The Painless Stop Smoking Cure

Quit Smoking Magic

Mike Avery is the author of the quit smoking magic program. He is an ex-smoker (20 year habit) and a researcher who has carried out lots of tests on this topic for many years. He used himself as a test subject, after trying everything you can think of to stop smoking. He then tested his quit smoking magic theory on himself and got the results needed. Mike Avery's program of quit smoking magic has successfully helped hundreds of people all over the world quit smoking, including his family members and co- workers. He should be trusted because he has been in the shoes of being a smoker and has cured himself from smoking addiction. So if you are planning on doing the same, you should go to the one person who understands what you are going through. This program will provide you with information about smoking in general and ways on how to stop the smoking addiction from eating you up. Its contents are based on real-life experiences rather than theories that were imagined by someone. It is an e-book program on the subject of quitting smoking and comes with three different bonus e-books on the following topics; how to whiten your teeth, end bad breath and how to clean your lungs. Purchasing this program does not require you to have any technical skill to be able to use it, it only requires you to read and understand. Read more here...

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Clinical studies lung cancer

There were early nonsurgical trials that examined combinations of cisplatin or carboplatin with thoracic radiation (120). There have been several phase II trials evaluating concurrent platinum chemotherapy and radiation therapy as preoperative treatment (121-125). Thoracic irradiation was compared with cisplatin and concurrent radiation therapy in at least four randomized trials in stage III nonsmall-cell lung cancer by the early 1990s (126-129). Although the cisplatin regimens and radiation regimens varied, none of these clinical trials showed a significant survival benefit for the combined modality treatment vs radiation therapy alone. Schaake-Koning et al. (126), in a phase II study in patients with inoperable lung cancer, showed that the best improvement in survival occurred when cisplatin was administered daily with radiation therapy rather than weekly with radiation therapy (Fig. 4). The earliest combination chemotherapy and radiation trials in nonsmall-cell lung...

Smallcell lung cancer

The concept of delivering concurrent chemoradiation has long since been established in the therapy of limited-stage small-cell lung cancer. It has been shown to contribute to both local control and survival in two meta-analyses (72,73). Standard therapy includes the concurrent delivery of thoracic radiation with either the first or second cycle cisplatin-etoposide chemotherapy (74,75). With the advent of a newer generation of chemotherapeutic agents, investigators have hoped that their incorporation into treatment regimens may allow the cure rates to be pushed beyond their current 20-25 range for limited stage disease.

How to Motivate Smokers to Quit

Smoking is associated with a range of diseases, causing a high level of morbidity and mortality. It represents one of the leading causes of preventable death with more than 3 million smokers worldwide dying each year from smoking-related illnesses. Stopping smoking has major health benefits. Smokers who quit before the age of 35 can expect a life expectancy only slightly less than those who have never smoked. Quitting at any age provides both short- and long-term benefits, with those who do so in middle age gaining improvements in health and reducing their excess risk of death. Despite the well-known health consequences of tobacco and the benefits of quitting, a quarter to a third of the adults in industrialized countries continue to smoke 14 . Although a majority of current smokers wish to quit smoking and effective interventions exist 15 , very few request or receive formal smoking cessation interventions. Physicians are in a unique position to intervene yet studies suggest that...

For Smokers Unwilling to Quit

Intervention efforts will not be successful without sufficient motivation or readiness to quit smoking on the part of the smoker. For the patient who is presently unwilling to quit smoking, recommending entering a smoking cessation programme may be premature and ineffective. The US practice guidelines suggest following the 5 R's motivational intervention as listed in Table 2 15 . The 5 R's for enhancing motiva- Risks The clinician should ask the patient to identify potential negative consequences of tobacco use. The clinician may suggest and highlight those that seem most relevant to the patient. The clinician should emphasize that smoking low-tar low-nicotine cigarettes or use of other forms of tobacco (e.g. smokeless tobacco, cigars, and pipes) will not eliminate these risks. Examples of risks are Environmental risks Increased risk of lung cancer and heart disease in spouses higher rates of smoking by children of smokers increased risk for low birth weight, SIDS, and respiratory...

Are there cigarette smokers who are susceptible to COPD

It is well known that less than 20 of smokers develop clinically significant chronic obstructive pulmonary disease (COPD) 1-3 . From a number of epidemiological studies, it has become apparent that there are susceptible smokers who will develop COPD 1,3 . However, the characteristics of such susceptible individuals are not known 4 . The questions 'Is there a distinct group of susceptible smokers ' and 'What is the distribution (bimodal or unimodal) of susceptible individuals ' are extremely difficult to answer on the basis of the current scientific knowledge. According to a new working definition developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) group, COPD is a 'disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and results from an abnormal inflammatory response of the lungs to noxious particles and gases' 5 . It is likely that the reason why fewer than 20 of smokers develop COPD...

Actions Of Nicotine On The Brain

The nicotine molecule is shaped like acetycholine (Benowitz, 2001). Nicotine activates certain cholinergic receptors in the brain that would ordinarily be activated by acetylcholine. By activating cholinergic receptors, nicotine enhances the release of neurotransmitters and hormones, including acetylcholine, norepinephrine, dopamine, vasopressin, serotonin, and beta-endorphin. The cholinergic activation leads to behavioral arousal and sympathetic neural activation. The release of specific neurotransmitters has been specifically linked to particular reinforcing effects of nicotine. Enhanced release of dopamine, nor-epinephrine, and serotonin may be associated with pleasure, mood elavation, and appetite suppression. Release of acetycholine may be associated with improved performance on behavioral tasks and improvement of memory, and the release of beta-endorphin may be associated with the reduction of anxiety and tension (Benowitz, 2001).

Genetic basis of lung cancer

The p53 gene is one of the most commonly mutated genes in all cancers and is felt to be a critical tumor suppressor gene (2). The gene is mutated in 50-70 of patients with lung cancer. Additionally, in a large proportion of cases in which there is no mutation, p53 is inactivated through binding by high levels of Mdm-2 protein or is functionally inactive because downstream genes such as the pro-apoptotic Bcl-2 family members which p53 transactivates are mutated or transcriptionally inactive (3). There is also evidence that the E6 protein of human papilloma virus can bind to and inactivate p53 protein (4). It has therefore been suggested that almost all lung cancer cells are p53 defective and potentially targeted by gene transfer approaches with wildtype p53.

Lung Cancer Single Projection Radiography and Computed Tomography

Lung cancer continues to rank as the leading cause of cancer deaths in the United States 39, 40 , and early detection may allow more timely therapeutic intervention and thus a more favorable prognosis for the patient 41-44 . Chest radiography has been used for detection of lung nodules (i.e., potential lung cancer) because of its low cost, simplicity, and low radiation dose. Radiologists, however, may fail to detect lung nodules in chest radiographs in up to 30 of cases that have nodules visible in retrospect 45, 46 . CAD schemes for nodule detection on chest radiographs are being investigated 19, 47, 48 , since studies have shown that use of computer output can improve radiologists' detection accuracy 49-51 by providing potential nodule sites. Because CT is more sensitive than chest radiography in the detection of small noncalcified nodules due to lung carcinoma at an early stage 61, 62 , lung cancer screening programs are being conducted 61-67 with low-dose helical CT as the...

Example of an IPD metaanalysis Postoperative radiotherapy in nonsmallcell lung cancer

Introduction Worldwide, over half a million new cases of lung cancer are diagnosed each year 58 and it is the leading cause of cancer deaths. Surgery is the treatment of choice for non-small-cell lung cancer (NSCLC), and around one fifth of tumours are suitable for potentially curative resection 59 . However, even for patients with apparently completely resected disease, survival rates are disappointing - around 40 per cent at two years. In an effort to improve both local control and survival, the use of adjuvant post-operative radiotherapy (PORT) has been explored. LCSG Lung Cancer Study Group, CAMS Chinese Academy of Medical Sciences, EORTC European Organization for Research and Treatment of Cancer, MRC Medical Research Council, GETCB Groupe d'Etude et de Traitement des Cancers Bronchiques Twenty small-cell patients excluded. LCSG Lung Cancer Study Group, CAMS Chinese Academy of Medical Sciences, EORTC European Organization for Research and Treatment of Cancer, MRC Medical Research...

Characteristics of a sample of smokers and nonsmokers

None of the continuous predictors are correlated with each other, either overall or within the smoking groups. Neither of the categorical predictors is significantly associated with a person's smoking habits (chi-square analysis). In addition, there is no significant association between gender and blood group. White blood cell count and body mass index both differ significantly between the two smoking classes. The white blood cell count is higher in the non-smokers but the body mass index is lower. However, if a correction is applied to the p value for multiple testing the difference in body mass indices becomes insignificant. The mean ages are very similar in the two groups.

Youth Smoking Cessation

Efforts to help adolescents quit smoking have received relatively little attention. Studies suggest that teenagers who smoke on a daily basis who were unable to quit in the past for an extended period of time who have parents who smoke, particularly mothers, and a number of friends who smoke who do poorly in school and score high on a depression scale are least likely to quit smoking (Burt & Peterson, 1998 Zhu, Sun, Billings, Choi, & Malarcher, 1999). The more risk factors, the less likely adolescents are to quit (Zhu et al., 1999). Reviews of quit-smoking programs for adolescents painted a bleak picture (Burton, 1994 Digiusto, 1994 Sussman, et al., 1999). Retention and recruitment of students were problematic, and end-of-group quit rates were modest. Many studies failed to use appropriate control groups, objective measures of smoking status, and long-term follow-up of graduates (Sussman et al., 1999). Teenage focus groups have provided insight into the nature of smoking...

Adult Smoking Cessation

Of the many nonpharmacological approaches to smoking cessation, here, behavioral approaches are the most germane. They have undergone the most extensive experimental study, are suitable for office and clinic-based physician interventions, and often are used in combination with pharmacological ap- proaches to smoking cessation (Fagerstrom, 1988 Hymowitz, 1999). Multi-component behavioral programs, whether in group, individual, or self-help formats, typically include a number of strategies (self-monitoring, stimulus-control procedures, behavioral contracting, alternative behaviors, aversive conditioning, relaxation training, diet and exercise, self-management skill training for relapse prevention, etc.) to motivate smokers, to help them gain control over smoking, and to eliminate smoking systematically from their behavioral repertoire. Once smokers stop smoking, many of the very same behavioral skills that helped them quit smoking are used to help them prevent relapse. Schwartz (1987)...

Lung Cancer

Lung cancer is the most common cancer worldwide and the leading type of cancer mortality in men. The incidence of lung cancer closely tracks the incidence of cigarette smoking, with a lag of about 20 years, in both men and women (Fig. 3-5).6a Since the mid-1900s in men and 1950s for women, the rate of lung cancer has risen dramatically. The highest rates include the United States, United Kingdom, Japan, and Australia and the lowest rates are in Africa and Southern Asia.6 Female incidence rates are highest in the United States, Canada, Denmark, and the United Kingdom but lower in countries such as France, Japan, and Spain, where the prevalence of smoking among women has been low until recently. The etiology of lung cancer is predominantly related to cigarette smoking. The data for this are overwhelming.6 Other proposed causes include environmental pollution, occupational exposure (e.g., asbestos, coal mining), passive smoke inhalation, and radon exposure. These are all minor players...

FPGs and Lung Cancer

Downregulation of the epidermal growth factor (EGF) receptor (100). Whether decorin has a similar effect in lung cancer has not been established. Studies in A549 cells, a human lung carcinoma cell line, have shown that decorin upregula-tion leads to enhanced apoptosis in cancer, but not normal, cells (101). Gene expression studies in lung squamous cell and adenocarcinomas have shown decorin underexpression (102). Finally, in lymphangioleiomyomatosis, a fatal interstitial lung disease characterized by excessive smooth muscle proliferation, abnormal staining for versican, biglycan, and decorin is evident (103).

Cigarette Smoking

As noted above, epidemiologists have attributed as many as 30 of all cancer deaths to tobacco use, primarily cigarette smoking. In 2005, for example, approximately 163,000 deaths due to lung cancer were expected to occur in the United States (90,000 men and 73,000 women), making up about 31 of all deaths from cancer in men and 27 in women.3 Although the most direct correlation is between cigarette smoking and lung cancer, tobacco use has also been implicated in cancers of the mouth, pharynx, larynx, esophagus, urinary bladder, pancreas, kidney, and, more recently, stomach and liver49 and perhaps colorectal cancer.52 Smoking of pipes or cigars has been implicated in the occurrence of cancers of the mouth, pharynx, larynx, and esophagus, but this form of tobacco use is generally considered much less dangerous because the smoke is usually not inhaled. A number of studies have also suggested a correlation between ''passive

Clinical studies head and neck cancer

Early clinical studies clearly demonstrated that cisplatin could be administered safely and concurrently with radiation therapy (73-75). Early clinical trials that demonstrated the promise of the combination of cisplatin and radiation therapy included the treatment of brain tumors (76,77), head and neck tumors (78), malignant melanoma (79), and bladder cancer (80). Early clinical trial integrating carboplatin administration with radiation therapy was carried out in patients with locally advanced nonsmall cell lung cancer (NSCLC) (81). A hypothesis put forth by Coughlin and colleagues (81) was that the best clinical outcomes would be achieved with the combination of cisplatin and radiation therapy in tumors that were responsive to cisplatin.

Subversion of Innate Immunity Receptors Stimulation of Toll Like Receptors on Lung Carcinoma Cells Modulates Cell

Lung being a site of frequent inflammation and lung cancers often developing in a context of chronic inflammation, we investigated the presence and the role of Toll Like Receptors (TLR) on lung cancer specimens from Non Small Cell Lung Cancer Some patients with lung cancer are treated by neo-adjuvant polychemotherapy, consisting in platinum salts and often gemcitabine or navelbine. Both A549 and SK-MES cells stimulated by Loxoribin or Poly U were found to be resistant to chemotherapy-induced cell death. It is therefore tempting to postulate that tumoral cells which express TLR7 or TLR8 at high levels could be stimulated upon viral induced inflammation and become resistant to chemotherapy (Cherfils-Vicini et al. 2010). We are currently analyzing a cohort of lung cancer patients having received neo-adjuvant chemotherapy before surgical resection in order to assess whether high TLR7 or TLR8 expressors are less susceptible to chemotherapy than low expressors. If it were so, it would...

Use in Prevention and Therapy

Vitamin A is one of nature's primary anticancer substances, particularly in the skin and mucous membranes. Ample intakes of vitamin A have been shown to protect against cancers of the lung, bladder, prostate, larynx, esophagus, stomach, and colon. Vitamin A can prevent precancerous lesions, such as oral leukoplakia (white patches on the lips and mouth often found in smokers) and cervical dysplasia, from developing and may produce regression and disappearance of these disorders.15 As a cancer treatment, large doses of retinoic acid may reduce growth and recurrence of certain forms of skin cancer.16 As an antioxidant, beta-carotene helps provide protection against damage from many xenobiotics (such as polychlorinated biphenyls PCBs ). It may also reduce the risk of skin cancer associated with exposure to sunlight6 and radiation.2 pulmonary disease and asthma, particularly in regular smokers.17

Cardiac Markers In Trials Of Newer Treatment Modalities

(28) helped to establish the effectiveness of LMWHs in the setting of ACS. Subgroup analysis of the FRISC I study revealed that the beneficial effects of dalteparin at 40 d seemed to be confined primarily to the 80 of the study population who were smokers and to those who qualified for the study with a diagnosis of NSTEMI. This was one of the first studies published to indicate that cardiac markers could effectively define a subgroup of ACS patients who could specifically benefit from a particular treatment (26).

Radiosensitizing abilities of the taxanes

The major rationale for combining a taxane with radiation relates to the induction of a cell cycle block at the G2 M point where cells are more sensitive to the damaging effects of radiation. Tishler reported an enhancement factor of 1.8 when human astrocytomas cells were incubated with paclitaxel for 24 h prior to receiving radiation (39). Choy et al. have reported on paclitaxel's sensitizing effects in a human lung cancer cell line, HL-60, finding a slightly lower enhancement ratio, 1.48 (40), using a 1-h exposure of paclitaxel at a concentration of only 3.0 x 10-8 (see Fig. 2). It is important to note that in all studies Fig. 2. The radiation sensitizing effects of paclitaxel and concurrent ionizing radiation in a human lung cancer cell line, HL-60. From ref. 40. Fig. 2. The radiation sensitizing effects of paclitaxel and concurrent ionizing radiation in a human lung cancer cell line, HL-60. From ref. 40.

Treatment Options for Major Cancers and Future Directions

Treatment options for lung cancer are determined by the type small cell lung carcinoma (SCLC) or non-small cell lung carcinoma (NSCC), and by stage of the tumor.75 Small cell lung carcinoma, which accounts for approximately 20 of all primary lung cancers and tends to be particularly aggressive, is often widespread by the time of diagnosis and treatment is often limited to chemotherapy and or chest radiation therapy. Representative examples of combination therapies for SCLC are etoposide and cisplatin (EC) etoposide, cisplatin, and vincristine sulfate (ECV)

Application in the clinic

Response rates in several solid tumor types (48-50). The large bulk of experience has been acquired with locally advanced nonsmall-cell lung cancer and advanced head and neck primary cancers where protocols have integrated both taxanes with concurrent radiation to improve responses and outcomes. Ongoing research continues in order to refine the administration, sequencing, and integration of these agents with other chemotherapies, new biological response modifiers and radiation therapy.

Web Based Imaging Electronic Patient History

The WEBI-EPH was designed to accommodate the sequence of events that occurs when a patient is assessed prior to undergoing a scan, which is shown schematically in Figure 2.5. The fields were designed, tailored, and piloted for two common medical conditions where PET-CT scanning provides unique information lung cancer and the evaluation of lymphomas (a type of blood cancer). A look-up list was generated for expected answers to common questions, and the design reflected the usual sequence in which these questions were asked. The graphic component was used to define basic units. A basic unit was a dataset where the elements had distinctive properties that were described separately. Each unit consisted of several descriptive elements including properties and values. In the classification of current symptoms, a basic unit was pain, and it included information about the location and duration as properties and values. Data input was achieved by selecting the relevant item from a list of...

FSee 708 Kinase Inhibitors for Cancer

Cyclophosphamide, doxorubicin, and vincristine sulfate (CAV) cyclophosphamide, doxorubicin, and etoposide (CAE) etoposide and cisplatin (EP) and cyclophosphamide, etoposide, and vincristine (CEV). Depending on the extent of the disease, non-small cell lung carcinoma can be removed by surgical resection or treated with radiation therapy in combination with chemotherapy (e.g., gemcitabine hydrochloride together with cisplatin and vinorelbine). In addition to the preceding treatment modalities, photodynamic therapy is use for the care of patients with inoperable lung cancer or with distant metastasis. Surgery is the treatment of choice for colorectal cancer and, depending on the stage of the disease, chemotherapy and radiation are used as adjuvant treatment.76 For example, a cocktail of different agents (fluorouracil, leucovorin, and irinotecan) is used for metastatic colorectal cancer. An important advance in the treatment of colorectal cancer has been reported recently with...

Brief Counselling Interventions

Brief counselling interventions of one to three visits can substantially help patients change problem behaviours, particularly in the areas of smoking cessation, hazardous alcohol use, and exercise. The acronym FRAMES has been used to define the elements of an effective brief intervention which helps to trigger the patient motivation to change 13 .

Scientific Foundations

Anticancer drugs interfere with the growth of tumor cells, eventually causing their death. Common chemotherapy drugs used in various cancers include doxorubicin (Adriamycin) in breast cancer, often administered with cyclophosphamide (Cytoxan) paclitaxel (Taxol) in lung cancer and fluorouracil (5-FU) in colon cancer. Some are given only as injections. Others, such as imatinib (Gleevec) for leukemia are taken by mouth in tablet or liquid form.

Genetic Predisposition and genetic Susceptibility

In middle to late adult life, cancer occurs as a result of multiple, serially accumulated, genetic changes following decades of exposure to carcinogens like, for example, tobacco smoke. The occurrence of cancer at young ages, when the opportunity for such chronic environmental exposures has not had sufficient time to exist, suggests strongly that individuals are genetically predisposed to develop certain cancers or are genetically susceptible to the carcinogenic effects of environmental agents. In such individuals, the number of genetic changes required to achieve malignant transformation at the cellular level may be reduced and or metabolic processes modified. In many instances, gene-environment interactions in this age range are more likely to be operative.

Trends In Problems Across Time And Space

The appearance of new drugs (or reappearance of old ones in new forms) exposed social groups to agents against which they had no sociocultural protection or immunity that is, the community or nation had no tradition for problem-free, or at least controlled, use of the substance. Users themselves may not have perceived the actual risks associated with the new psychoactive substance. This situation also occurred when the group was familiar with the substance but in a different form. For example, traditions may exist for wine but not beer or distilled alcohol pipe smoking may be subject to customs that do not extend to cigarette smoking.

Adjuvant Radiation Therapy

For example, the Lung Cancer Study Group compared four cycles of CAP (cyclophosphamide + doxorubicin + cisplatin) chemotherapy to no further therapy in 269 patients with stage I disease. No benefit was seen for chemotherapy (only 53 of patients were even able to complete the chemotherapy) (13). A study testing a lower-dose CAP regimen in T1 T3 N0 disease seemed to show a benefit in time to recurrence and survival. How Surgery is the treatment of choice for patients with stage II non-small cell lung cancer says the PDQ. Once again, however, it is not clear if the phrase treatment of choice is descriptive or prescriptive. In either case, there is no scientific documentation of the beneficial effects of surgery for this stage of NSCLC. In fact, many of the patients who are surgically treated develop second, or recurrent, lung cancers despite the treatment. An NCI media release of 26 October 2000 concludes Adding chemotherapy to radiation therapy does not prolong survival in operable,...

Efficacy equivalence or noninferiority

Both equivalence and non-inferiority trials have perhaps their greatest role where cure rates are high, but there is a wish to reduce as far as possible the morbidity of treatment without compromizing efficacy (for example, stage I testicular seminoma) or where survival rates are very low, and the aim is to provide the best palliation while again avoiding adverse effects on already low survival rates (for example, poor prognosis small cell lung cancer patients).

Psychosocial Impact of Placebo and Nocebo in Advanced NSCLC

The difference between the results in treated and untreated patients in all of these studies is so small that even a minor impact of mental state could vitiate the seemingly positive effect of aggressive treatment. We do know that a study at the Radium Hospital in Oslo has shown that the greatest predictors of survival among NSCLC patients were general symptoms and psychosocial well-being (36, 37). Lung cancer patients in fact tend to have very high levels of distress (seen in 43.4 of patients) (86). One needs to gauge the psychological as well as the physical effects of treatment or nontreatment

How to Motivate Sedentary People to Be More Active

The efficacy of primary care physicians in changing unhealthy lifestyle habits has already been demonstrated in other fields (smoking cessation for example), particularly when they have been adequately trained 21 . With regard to physical activity promotion in a primary care setting, more than 20 original papers 32-51 and ten reviews of the literature have been published 52-61 . There is a fair amount of evidence

Recurrences of Stage Iv Nsclc

Much the same can be said about the treatment of recurrences of lung cancer as has been said about stage IV disease. Radiation therapy is well known to provide excellent palliation of symptoms from a localized tumor mass. The use of chemotherapy in recurrent lung cancer is largely palliative. It has produced objective responses and small improvement in survival for patients with metastatic disease. While the survival benefit is small, improvement in subjective symptoms has been reported to occur more frequently than an objective response. Whether this occurs because of a physical reduction of the tumor burden or because of psychological factors has not been explored.

What is the evidence for cigarette smoke increasing susceptibility to COPD

Among the risk factors that have been related to COPD, cigarette smoke is the best studied and is a consistent finding in numerous studies 1,52,53 . In all recent guidelines on COPD, cigarette smoking has been regarded as the best-established risk factor for the development of the disease 54,55 . In addition, passive cigarette smoking has been related to chronic cough and sputum and is also a candidate risk factor for the development of airflow limitation 53,56,57 . However, from the above epidemiological studies, it is apparent that not all smokers develop clinically significant COPD, and also that there is no direct dose-effect relationship. A passive smoker may develop the disease, whereas a heavy smoker may not. These observations have led to the hypothesis that there are smokers who are susceptible to COPD. Longitudinal epidemiological studies have suggested that a more important factor than the dose (pack years) is the timing of the exposure to cigarette smoke 58,59 . This is...

Do risk factors act in combination in the development of COPD

Explain why there are susceptible smokers. Exposure to a mixture of known noxious agents, such as active plus passive smoking, and environmental pollution and occupational pollution could cause COPD. However, current data do not support the hypothesis of combinations of these risk factors as the basis for the existence of susceptible smokers 3 . A number of other risk factors have been proposed that may play a role in the development of COPD. COPD patients in comparison with control individuals 63 . Incorporation of adenoviral DNA in animal epithelial cells has also been shown to amplify the inflammatory response on exposure to cigarette smoke 64,65 . A possible scenario might therefore be that susceptible smokers are those in whom a viral infection early in life leads to an excess load of adenoviral DNA in the epithelial cells. These cells might then orchestrate an 'abnormal' inflammatory response to cigarette smoke. However, results of this type have not been reproduced by other...

What is the place of the Dutch hypothesis in COPD

A relationship between increased airway reactivity, atopy and the development of COPD was first proposed by Orie et al. in 1961 69 . In other words, smokers with hyperreactive airways could be the susceptible ones who will develop COPD. This hypothesis is still open to debate, as it is not clear whether hyperresponsiveness is the cause or the effect of the decrease in FEV1 in smokers. Airways reactivity and atopy are complex disorders related to a number of genetic and environmental factors leading to allergic inflammation (asthma). This inflammation, however, has recently been shown to be different from that caused by cigarette smoke 70 . In addition, other investigators have suggested that the hyperresponsiveness seen in smokers is the result of abnormal geometry of the airways caused by prolonged smoking, leading to 'reactivity'. In addition, the majority of the studies investigating FEV1 decline have tested airways reactivity at the end of the study (after the initiation of...

How do genetic factors modify COPD

It is most likely that the answer to the mystery of why only a minority of smokers develop COPD is to be found in the field of genetics. Familial aggregation has been reported in COPD 79,80 , but it is difficult to exclude confounding factors. In addition, COPD is a disease of middle age by which time parents or grandparents are rarely still alive, so that it is difficult to conduct classical hereditary studies. It is also likely that many genetic factors interact to increase or decrease the risk of developing COPD. Thus, Mendel's laws of inheritance of 'susceptibility' to cigarette smoke could be ruled out 81 .

Rationale for the Use of Antiandrogens in Cancer Treatment

Prostate cancer is the most frequently diagnosed malignancy in males and ranks second only to lung cancer in terms of annual mortality. Great efforts have been made in the past to develop novel approaches to the treatment of prostate cancer. The two main options for the treatment of prostate cancer are

The Intentionto Treat Principle

An extreme example of a violation of the ITT principle was apparent in a multicenter trial of adjuvant active specific immunotherapy of lung cancer, in which a statistically significant survival advantage was claimed for the ASI group (43). Initially 264 patients were recruited. In the first analysis of the study results, published in 1987, only a subset of 126 patients was included, providing the basis for the authors' positive judgments of the therapy. Subsequent reports of this study did not even mention the fact that the original sample size of the study was much larger (42). Those study centers in which the patients' reactions in the skin test was too weak (it is unclear how this was defined precisely, and which centers were affected exactly) were excluded entirely from the final analysis. The authors argued that these centers did not adhere to the treatment protocol in a strict way (as evidenced by the weak delayed hypersen-sitivity reactions). Possibly they were unaware that,...

Noninflammatory Vasculopathies

Thromboangiitis obliterans occurs chiefly in middle-aged men who smoke heavily. It commonly involves the peripheral arteries. The disease may also involve the medium-sized and small meningeal and cerebral arteries, producing intimal proliferation, luminal obliteration, and multiple small infarctions (Fig. 4.30).

DNA microsatellite instability MSI in COPD

This method had been applied to sputum cells of COPD patients, and it was shown that this defect can be detected 118 . Recently, sputum cells from groups of smokers without COPD and smokers with COPD were tested for MSI 119 . The two groups had similar smoking histories. MSI was detected in 24 of COPD patients, but in none of the non-COPD smokers. These results suggest that MSI may be part of the complex genetic basis of COPD and could serve as a marker of genetic alteration caused by smoking, leading to the development of COPD. MSI may therefore be an index of the susceptible smoker 119 . However, more studies are needed to verify these results.

Chronic Obstructive Pulmonary Disease

In COPD patients, the prevalence of anorexia is particularly high, since most patients suffer from breathlessness, which affects food intake. Recent data indicate that 67 of chronic lung disease patients experience anorexia during the last year of life. This figure is not much different from the prevalence of 76 found among lung cancer patients 12 . More striking, however, are data showing that although COPD patients have physical and psychosocial needs at least as severe as those of lung cancer patients, their symptoms, including anorexia, receive much less attention from health care professionals 12 .

What is COPD Is it to do with cough and sputum

The productive cough that occurred particularly in smokers and in those working in dusty jobs was shown in the 1950s to be primarily a large-airway problem. Several studies demonstrated an increase in mucosal goblet cells, and the Reid index defined the increased thickness of the mucosa pathologically 1 . The definition of chronic bronchitis used today is that produced by the Medical Research Council (MRC) for epidemiological surveys and not for clinical purposes 2 . The definition restricted chronic bronchitis to 'a productive cough for more than 3 months of the year in each of two successive years'. Thus, chronic bronchitis is related to the productive cough and not to any level of airflow limitation. This symptomatic definition has been used in many epidemiological studies, in which it has been of considerable value, but it is less helpful in managing individuals in clinical practice. For example, patients with bronchiectasis and or with chronic asthma very different pathological...

Endogenous Carcinogenesis

An important question that arises is, what is the source of mutations in the human genome that leads to cancer One might argue that the answer is obvious. We live in a sea of carcinogens PAHs from automobile exhaust, industrial pollution, pesticide residues in foods, chlorinated organic compounds in drinking water, etc. Furthermore, epidemiologists argue that almost 30 of human cancers are related to cigarette smoking. Yet, a significant amount of cancers occur in people with no clear evidence of exposure to clearly defined carcinogens. For a number of cancers of the pancreas, ovary, kidney, and breast, for example, there are in most cases no clear geographic or genetic risk factors (although heritable genetic changes may account for 5 to 10 of some cancers such as breast cancer). Thus, if cancer is initiated through a mutation or a series of mutations, how might these arise

General Treatment Consideration

Plete remission after 3-6 cycles of chemotherapy received some sort of consolidation therapy in the form of additional chemotherapy, obviating the benefit of radiation. However, such strategies lead to high cumulative doses of chemotherapy and the risk of male infertility due to the use of alkylating agents, cardiomyopathy from anthracyclines, pulmonary fibrosis from bleomy-cin, and of secondary leukemia and lung cancer after alkylating agents and etoposide.

Biological Background and Rationale

Overexpression of ErbB2 has been observed in cancer, particularly in breast cancer 5 . Trastuzumab, a monoclonal antibody directed against ErbB2 for treating ErbB2-positive breast cancer, was the first agent to validate growth factor receptors as molecular targets for therapeutic intervention 6 . Overexpression of EGFR has also been detected in many human cancers, including more than 65-85 of non-small cell lung cancer (NSCLC), and has Ras, a historical proto-oncogene, is frequently mutated in many human cancers, including 90 of pancreatic cancers, 50 of colorectal cancers, 30 of lung cancers, and 15-30 of melanomas 10-12 . There are three Ras genes that encode four family members K-Ras (two alternatively spliced isoforms), H-Ras, and N-Ras. Mutations are most commonly found in K-Ras 13 . These mutations result in impaired GTP hydrolysis, which shifts the equilibrium toward GTP-bound active Ras, and results in constitutive in-tracellular signaling.

Can COPD be diagnosed on symptoms and signs

The young 25-year-old smoker has no symptoms or measurable signs, despite a decade of smoking. Large epidemiological studies can demonstrate small statistically significant decrements in lung function, but the magnitude (25mL) is too small to be detectable in the individual 13 . Although the disease process is already active, the exercise ability of young people is usually limited by the cardiovascular system, and the in-built respiratory reserve (about 30 of respiratory function) is never called upon. Only a minority of these smokers will even report a smoker's cough. It is only when the continuing damage from smoking erodes the respiratory reserve and lung function becomes abnormal that patients begin to notice the first signs of breathlessness in their 40s or 50s. Even at this stage, only a minority will report cough and sputum, and breathlessness on heavy exertion may be the only symptom. Those who do not have a heavy task or who do perform active physical exercise will be unaware...

Trials of chemotherapeutic agents

By histology, with anaplastic astrocytoma patients having a MST of 49.4 mo compared to 13.7 mo in the GBM patient population (p < 0.000001). Among the AA patients under 50 the only additional nodal split was seen when comparing normal vs abnormal mental status. GBM patients under 50 were further subdivided only by KPS. For the 1037 patients over 50 the primary split was defined by KPS, with a MST of 10.3 mo seen in those with a KPS 70 or more vs 5.3 mo in patients with KPS below 70. Patients with KPS below 70 were further split by normal vs abnormal mental status. Definition of the terminal nodes for patients with KPS above 70 was slightly more complex. The first split segregated patients by histology with MSTs of 21.7 mo for the AA patients and 9.7 mo for the GBM patients. AA patients were further divided only by duration of symptoms, whereas GBM patients were additionally divided by extent of surgery, neurologic function, and RT dose. The MSTs by patient classes ranged from 58.6...

Do The Preclinical Studies Predict Outcomes In Human Trials

In the clinical setting, a number of studies have tested many of the same personalized vaccine approaches described above in patients with melanoma, colon cancer, non-small cell lung cancer, and lymphoma (Table 2). Among these were two randomized, controlled trials where efficacy findings can be interpreted

Determining the size of difference to detect in a specific trial

The questionnaires described below are based on those developed by Freedman and Spiegelhalter 8 . They comprise two sections, the first identifying the expected differences in survival, the second attempting to elicit the clinically important differences as well as the factors which affect these values. In describing these questionnaires, the CHART bronchus trial 9 is used as an example. This was a randomized trial comparing conventional radiotherapy with Continuous, Hyperfractionated, Accelerated RadioTherapy (CHART) in the treatment of inoperable non-small cell lung cancer. Conventional radiotherapy was delivered in thirty fractions of 2 Gy, given once a day, Monday to Friday only, over six weeks. CHART was given to a total dose of 54 Gy, given in thirty-six fractions of 1.5 Gy, with three fractions given at 8-hour intervals for twelve consecutive days including weekends. This approach would, it was hoped, improve survival by minimizing the opportunity for tumour repopulation...

Analysis of Cytotoxic Agents in Xenograft Models

Retrospective evaluation of activity of established cytotoxic agents in clinical trials versus preclinical models shows that, in general, activity in xenograft models is predictive of some level of clinical response. Several reports have detailed good correlations between xenograft response and clinical response for rhabdomyosarcoma, colon cancer, lung cancer (particularly small-cell lung cancer), breast cancer, and myeloma.26,52,53 Table 1 shows a partial compilation of data generated in our department examining the activity of numerous standard cytotoxic agents as well as selected novel targeted agents in a variety of xenograft and syngeneic flank tumor models. Both early treatment (ET) and staged tumor (ST) trials are included and it can be seen that in some cases the magnitude of response is quite similar in the two cases (e.g., paclitaxel in the A549 model), while in others there are significant differences in response (e.g., paclitaxel in breast cancer). The data include several...

Chemotherapy Plus Active Immunotherapy

In another study, a striking response rate of 62 among 21 extensive-stage small cell lung cancer patients treated with second-line chemotherapy was observed after vaccination with DCs transduced with full-length p53 (79). Thirteen of the 21 patients were platinum-resistant and 61.5 of these were responders. In a third study of patients with various metastatic cancers treated with a DNA vaccine encoding a common tumor antigen, five of six immune responders who received subsequent salvage therapy experienced unexpected clinical benefit (80). Among those benefiting from the salvage therapy were four patients with progressive disease after vaccination. Among eight patients who did not demonstrate immunity to vaccination and who survived to receive additional therapy, only one derived clinical benefit.

NNitroso Compounds Diet and Smoking

Tobacco smoke is a potent source of NOCs and polycyclic aromatic hydrocarbons (PAHs), among other carcinogens. Meta-analyses have provided little evidence of an association between maternal smoking during pregnancy and childhood brain tumors 20, 21 . Preconception and childhood exposure to paternal tobacco smoke revealed a raised risk, but confounding with other risk factors could not be ruled out 20 . The results of studies of smoking as a risk factor for CNS tumors in adults have been inconsistent 8 . Likewise, there is no consistent evidence for an elevated risk associated with alcohol consumption 8 .

Nicotinic acetylcholine receptors nAChRs

NAChRs are homo- or heteropentameric ligand-gated ion channels present in the CNS, peripheral nervous system, and neuromuscular junction. Various subunits can combine to provide a diversity of receptor subtypes with unique brain and neuron-specific distributions.37 Activation of nAChRs mediates calcium influx and neurotransmitter release, again specific to the neuronal subtype (i.e., cortical, hippocampal). Interest in nAChRs comes from observations that they are reduced in AD and that nicotine improves attention in AD patients. Also A 42 can bind to a7 nAChRs and antagonists of this receptor promote neuron survival. Several nAChR agonists have entered the clinic (e.g., ABT-418 14, SIB-1553A 15, GTS-21 16, TC-1734 17). The progress of these agents has been slow due to efficacy issues and side effects, including emesis, motor dysfunction, and hallucinations, although these are reduced in comparison to nicotine due to improved receptor subtype selectivity. The first a4b2 agonist to...

Practical considerations

This is perhaps the most common type of situation in which even quite small alterations to the allocation ratio can make participation in the trial much easier, the resulting increase in accrual more than compensating for the slight loss in power associated with moving the allocation ratio away from equality. One example involved the trials of continuous, hyperfractionated accelerated radiotherapy (CHART) in head and neck, and also lung cancer described earlier in this chapter 9 . As CHART is given in multiple daily fractions, without breaks for weekends, patients are treated outside of normal hours and this therefore incurs additional staff costs. It is clearly more cost effective to have several patients ready to treat in succession. In the MRC CHART trials, 3 2 randomization was used to increase the number of patients allocated CHART, and therefore increase the chance that participating centres would have several patients to treat simultaneously.

Biological Background

Largest organ of the body, with an average weight of 7 kg in adults. With a surface area of approximately 2 m2, the skin offers a unique and easily accessible body surface across which drugs can be delivered. Transdermal administration is noninvasive, and allows for the attainment of constant plasma levels over extended periods of time. Additionally, the incidence of side effects after transdermal administration may be lower than after oral administration, such as in the case of estradiol.85 Transdermal patches are discreet to wear and were preferred for nicotine replacement therapy over other administration devices (nasal sprays and pulmonary inhalers) that, although equivalent in efficacy, were considered embarrassing to use.86

Central Neural Mediation of Cytokine Induced Anorexia

The major hypothalamic detection site for blood-derived signals. Yet, severing the ARC from PVN or its connections with the PVN only slightly attenuated peripheral IL-1p-induced anorexia 35 , indicating that the ARC is involved but not necessary for peripheral IL-1p-induced anorexia. Several lines of evidence 20 implicate activation of hindbrain to forebrain aminergic neurons in the feeding suppression and hypermetabolic effects of circulating IL-1 p. IL-1p-induced anorexia may in part be mediated through prostaglandin E2-dependent activation of serotoninergic neurons originating in the raphe nuclei and projecting to the hypothalamus 36 . In line with this idea, systemic administration of a serotonin (5-HT2c) receptor antagonist and microinjection of the 5-HT1A autoreceptor agonist 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) directly into the raphe nucleus both markedly attenuated the feeding-suppressive effect of peripherally injected IL-1-p 3 . Interestingly, anorexia...

Chemoattractant For Monocytes

Lung cancer cell line (Calu-3) (87) The identification and cloning of MCP-1 provided an opportunity to screen tumors for their expression of a bona fide monocyte-specific chemoattractant. Table 1 lists several types of cell lines, tumor explants, and primary tumor tissues that express MCP-1. Although the list appears to be extensive, MCP-1 expression is not a universal property of tumor cells since there are many tumor types that do not express MCP-1, e.g., prostate carcinoma and many lung cancers (44).

Caveolin1 and the Proliferation of Cancer

Although Cav-1 has been shown in multiple settings to be critical for pancreatic tumorigenesis, the exact role of Cav-1 in pancreatic tumor cell promotion and survival is unclear. Recent data show its importance in a newly described tumori-genic mechanism involving the tumor microenvironment called the reverse Warburg effect 10 , Many previous studies suggest that Cav-1 is a tumor suppressor gene. For example, down-regulation of Cav-1 expression was observed in breast, lung, colon, and ovarian cancers 11-13 . Ectopic expression of Cav-1 in transformed normal cells and tumor cell lines inhibited cell growth in vitro and tumorigenesis in vivo. Further, Sunaga et al. reported that Cav-1 acted like a tumor suppressor gene in small cell lung cancer, whereas in nonsmall cell lung cancer it is required for cell survival and growth 14, 15 , In contrast, other studies have reported that Cav-1 expression was up-regulated in human cancers, including prostate cancer and esophageal squamous cell...

Mechanisms Of Mcp1 Antitumor Effects

An alternative approach to using MCP-1 was demonstrated by transfecting an MCP-1 cDNA into small-cell lung cancer cell lines that express P-glycoprotein (72). As in other systems, MCP-1 did not alter the growth rate of these cells in vitro, but in this model, MCP-1 expressers formed tumors in nude mice with the same efficiency and growth rate as control cells. However, the tumor-suppressive effects of systemi-cally administered anti-P-glycoprotein antibody were much greater against the MCP-1-expressing cells. This suggests that even when MCP-1-mediated macrophage attraction is insufficient to produce tumor cell death, the presence of MCP-1 can enhance antibody-dependent cellular cytotoxicity. (The MCP-1 effect is probably related to macrophage elicitation in vivo since the addition of recombinant MCP-1 to mixed macrophage tumor cell cultures in vitro did not enhance cytotoxicity.)

What is quality of life

An example of the value an assessment of QL can add was in a randomized trial of cisplatin and vinblastine plus either hydrazine sulphate (HS) or a placebo for patients with advanced non-small cell lung cancer. Herndon et al. 7 reported similar results in terms of survival, response and weight gain. Although patients in the HS group experienced significantly more severe neuropathy this was only one of eighty types of toxicity recorded, and it was therefore felt that this alone did not provide a clear indication of which treatment was better. However, QL analyses revealed worse physical functioning, fatigue, lung-cancer-specific and cancer-specific symptoms for patients in the HS group, and the authors concluded that the QL assessment provided a unique viewpoint from which to compare the treatments.

Postoperative radiation therapy

In the Lung Cancer Study Group (LCSG) 773 study, subgroup analysis showed no survival benefit for the N2 patients and local recurrence analysis was not done for the N2 subgroup (29). The larger Medical Research Council (MRC) study (190 N2 cases) showed a trend (p 0.07) toward a lower local recurrence rate and a trend (p 0.18) toward an improved survival rate (36 vs 21 ) in the irradiated group compared to surgery alone (30). However, the freedom-from-distant-metastases rate was significantly lower (p 0.03) in the RT group. A recent MRC meta-analysis suggested neither a decrease nor an improvement in survival rate with postoperative RT for N2 patients (31).

Postoperative chemotherapy or chemoradiation

Three prior Lung Cancer Study Group (LCSG) studies have suggested postoperative cisplatin-based chemotherapy may have an impact on survival of NSCLC patients with pathologically documented stage II III disease. Although a treatment effect has been detected for nonsquamous cancer, and is suggested for squamous cancer, the treatment effect has been of marginal significance (35). Other studies have shown a modest improvement in disease-free survival with the use of chemotherapy after surgery, but little impact on overall survival (36,37). A frequent problem with postoperative chemotherapy has been the inability to deliver all the planned amount of drug in patients recovering from lung resection. Drug delivery rates of around 50 are often the rule.

Identifying key symptoms

It may also be important not to focus only on the possible positive aspects of a treatment. Treatment-related adverse effects may also be relevant. For example, in a trial of two thoracic radiotherapy regimens for lung cancer, the key QL outcome might be the duration and severity of dysphagia. In an MRC Lung Cancer Working Party trial 39 , patients with non-small cell lung cancer were asked to complete a daily diary card, and the proportion of patients reporting moderate or severe dysphagia was plotted. This suggested that in terms of dysphagia, the shorter radiotherapy schedule (17 Gy in 2f) affected fewer patients and was transient, whereas the longer radiotherapy schedule affected more patients for longer (Fig. 6.3). Fig. 6.3 Proportion of patients reporting moderate or severe dyspagia on a daily diary card (adapted from MRC Lung Cancer Working Party, 39 ). Sometimes more than one symptom may be important. For instance, patients may present with a complex mixture of symptoms which...

Leptin and Cancer Anorexia Cachexia

The persistence of anorexia and the onset of cachexia in cancer patients, therefore, implies a failure of this adaptive feeding response 86 . Leptin, a member of the gp 130 family of cytokines, induces a strong T helper-1 lymphocyte response and is regarded as a proin-flammatory inducer 87 . Several data suggested a role of leptin in inflammatory diseases. Proinflammatory cytokines up-regulate leptin expression in white adipose tissue and increase plasma leptin levels in hamsters and mice 88 . However, in many common diseases associated with cachexia, such as chronic obstructive pulmonary disease and chronic inflammatory bowel disease, there is an inflammatory status caused by high proinflammatory cytokine levels, whereby leptin concentrations are decreased related to body fat mass. In patients with advanced non-small-cell lung cancer, serum leptin levels were lower than in controls and lower still in those who were cachectic who also showed an increase of...

Search Detection Description Diagnosis

When the radiologist has data available that are not image data, that may guide him or her to look for certain patterns of disease. Thus, if the radiologist knows that the patient has smoked cigarettes for many years, the radiologist may search more fully for signs of lung cancer and emphysema. To some extent, the radiologist will see what he or she expects to see. This has good and bad features. To some degree, it enhances the likelihood that disease will be detected and the correct diagnosis will be made. It has the detrimental feature, however, of what is called assignment or attribution error in diagnosis. If a finding on the image is consistent with the expected diagnosis, the radiologist is more likely to assign a finding as caused by that expected diagnosis, when it may actually have another cause.

How many patients are required

For example, the primary aim of the QL aspect of a lung cancer trial might be to compare the difference in the proportion of patients who have relief from their cough at three months. If the standard treatment is expected to give 50 per cent of patients However, this sample size assumes that all patients will be assessable. In many advanced cancers, attrition due to death, even at three months, may have reduced the trial population by 10 or 15 per cent. In addition, the above scenario requires complete information on all patients and indeed all patients to start with a cough otherwise how could relief be assessed The framing of the hypothesis is again important, as, for example, Stephens etal. 43 have suggested redefining 'palliation' as not just improvement, but also prevention (for asymptomatic patients), and control (for patients with minimal symptoms). In this way all patients could be included in the analysis. Nevertheless, the calculated QL sample size must be adjusted by adding...

Development of QL questionnaires

The daily diary card (DDC) grew out of the idea that, in chemotherapy for lung cancer, it was felt that the main side effects were known but not their duration or the pattern of severity. Thus, the daily diary card was developed based on previous work in other conditions, such as the assessment of night cough in asthma patients and vaginal bleeding patterns. As patients complete the card each evening it was considered imperative to keep the number of questions to a minimum and for practical reasons to use a four or five point categorical scale. In the first MRC trial to use DDCs the consensus opinion was that the questions should address overall QL, a functional measure (physical activity), the main expected side-effect (nausea and vomiting) and two psychological items (mood and anxiety). These questions were changed in subsequent MRC trials depending on the research question.

Choosing a questionnaire

Several papers have asked patients to complete more than one questionnaire and have then compared the results. The questionnaires compared in this way include the FACT-G and the EORTC QLQ-C30 72 , the FLIC and the EORTC QLQ-C30 73 and three lung-cancer-specific questionnaires, the EORTC, FACT, and LCSS 74 .

Pathology biology diagnosis and staging

Rapid tumor growth and early dissemination characterize small-cell lung cancer. Common presenting symptoms such as cough, hemoptysis, chest pain, and dyspnea are caused by large tumor masses. Less common presenting symptoms include dysphagia caused by esophageal compression, hoarseness caused by laryngeal nerve paralysis, and facial swelling caused by superior vena cava compression (2). Also, paraneoplastic syndromes such as Cushing's or Eaton-Lambert syndrome or inappropriate secretion of antidiuretic hormone can be present. 3. Combined (small-cell lung cancer with squamous or adenocarcinoma features) (10). In 1988, because of the imprecision of this classification, the International Association for the Study of Lung Cancer (IASLC) revised the classification to include 1. Pure small-cell lung cancer. 3. Combined (small-cell lung cancer with squamous or adenocarcinoma features) (11). Besides the pure small-cell lung cancer, the mixed small-cell and large-cell carcinoma comprises less...

Production by Lung Hyaluronidases

Hyaluronan is the natural substrate of hyaluronidases, a family of enzymes (54,55) which are discussed in a separate chapter of this book. At least two hyaluronidases are expressed in the lung. They are HYAL1 (56) and HYAL2 (57), which was first described as a product of lung fibroblasts (58) and is expressed in many tissues. Both these enzymes are lysosomal enzymes and they degrade HA differently than testicular hyaluronidase and provide a large piece of approximately 20 kDa. The genes HYAL1, -2 and -3 are located on the chromosomal region 3p21. This region is deleted in many small cell lung cancer lines. In fact, these genes were known as LuCa-1, -2 and -3 before it was realized that hyaluronidases could result from their expression (57). Another peculiarity concerning the lung relates to HYAL2. Rai et al. (59) expressed HYAL2 in NIH 3T3 cells and could not detect hyaluronidase activity, whereas a construct of HYAL1 in the same cell system did produce hyaluronidase. Furthermore,...

History And Overview Of The Problem Early Beginnings

The use of tobacco (Nicotine tobaccum) has been traced to early American civilizations, where it played a prominent role in religious rites and ceremonies. Among the ancient Maya, tobacco smoke was used as solar incense to bring rain during the dry season. Shooting stars were believed to be burning butts cast off by the rain god. The Aztecs employed tobacco (Nicotine rustica) as a power that was used in ceremonial rites as well as chewed as a euphoric agent with lime (Schultes, 1978). The popular weed was not without its detractors. James I of England published a counterblaste to tobacco in 1604, and he arranged a public debate on the effects of tobacco in 1605. Pope Urban III condemned tobacco use in 1642, threatening excommunication of offenders. In Russia, a decree in 1634 punished tobacco users by nose slitting, castration, flogging, and banishment. These harsh measures were abolished by Peter the Great, who took to smoking a pipe in an effort to open a window to the West. It is...

Timing and Sequence of Chemotherapy and Radiation

The optimal timing and sequence of combining chemotherapy and radiation therapy is unknown for the treatment of limited-stage small-cell lung cancer. Radiation can be combined with chemotherapy sequentially, alternating, or concurrently. When combined concurrently, radiation can be started early in the treatment or later during the treatment schedule.

Antitumor Sulfonamides

The development of CAIs possessing potent tumor cell growth inhibitory properties was reported by this group (Supuran and Scozzafava 2000b, 2000c Scozzafava and Supuran 2000a Supuran et al. 2001). Such compounds were discovered in a large screening program in collaboration with the National Institutes of Health (NIH) of sulfonamide CAIs. Several hundred aromatic heterocyclic sulfonamides were assessed in vitro as potential inhibitors of growth of a multitude of tumor cell lines, such as leukemia, nonsmall cell lung cancer, ovarian, melanoma, colon, CNS, renal, prostate and breast cancers. The active compounds (most of them nanomolar inhibitors of CA II and CA IV), of types 4.212 to 4.223, belong to both the aromatic and the heterocyclic sulfonamide classes and showed GI50 values (molarity of inhibitor producing a 50 inhibition of tumor cell growth after a 48-h exposure to the drug) in the micromolar range (Supuran and Scozzafava 2000b, 2000c). Better antitumor compounds were then...

The Cigarette Century

In 1900, the total consumption of cigarettes in the United States was 2.5 billion (U.S. Department of Health and Human Services, 1989b). Major advances in agriculture, manufacturing, and marketing, the Great Depression, two world wars, and changing cultural norms led to a marked increase in consumption. Total consumption increased from 2.5 billion in 1900 to 631.5 billion in 1980 (U.S. Department of Health and Human Services, 1989b). Cigarette consumption peaked in 1981 (640 billion) but declined in 1987 to an estimated 574 billion, the equivalent of more than 6 trillion doses of nicotine (Jones, 1987). An estimated 430 billion cigarettes were consumed in 2000 (U.S. Department of Agriculture, 2001). The decline in per capita cigarette consumption during the latter part of the 20th century was due in large part to growing concerns about the adverse health consequences of cigarette smoking and the growth of the anti-smoking movement. Early case reports and case studies called attention...

Both Collagen and Elastin are Affected in Pulmonary Emphysema

In emphysema, major disruptions of the extracellular matrix occurs with a resulting enlargement of the air spaces. For many years, the focus has been on elastin since the most prominent histological change is a loss of elastin fibers particularly at junction points in the alveolar walls (98). Chemically, there are changes in all components of the connective tissue including elastin (99) and the total elastin content of emphysematous lungs is less than for normal lungs (100). It has been assumed that an imbalance between proteolytic enzymes, especially elastase, and proteinase inhibitors such as a-1-antitrypsin results in the loss of elastin fibers (101,102). This assumption is strongly supported by five facts 1 Individuals homozygous for a-1-antitrypsin deficiency often go on to develop emphysema (103). 2 Cigarette smoking, which alters a-1-antitrypsin chemically (104) and which leads to an increase in neutrophil elastase-derived fibrinopeptides in the serum of smokers (105), is a...

Hyaluronan in Emphysema

Evidence relating HA to emphysema is accumulating. Konno et al. (114) found HA to be decreased in emphysematous lungs. Data from animal models show that HA is involved in cigarette smoke-induced emphysema and in elastase-induced emphysema. Guinea pigs exposed to tobacco smoke have reduced levels of lung HA (115). Cantor et al. (116) showed that instillment of hyaluronidase and the addition of 60 oxygen, which is a non-toxic concentration of oxygen, produced air-space enlargement. They also showed that prior hyaluronidase treatment increased the effect of elastase instillment (117), an observation that was confirmed by Murakami et al. (118). Further, HA protected elastin fibers in vitro and lead to a decrease in air-space enlargement caused by elastase instillment in vivo (119).

Angiogenesis and Cancer

VEGF overexpression is associated with tumorigenesis and a poor prognosis in a multitude of cancers, including gastric carcinoma (Maeda et al. 1996), colorectal carcinoma (Lee et al. 2000 Takahashi et al. 1995), lung cancer (Fontanini et al. 1997), melanoma (Gorski et al. 2003), prostate cancer (George et al. 2001), breast (Berns et al. 2003), and ovarian carcinoma (Paley et al. 1997). VEGF is upregulated in cancer cells in vivo by hypoxia and starvation (Zhang et al. 2002), and also by oncogene activation, which drives constitutive VEGF overexpression (Zhang et al. 2003b). VEGF directly promotes tumor angiogenesis through multiple mechanisms such as endothelial cell proliferation and survival, endothelial cell migration, vessel destabilization via Tie-2 (Zhang et al. 2003c), and enhancing chemotaxis of bone marrow-derived vascular precursor cells (e.g., endothelial cells, pericytes, vascular leukocytes) (Conejo-Garcia et al. 2004 Ellis and Hicklin 2008). In addition, VEGF promotes...

Differential Diagnosis

The diagnosis of nicotine dependence is relatively straightforward, particularly in adults. Most adults admit that they smoke cigarettes, and they typically smoke on a daily basis. For adolescents and teens, smoking may not occur on a daily basis. The physician should ask them if they ever smoked and how frequently they smoke. If they do not smoke, or smoke only on occasion, the physician should inquire about expectations for smoking in the future. Older teens, of course, are more likely to report that they smoke on a daily basis, although the number of cigarettes smoked per day may be fewer than those smoked by adults. The clinician often wishes to determine the severity of tobacco dependence, because such information provides insight into how difficult it will be for the smoker to quit and what kind of quitting strategy will be most effective. Fagerstrom (1978) developed a brief nicotine dependence questionnaire. Among the most discriminating questions are the following How soon...

Dendritic Cell Defects in Cancer Patients and Mouse Models A Role for VEGF

The clinical significance of DC dysfunction has been demonstrated in a study of patients with breast, neck head, and lung cancer (Almand et al. 2000) DCs isolated from cancer patients were functionally impaired in a mixed leukocyte reaction, and this functional impairment corresponded to a more severe cancer diagnosis (higher stage) (Almand et al. 2000). Further, both the percentage and the total number of DCs were significantly reduced in the peripheral blood of cancer patients, and this observation correlated with an increase in the total number of immature hemato-poietic cells. The increase of immature cells in the blood was closely correlated to serum VEGF levels, but not transforming growth factor-beta (TGF-p), IL-6, or granulocyte macrophage colony stimulating factor (GM-CSF) (Almand et al. 2000). Importantly, these aberrations in DCs were somewhat corrected following chemotherapy and anti-VEGF therapy (Almand et al. 2000).

Age Related Macular Degeneration

The main unmet medical need is that there is currently no accepted medical therapy to treat dry AMD. Based on epidemiological studies many cases of dry AMD could be prevented by reducing cigarette smoking for example, almost 30 000 cases of AMD in the UK could be attributed to smoking.23 The role of oxidative stress in disease pathology suggests the advisability of antioxidant, carotenoid, and vitamin supplementation. One difficulty with dry AMD is that, as a largely asymptomatic and slow-developing disease, it is frequently the case that significant morphological damage (RPE cell and photoreceptor death) has occurred before the patient experiences visual deficit and thus is aware of the disease. On the positive side, a therapy that even just significantly slowed AMD progression in an elderly population might be sufficient to mostly preserve visual acuity for the rest of a patient's life.

Clinical Practice Guidelines

Physicians have a unique role to play in the anti-smoking arena (Sullivan, 1991). Past reviews (Orleans, 1993), monographs (U.S. Department of Health and Human Services, 1994b), and guidelines (American Psychiatric Association, 1996) underscore the importance of physician intervention on smoking in a variety of medical settings. The Public Health Service-sponsored Clinical Practice Guideline, Treating Tobacco Use and Dependence (Fiore et al., 2000), provides clinical and systems interventions that are intended to increase the likelihood of successful quitting. The major findings and recommendations may be summarized as follows 1. Tobacco dependence is a chronic condition that often requires repeated intervention. However, existent effective treatments can produce long-term or even permanent abstinence. 2. Because effective tobacco dependence treatments are available, every patient who uses tobacco should be offered at least one of these treatments Patients unwilling to try to quit...

Dual Transfer Function

The scenario of detecting tumor structures in a lung cancer patient illustrates the requirement to define transfer functions independently in PET CT visualization. Selecting the VOI from CT (e.g., by transfer function) and adjusting window level via transfer functions of PET necessitate manipulation of individual volumes, with the ability to visualize the changes in the fused volume in real time. Physicians may benefit from visualizing the functional tumor apparent in the PET scan alongside corresponding anatomical structures for localization from the CTscan. Kim et al. 76 suggested using dual-transfer functions for PET CT images, thereby providing separate 1D LUT transfer functions independently to the PET and CT volumes to be controlled, with the resultant volumes being fused in real time. Results from use of dual-transfer functions are shown in Figure 9.10. An axial view of a fused PET CT volume is shown in Figure 9.10(a), with its dual-LUT transfer function in Figure 9.10(b)....

Prevention Of Smoking

The prevention of tobacco use in children and adolescents requires a multi-pronged approach that targets the social environment, as well as individual behaviors (Bonnie, 2001 Lantz et al., 2000 Lynch & Bonnie, 1994 U.S. Department of Health and Human Services, 1994a). Individual behavior change strategies include school-based prevention programs, computer-based systems, and peer-based interventions (Lantz et al., 2000). Pediatricians and other health professionals also have an important role to play in preventing smoking initiation (Hymowitz, Schwab, & Eckholdt, 2001). Sussman, Lichtman, Ritt, and Pallonen (1999) reported that average reductions in smoking onset among youth generated by school-based prevention programs was about 6 , with a range of 0 to 11 . Programs that focused on teaching young people resistance skills to deal with social and other influences to smoke were most successful and had a longer lasting impact (Lantz et al., 2000). At the environmental level, mass...

Psychopharmacotherapy General Considerations

There are numerous approaches to smoking cessation and many comprehensive reviews of the literature (e.g., Hymowitz, 1999 Lando, 1993 Leventhal & Cleary, 1980 Schwartz, 1987). Although many approaches to smoking cessation have been successful in the short run, few, if any, have proved satisfactory in the long term. This is true for traditional group and individual counseling programs, hypnosis and acupuncture, self-help stop-smoking strategies, multi-component behavioral interventions, and pharmacological therapies (Hunt & Bespalec, 1974 Hymowitz, 1999 Yudkin et al., 2003). The tendency of smokers to quit, relapse, and quit highlights the cyclic nature of the quitting process and serves as a reminder that as much care and effort must go into helping smokers remain cigarette-free as into helping them stop smoking in the first place.

For Cellbased Interventive Therapies

Chronic neuropathic pain following damage to the peripheral or CNS has been difficult to treat clinically (14). As an illustration of the severity of pain following spinal cord injury (SCI), patients often report pain, rather than immobility, as the major deterrent to good quality of life (15). Pharmacological pain management is based on nonopioid and opioid analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase 2 (COX-2) inhibitors (16), calcium channel blockers (17), capsaicin (18), nicotine receptor agonists (19), and opioids (20) (e.g., morphine and its derivatives). Adjunct drugs, such as antidepressants and anticonvulsants, often accompany more antinociceptive agents in certain types of pain, like diabetic neuropathy (21). Gabapentin, an anticonvulsant, has become the most common medication for SCI pain (22), probably owing to its calcium channel-blocking functions (23). Combination of medications, such as NSAIDs with opioids, seems to be more...

Guidelines for Bone Density Testing in

Determining when testing is appropriate in men has become increasingly important with the advent of prescription pharmacologic therapy for the treatment of osteoporosis in men. The prevalence of osteoporosis in men, although not as great as that in women, is high. In one study (19), the prevalence of osteoporosis in a population-based sample of 348 men was 19 when osteoporosis was defined as 2.5 SD or more below the average peak BMD for men. The major risk factors for osteoporosis in men are not dissimilar from those seen in women cigarette smoking, advancing age, risk of falls, and the presence of diseases or the use of medications known to affect bone metabolism (20-22). Heavy alcohol consumption is considered a major risk factor in men, more so than in women. Other risk factors include a sedentary lifestyle, lifelong low calcium intake, and low body weight.

Industrial Chemicals and Occupational Cancers

The chemicals and industrial processes that have a known or suspected etiologic role in the development of cancer are listed in Table 3-6. As noted above, about 2 -5 of all cancer deaths are attributed to occupational hazards. Of those agents listed as carcinogenic for humans, a number were identified because of their close association between an abnormal clustering of certain cancers and exposure to an industrial chemical or process. For example, epidemiologic studies of workers occupationally exposed to industrial levels of 4-aminobiphenyl have a higher incidence of bladder cancer.80 Occupational exposure to asbestos fibers results in a higher incidence of lung cancer, mesotheliomas, gastrointestinal tract cancers, and laryngeal cancers.81 As mentioned earlier, cigarette smoking and occupational exposure to asbestos act synergistically to increase the incidence of lung cancer. Several epidemiologic studies have shown increased frequency of leukemia in workers exposed to...

Epidemiology and Etiology

Individually, these tumors are so rare in the 15- to 20-year-old age range that several of them do not merit attention in the Surveillance, Epidemiology, and End Results pediatric monograph 1, 2 . Most adult epithelial malignancies are thought to arise as a result of cumulative chronic genotoxic exposure 3 . Cigarette smoking accounts for a high proportion of attributable risk in many cancers, including TCC of the urothe-lium, which will be discussed herein. In contrast, the diagnosis of one of these tumors in a teenager should prompt consideration of genetic predisposition to cancer. Several well-characterized inherited syndromes are associated with an increased risk of malignancy (e.g., von Hippel Lindau syndrome and RCC). Furthermore, it is increasingly recognized that polymorphisms in genes that regulate DNA repair and the metabolism of carcinogens may be associated with a general increased risk of developing cancer. The most well known of these is the Li-Fraumeni syndrome, which...

Hyaluronan in Adhesion Migration and Invasion of Cancer

Two subsets of B16-F1 mouse melanoma cell lines, which had different rates of HA synthesis and consequently a 32-fold difference in surface HA, were injected into the tail vein of mice (62). The melanoma cell line expressing high levels of HA formed a greater number of nodules in the lung and increased rate of mortality compared to the lower HA expressing melanoma cells. The higher HA expressing cells also showed an enhanced interaction with CD44 expressing endothelial cells. Similarly, Itano et al. (65) compared the metastatic potential of a murine mammary carcinoma FM3A HA1 with HA deficient mutant cells. The mutant clones lacked the ability to form HA-rich pericellular coats and had a decreased ability to form metastases compared to the parental cells. Additionally the number of lung metastases by the HA-deficient cells was increased upon rescue of HA levels by transfecting in HAS1. HA and HAS expression have also been examined in human primary tumours and in metastases, if...

Air and Water Pollutants

Air, water, and soil pollution is estimated to account for only 1 -4 of all cancers. A small percentage of lung cancer (less than 5 ) may be due to chronic inhalation of outdoor air pollutants such as industrial or engine exhaust chemicals. Indoor air pollutants such as secondhand smoke and radon are thought to be contributors, but this risk is most likely exaggerated (see below). In China and some other Asian countries, chronic inhalation of cooking oil smoke may be a causative agent of lung cancer.90 The contamination of the atmosphere by chlorofluorocar-bons (whose production is now banned in developed countries) in refrigerant and propellants has been implicated in destruction of the ozone layer and a resultant increase in skin cancer due to a lower filtering of UV irradiation from the sun. Occupational exposure to inhaled asbestos, such as occurred in Liberty Ship building in World War II, has been clearly linked to me-sothelioma. cancers) for any given level of low-dose...

Applications in Substance Abuse Research

Since all drugs of abuse are fundamentally organic (i.e., carbon containing) molecules, 11C radiochemistry makes PET uniquely suited to the study of their pharmacokinetics (i.e., since insertion of the radiolabel does not alter the native pharmacology of the parent drug). In fact, PET radiotracers currently exist for 11C cocaine, 11C heroin, 11C morphine, and 11C nicotine (Hartvig et al., 1984 Fowler et al., 1989 Halldin et al., 1992), and tracer doses of these compounds have been used to study the pharmacokinetics of each in vivo. Among the earliest applications is work by Fowler and colleagues (Fowler et al., 1989). Their pioneering work with 11C cocaine in humans demonstrated extremely high levels of brain uptake (8-10 of the injected dose) into basal ganglia (a brain region containing the highest concentrations of dopamine transporters) that occurred rapidly (peaking within 4-6 min) and cleared quickly (with an initial brain half-life of approx 20 min). These studies were...

Inhibitors of Microtubule Assembly

In addition to the naturally occurring vinca alkaloids (Figure 2), a semisynthetic analog, vinorelbine 4,17,18 has been approved by the US Food and Drug Administration for treatment of nonsmall-cell lung cancer either as a single agent or in combination with cisplatin.19 Further evaluation of the vinca structure-activity relationship (SAR)20-23 has led to the identification of several analogs, including vinflunine 5 and KAR-2 6, that have progressed to advanced preclinical and

Modification Of Allogeneic Cell Vaccines With Costimulatory Molecules

Studies using human cells have shown that introduction of costimulatory molecules results in a large alloresponse, but despite this finding, tumor-specific CTLs could also be demonstrated 41,42 . Furthermore, HLA-A2+ allogeneic breast cancer cells modified to express CD80 were shown to stimulate CD8+ T cell responses from PBMCs of an HLA-A2+ patient 43 . In a phase I clinical trial to treat 19 patients with relapsed metastatic NSCLC, an allogeneic vaccine modified to express CD80 and a patient-matched HLA-A molecule (either A1 or A2) was used 44 . In the majority of patients, IFNy release from CD8+ cells was seen (as measured by ELISpot) in response to stimulation with mock transfected vaccine cells (CD80- HLA-A1 A2-). Patients had a 32 response rate (one partial response and five stable disease) with a median overall survival of 18 months compared to the previously reported median survival of less than one year for metastatic lung cancer.

Comparing the performance of selfassessment questionnaires

Several studies (19-22) have compared the performance characteristics of the various indices. Cadarette and colleagues (19) compared the performance of the ORAI index to that of SCORE, ABONE, the 1998 NOF guidelines22 and the body weight criterion in a population of 2365 postmenopausal women age 45 and older who were participating in the CaMos study. These women were otherwise healthy women who had not taken HRT or any other bone-sparing agent or who had taken HRT for 5 years or more. The average age was 66.4 years and the average weight was 152 lb (69 kg). Bone density was measured at the femoral neck and T-scores were calculated using the manufacturer's reference data for Canadian women in which the mean and SD were 0.857 g cm2 and 0.125 g cm2, respectively.23 To compare the performance of the 1998 NOF guidelines to the risk indices, the authors converted the NOF guidelines to an index scoring system in which 1 point was awarded for age 65 or older, weight less than 127 lb (57.6...

Current serum biomarkers of cancer

CEA, for example, is a human tumour marker typically associated with malignant epithelial neoplasms. The CEA gene belongs to a family of more than 20 members, clustered on the long arm of chromosome 19 31 and belonging to the immunoglobulin supergene family. Its main use is to monitor patients with colorectal carcinoma, but the antigen is not specific and elevated levels may be observed with some nonmalignant diseases including inflammatory bowel disease, liver disease 32 , pancreatitis and renal failure 33 . In healthy individuals, plasma levels are in a range of 0-5 ng ml and 3-10 ng ml in smokers, whereas patients with colorectal cancer exhibit levels > 20 ng ml.

Influence Melanoma Tumor Progression

Horuk et al. (50) as well as Roby and Page (31) have suggested that melanoma cells might make a novel receptor for MGSA GRO proteins (15,45). Such a novel receptor may be responsible for the growth response of melanoma cells to MGSA GRO-a or IL-8, which is not inhibited by antibody to CXCR2. Although antibodies to both the MGSA GRO-a ligand and receptor have been shown to block the growth of six different melanoma cell lines, owing to the redundancy of MGSA GRO-a, -p, and -y and the stability of the MGSA GRO proteins, antisense experiments are not informative and do not reduce the levels of protein sufficiently to inhibit growth (Richmond, unpublished). Recently, Olbina et al. (57) have demonstrated that antisense oligonucleotides to CXCR2 will inhibit the growth of tumors from nonsmall-cell lung cancer (38). An important experiment will involve the expression of antisense CXCR2 constructs in melanoma cells to determine whether this alters the growth and transformation properties of...

Pancreatic cancer 31 Background

Many dietary and environmental factors have been implicated as possible etiologic factors in the development of pancreatic cancer, but no definite causal relationships have been established. The strongest evidence points to cigarette smoking as a risk factor associated with pancreatic cancer (20-24). Occupational exposure to certain chemicals has also been linked to pancreatic carcinoma (25). Others in the high-risk group include stone miners, cement workers, gardeners, textile workers, and leather tanners (17,26).

The Great Cancer Myths

These authors have developed charts for men and women that show the chance of dying from various causes based on age and smoking history (Figs. 3-11 and 3-12). Instead of giving risks in terms of population percentages, these data show risk in terms of individual risks. For example, their data indicate that a 60-year-old woman, even one who smokes, has a 4.5 chance of dying of a heart attack in the next decade, a 6.5 chance of dying of lung cancer, and a 0.7 chance of dying of breast cancer. Or to look at it another way, for every 1000 60-year-old women who are smokers, 45 will die of heart attacks, 65 of lung cancer, and 7 of breast cancer in the next 10 years. For 60-year-old women who have never smoked, 14 of 1000 will die of heart disease, 5 of lung cancer, and 7 of breast cancer by the time they reach 70 years of age. For 60-year-old men who are smokers, 84 of 1000 will die of heart disease and 98 of lung cancer, but only 4 of 1000 will die of prostate cancer. cigarette smoking,...

Three Biological Examples

Rosenberg's last example concerns the units of selection controversy. He uses a strengthened version of an idea about causality that Sober and Lewontin (1982) defended. This is the idea that C is a positive causal factor for bringing about E precisely when C raises the probability of E in at least one background context, and does not lower it in any. For example, smoking is said to be a positive causal factor for lung cancer, if smoking increases some people's chances of getting cancer and does not lower anyone else's. Lewontin and I intended the range of background contexts to be the ones that are actually exemplified in the population. However, Rosenberg expands this set to include background contexts that are merely conceivable. It is no surprise that causal claims that seem to be true turn out to be false under his strengthened criterion. Just imagine a science fiction circumstance in which smoking actually reduces the chance of lung cancer, e.g., by causing physicians to supply a...

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