnormalities in cells, which is the basis of malignant transformation and tumor progression .

21 the molecular diagnosis of lung cancer
Recent advances in understanding biological basis of lung tumor genesis provide new tools for detecting malignant cells or the process of malignant transformation and progression. Along with identification of molecular abnormalities in the early lung tumor genesis, advanced molecular analytic technologies have been emerged, which may facilitate development of rapid and effective methods for early diagnosis and risk assessment

22 the molecular diagnosis(con)
Some genetic abnormalities occur in the early carcinogenic process in lungs of chronic smokers and certain abnormalities may persist for many years after smoking cessation . such as mutations in the p53 tumor suppressor gene and K-ras proto-oncogene hypermethylation of the p16 tumor suppressor gene loss of heterozygosity (LOH) in multiple critical chromosome regions.

23 The Cell Cycle and Cancer

24 There are several factors that regulate the cell cycle and assure a cell divides correctly.
Before a cell divides, the DNA is checked to make sure it has replicated correctly. (If DNA does not copy itself correctly, a gene mutation occurs. DNA replication animation:click on DNA picture

25 p53 The p53 gene involved in the cell cycle control DNA repair, cell differentiation, genomic stability and programmed cell death) This protein is rapidly degraded in normal cells so its concentration is very low. In response to DNA damage in G1, the protein level of p53 rises dramatically due to the activation of a checkpoint protein kinase (chk2) that phosphorylate p53 and make it less susceptible to degradation

26 (bronchial metaplasia, dysplasia, and carcinoma in-sit
Frequent accumulation of p53 protein has been found in preneoplastic bronchial lesions, such as (bronchial metaplasia, dysplasia, and carcinoma in-sit Mutations of the p53 tumor suppressor gene play an important role in lung tumor genesis and occur in about (50% of NSCLC and more than 70% of SCLC)

27 K-ras proto-oncogene K-ras proto-oncogene .
Mutations of K-ras proto-oncogene is the most commonly mutated gene in the ras gene family, representing approximately 90% of the mutations identified. In lung cancer, mutations in K-ras gene are found in about 20% of the tumors. . Common in lung adenocarcinomas, accounting for about 30% of these tumors, but rare in other subtypes mutations in K-ras may be important in development of adenocarcinoma of the lungs and early progression.

28 Abnormal protein expression
Both epidermal growth factor (EGF) and its receptor (EGFR) over express in more than 60% of NSCLC Abnormal expression of Cyclin-dependent kinase (CDK4) was found expressed in about 90% of NSCLC and the expression associated with poor differentiation

29 The (p16) tumor suppressor gene
(p16) is inactivated by hypermethylation in many tumor types including lung cancer Ethylated p16 could represent a critical step in the genesis of NSCLC by allowing the uncontrolled clonal expansion of some of these premalignant lesions to cancer . %) lesions. detecting aberrant methylation of p16 in the shedding cells from airway after sputum induction from radio graphically cancer-free persons could be a biomarker for impending disease.

30 Methylated (p16) Aberrant methylation of the p16 and/or 6-methyl-guanine-DNA methyltransferase (MGMT) can be detected by PCR in 100% of patients with squamous cell lung carcinoma up to 3 years before clinical diagnosis. About 10% of sputum from cancer-free, high-risk subjects also contained the methylated DNA sequence

31 the frequency of p16 methylation increased during disease progression
(p16) tumor suppressor gene (con) the frequency of p16 methylation increased during disease progression basal cell hyperplasia (17%) squamous metaplasia (24%) carcinoma in situ (50%). . January 9, 1998; Accepted July 29, 1998

32 Summary of the frequency for p16 methylation in premalignant lesions,

33 Telomerase Telomeres don’t determine whether or not we live,but whether or not we age, which ultimately affects how long we live. Telomeres are often described as “clocks” that regulate aging . Telomere shortening leads to decreased ability of stem cells to leave the stem cell niche and to regenerate tissues

34 Telomerase Telomerase is a ribonucleo protein enzyme complex that maintains the length of telomeres It actually is not found in normal somatic cells, but it is found in 'immortal' cells, or cells which divide rapidly, including germ cells, inflammatory cells, and tumor cells. the telomeres being the caps on DNA ends. If the telomeres are shortened, cells age. Conversely, if telomerase activity is high, telomere length is maintained, and cell longevity is increased

35 telomerase The role of telomerase appears to be manipulating the life of the cell by presiding over the mechanism that controls how long the cell lives. Some cancer researchers believe that the creation of a targeted telomerase inhibitor may actually be able to stop a cancer cell's ability to divide thus stopping the spread of cancer

36 Telomerase in Action

37 Telomerase Although activation of telomerase alone may not
transform a normal cell to a cancer cell, it can substantially prolong the lifespan of cells and therefore permit time for accumulation of molecular damages under insult of carcinogens .

38 Telomerase . Telomerase activation can be detected in almost all SCLC and 80-85% of NSCLC indicating telomerase reactivation is important in lung tumor genesis and the major cause of cell immortality in primary NSCLC Telomerase activity may also be detected in precancerous lesions in lungs reflecting the early involvement of the molecule in lung tumor genesis

39 Volatile biomarkers Among totally non-invasive tests, the analysis of exhaled air for volatile organic compounds (VOCs)seems to be very promising for early diagnosis of lung cancer: exhaled breath contains a pattern of VOCs which distinguishes patients with and without lung cancer lung cancer patients metabolism is different than the metabolism of healthy people. And so the molecules that make up cancer patients' exhaled breath are different too . In 1999 Phillips et al. used, for the first time in medicine, the term “breathalyzer” for lung cancer.

40 Volatile biomarkers gaseous chemical sensing devices have been developed. The premise of these sensors is absorption of gases causing a change in conductivity, mass vibration or color of the sensor, thus altering the output ScienceDaily (Nov. 17, 2011) —

41 New Device Uses Gold Nanoparticles to Test for Lung Cancer
A new device uses gold nanoparticles to trap and define these molecules in exhaled breath. Like the human nose, its electronic counterpart responds in concert to a given odor to generate a pattern or 'smellprint,' which is analyzed, compared with stored patterns and recognized By comparing these molecular signatures to control groups, the device can tell not only if a lung is cancerous, but if the cancer is small-cell or non-small-cell, and adenocarcinoma or squamous cell carcinoma

42 This new device could eventually help doctors quickly, simply, and inexpensively define patients' lung cancer subtypes, allowing them to pair therapies with subtypes early in the treatment process.

43 Nanotechnology is an emerging field that may have potentials to make advanced changes in the detection, treatment, and prevention of cancer . The development of biocompatible nanoparticles for molecular targeted diagnosis and treatment is an area of considerable interest. One nanometer (nm) is equal to one-billionth of a meter .A human hair is approximately 80,000 nm wide

44 QUANTUM DOTS QUANTUM DOTS Quantum dots are semiconducting nanocrystals, which range in size from 2 nm to 10 nm. They can be used for both diagnosis and drug delivery, especially for cancer treatments. QD is made ready for injection. The QD enters the bloodstream and attaches itself to a cancer cell using the antibodies. The cancer cell takes in the QD, and the location is radiated with infrared light. This causes the QD to emit photons, allowing the site of the tumor to be located, and release the anti-cancer drug directly into the cancer cell.

45 QUANTUM DOTS QD based detection is rapid, easy and economical enabling quick point-of-care screening of cancer markers. QDs have got properties which make them ideal for detecting tumors. These include intense and stable fluorescence for a longer time; resistance to photo bleaching , large molar extinction coefficients, and highly sensitive detection due to their ability to absorb and emit light very efficiently. Various types of biomarkers such as proteins, specific DNA or mRNA sequences and circulating tumor cells have been identified for cancer diagnosis from serum samples. Therefore, QD based identification of many biomarkers would lead to more effective diagnosis of cancer.

46 In this illustration, quantum dots are depicted as gold spheres that attract DNA strands linked to cancer risks. When the quantum dots are exposed to certain types of light, they transfer the energy to fluorescent molecules, shown as pink globes, that emit a glow. This helps researchers to detect and count the DNA strands linked to cancer.

47 Applications of Nanotechnology in early diagnosis of lung cancer
Nanoprobes (miniature machines) can attach themselves to particles in the body (e.g., antibodies) and emit a magnetic field. Probes that aren’t attached to anything don’t create a detectable magnetic Nano-tracking may be able to detect tumors that are a few cells in size. (Alivisatos, 2001)

48 MINIMALLY INVASIVE diagnosis OF EARLY LUNG CANCER

49 bronchoscopy

50 1.autofluorescence bronchoscopy
Recent endoscopic techniques have been developed to more effectively detect and localize critical, early pathologic changes occurring in the bronchial epithelial and subepithelial regions in vivo . This includes 1.autofluorescence bronchoscopy 2.optical fluorescence and reflectance spectroscopy 3. high-magnification bronchovideoscopy 4.high-frequency endobronchial ultrasound 5.more recently, optical coherence tomography. ), high-amgnification bronchovideoscopy (), hi

51 Autofluorescence-reflectance
BRONCHOSCOPY

52 1.autofluorescence bronchoscopy
AFB was first developed at the British Columbia Cancer Research Centre and became commercially available in 1998 The original system, used a helium–cadmium laser for illumination and detected the emitted red and green autofluorescent light with two image-intensified charge-coupled device (CCD) cameras. Normal areas appear green and abnormal areas appear reddish brown,

53 AFB (con) Fluorescence bronchoscopy is based on observation that premalignant and malignant bronchial mucosa fluoresce less than normal tissue, SO allow detection of lesions (e.g., CIS) that may have a normal appearance during conventional white-light BRONCHPSCOPY AFB also have an important impact on the staging of potentially curable central lung cancers prior to endobronchial therapy, through more accurate assessment of the lesion size and margins

54 Right main bronchus carcinoma in situ under a) white light imaging
b) autofluorescence imaging

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57 and reflectance spectroscopy
2.optical fluorescence and reflectance spectroscopy AFB Subsequent technological improvements includ the combination of fluorescence and reflectance imaging in order to enhance contrast between normal and abnormal tissues. A red reflectance image is captured in combination with the green autofluorescence image. 

58 3-Optical coherence tomography (oct)
Is a promising endoscopic imaging method that enables micron-scale resolution of the bronchial epithelium It may become an imaging modality that helps address the relatively high false-positive rate of autofluorescence imaging. OCT is a noncontact method that delivers near-infrared light to the endobronchial tissue via a small probe via a bronchoscope. It allows imaging of cellular and extracellular structures from analysis of the back-scattered light depth penetration of ∼2 mm to provide near-histological images in the bronchial wall

59 (oct) OCT technology could prove useful for structural and functional assessment of suspicious lesions, staging (invasion of basement membrane) and feedback during endobronchial therapy Early studies have shown that dysplasia can be differentiated from metaplasia, hyperplasia or normal tissue and that carcinoma in situ can be differentiated from invasive cancer

60 Severity of the histopathology grade was associated with a progressive increase in the epithelial thickness and the nuclei of the cells also became darker and less light was scattered. The basement membrane became disrupted or disappeared with invasive carcinoma .

61 (oct) Optical coherence tomography image of early hilar-type lung cancer. Arrow symbols show a border of early cancer.

62 (oct) a–c) Representative optical coherence tomography (OCT) images and d–f) corresponding (H&E)-stained histological sections (a, d) mild dysplasia, b, e) moderate dysplasia and c, f) severe dysplasia. The nuclei in the epithelium become recognisable as darker dots with either moderate dysplasia or worse. The arrow in the OCT image of the area with severe dysplasia (c) points to the corresponding elevated area in the H&E section (f). e: epithelium; bm: basement membrane..

63 High-magnification video bronchoscopy
High-magnification bronchoscopy, combines both fibrotic and video bronchoscope technologies to produce 100–110× better magnification of the bronchial wall compared with standard video bronchoscopes Help in the visualization of micro vascular networks in the bronchial mucosa. Increase Increased vessel density in the bronchial submucosa is often present in squamous dysplasia and may play an early role in cancer pathogenesis Increase in microvascular density can be seen under high magnification in the majority of areas of abnormal autofluorescence

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65 Narrow band imaging Narrow band imaging is a novel system that also utilizes the changes seen in the microvascular network Use narrowband Blue light, which has a shorter wavelength than visible light, reaches into shallow surfaces which is helpful for detecting the submucosal vessels and patterns of vascularisation NBI uses three narrow bands: 400–430 nm (blue; covers haemoglobin absorption at 410 nm), 420–470 nm (blue) and 560–590 nm (green). Blue light has a short wavelength, reaches into the bronchial submucosa and is absorbed by hemoglobin Blue

66 Narrow band imaging this technique provided more accurate images of microvessels compared to high-magnification video bronchoscopy NBI, seemed to improve the detection dysplasia/malignancy when used as an adjunct to white light

67 EBUS Endobronchial ultrasound
introduced into clinical hospital practice i2000, as a new diagnostic procedure visualizing bronchial and peribronchial tumors, mediastinal lymph nodes and adjacent vascular structures, with the aim of assessing bronchial wall and extraluminal pathology

68 Endobronchial ultrasound probes have been developed for evaluation
The depth of invasion of malignant tumours in the central and peripheral bronchi Evaluation of lymph nodes located in the mediastinum in patients with lung cancer.

69 Primary Tumor Early Carcinoma
Alteration of the mucosa is concomitant with alteration in the sonographic structure.(either very low to very high echodensity). Sometimes submucosal tumor spreading was noticed by endobronchial ultrasound in spite of presence of intact mucosa.

70 Layers of the bronchial wall by EBUS
# (Kurimoto et al., 1999: Chest 115, ) # (Miyazu et al., 2002: Am J Respir Crit Care Med 165, 832–837)

71 Sq C C at the spure of B1+2&B3 of LtUL

72 The depth of tumor invasion EBUS vs Histopathology.

73 EARLY RADIOLOGICAL DIAGNOSIS OF LUNG CANCER

74 Spiral computed tomography (CT or CAT
scans are being tested as a new way to find early lung cancer in smokers and former smokers. At present, however, questions remain about the technology’s risks and benefits as a screening tool. Promising evidence from several studies shows that the scans can detect small lung cancers. But detecting these early tumors has not been proven to reduce the likelihood of dying from lung cancer, the gold standard for any cancer screening test

75 Positron emission tomography (PET)

76 resonance imaging (MRI) scans
PET scan is nuclear medicine imaging, to produce 3-dimensional, color images of the functional processes within the human body PET is now an important cancer imaging tool both for diagnosis and staging, as well as forprognostic information It is give information about the body's chemistry that is not available with other imaging techniques resonance imaging (MRI) scans A PET scan demonstrates the biological function of the body before anatomical changes take place

77 How PET Works injection of a glucose-based radiopharmaceutical (FDG), which travels through the body, eventually collecting in the organs and tissue .. . FDG undergoes the same uptake as glucose but is metabolically trapped and accumulated in the cancer cell after phosphorylation by hexokinase. which are assembled by the computer into a 3-D image of the patient's body. If an area is cancerous, the signals will be stronger there than in surrounding tissue, since more (FDG) will be absorbed in those areas

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79 Combination of PET with CT or MRI
the combination ("co-registration") of PET /CT Or MRI giving both anatomic and metabolic information (i.e., what the structure is, and what it is doing biochemically). PET scanners are now available with integrated high multidetector-row CT scanners. PET

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