EARLY DIAGNOSIS OF LUNG CANCER

2. EARLY DIAGNOSIS OF LUNG CANCER • By Dr: HODA ASAAD By By By 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. 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. EarlyDetection/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. 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 firstsymptom of lung cancer

13. Non Invasive early diagnosis of Lung Cancer NON INVASIVE 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) Sputum cytometry . 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 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 carcinogenesistakes 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. p53 • Frequent accumulation of p53 protein has been found in preneoplastic bronchiallesions, 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% ofNSCLC 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. (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 NSCLCindicating 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 precancerouslesions 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. Recentendoscopic techniques have been developed to more effectivelydetect and localize critical, early pathologic changes occurringin the bronchial epithelial and subepithelial regions in vivo . This includes 1.autofluorescence bronchoscopy 2.optical fluorescenceand reflectance spectroscopy 3. high-magnification bronchovideoscopy 4.high-frequency endobronchial ultrasound 5.morerecently, optical coherence tomography. ), high-amgnification bronchovideoscopy(), hi