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).

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)...

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.

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

Psychiatric Disorders 601411 Schizophrenia

Nicotine related disorders Nicotine use disorders Nicotine induced disorders DSM-IV-TR defines 11 classes of commonly abused substances (see 6.07 Addiction). These include alcohol, amphetamine and amphetamine-like compounds, caffeine, cannabis, hallucinogens, inhalants, nicotine, opioids, phencyclidine, and the class of drugs defined as sedatives, hypnotics, or anxiolytics. Substance dependence is defined as a pattern of repeated self-administration that can result in tolerance, withdrawal, or compulsive drug-taking behavior, and has as a basis an anhedonia, the inability to gain pleasure from normally pleasurable experiences. Tolerance is evident as either a need for increased amount of substance to produce a desired effect, or the diminished effect of the same dose of substance over time. All substances of abuse produce tolerance, but the actual degree of tolerance varies across classes. Withdrawal involves maladaptive physiological changes that occur with declining drug...

Variability in Micronutrient Requirements among Individuais

Moreover, besides these genetic differences, nutritional requirements can be profoundly influenced by many factors, including age, environment, and lifestyle choices. A smoker's requirement for vitamin C is two to three times that of a nonsmoker.30 Pregnancy doubles a woman's need for iron. Strenuous athletic training sharply increases requirements for the vitamin B complex and magne-sium.31 Therefore, across the population, there a broad range of optimum intakes for the essential nutrients. Factors which cause nutritional needs to vary from person to person are shown in the table below and are considered in detail in later sections.

Risk Factors and Cancer

The increasing knowledge of the process of carcinogenesis induced by chemical agents provides a major basis for cancer control and has unraveled the association between smoking and lung cancer. About 30 of all cancer deaths in the USA are due to the use of tobacco, and this death toll is still increasing reflecting smoking habits among young women since the 1950s.1,15 Smoking causes more than 90 of all cases of lung cancer and is the main cause of cancers of the larynx, mouth, esophagus, bladder, kidney, and pancreas, while about 25 of colon cancer and polyps can be attributed to smoking. Five years after stopping smoking, the risk of cancer decreases to half and to the level of lifelong nonsmokers after 10-15 years. Reducing the epidemic of tobacco smoking is currently the most effective means of cancer prevention.15-17 Occupational factors may account for 5 of all cancer deaths, and these include mostly cancers of the lung, bladder, and bone marrow.1,19 Workplace exposure, the most...

The Neurobiology of Substance Dependence

Tolerance, dependence, and addiction are all manifestations of brain changes resulting from chronic substance abuse and involve different brain pathways than those subserving acute drug reinforcement. Acute drug reinforcement appears to share a final common dopaminergic pathway from the ventral tegmental area of the brain to the nucleus accumbens. These acute processes are relatively unimportant for pharmacotherapy of dependence and addiction instead, the neurobiology of changes associated with chronic use forms the basis for rational pharmacotherapy. This translation of neurobiology into effective treatments has been most successful for opioids, with more limited success for alcohol, nicotine, and stimulant dependence. Opioid treatments such as metha-done, levo-alpha-acetyl methadol (LAAM), buprenorphine, and naltrexone act on the same brain structures and processes as addictive opioids, but with protective or normalizing effects. This concept of normalization is critical for...

Origins Of Drug Liking

For example, opioids and cannabinoids can inhibit activity in N-Ac directly, whereas stimulants such as cocaine and amphetamine act indirectly by binding to various DA transporters and either inhibiting the reuptake of DA into the VTA neurons (cocaine) or actively pumping DA out of the VTA (amphetamine) at its synapse with the N-Ac neurons (Kosten, 2002 Stahl, 1998). Since stimulation of the DA D2 receptor inhibits the cyclic AMP system, this increase in DA in the synapse leads to relative inhibition of the N-Ac neuron. The mechanism is more complex than this, however, since the D1 receptor has the opposite effect on the cyclic AMP system (e.g., it increases the amount of cyclic AMP) and both D1 and D2 receptors are present on the N-Ac neurons. The presumption is that the D2 receptor effects predominate perhaps simply due to more D2 receptors, or due to a higher affinity of the D2 than the Dt receptors for DA. Other substances may be even more indirect in their stimulation. For...

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.

Carboplatin and oxaliplatin

Carboplatin, introduced in 1981, as an alternative to cisplatin has a similar activity profile but a very different toxicity profile to the original platinum complex (146-148). Carboplatin and cisplatin have been compared in numerous studies and, in general, the carboplatin-containing regimens were essentially equivalent to and less toxic than the cisplatin-containing regimens (146,147). Belani et al. (149) performed a study of concurrent carboplatin and radiotherapy in patients with inoperable stage III nonsmall-cell lung cancer and achieved a response rate of 33 . Carboplatin with concomitant radiotherapy has been evaluated in head and neck tumors (150). In this study 103 patients with advanced head and neck carcinoma treated with radiation therapy plus carboplatin (60-70 mg m2 d, d 1-5 and 29-33) had 1-yr and 2-yr survival rates of 77 and 53 , respectively.

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

Neuronal Nicotinic Receptor Agonists

The incidence of smoking is high in patients with schizophrenia, a rate at least three times higher than the general population. In fact, nicotine appears to produce a modest transient improvement in cognitive and sensory deficits in these patients. It has been suggested that smoking in schizophrenia represents an attempt to self-medicate.39 However, these views must be interpreted with caution. Overall, schizophrenic patients have a high degree of comorbid abuse of a variety of substances including nicotine, alcohol, cannabis, cocaine, and amphetamine. Importantly, the rate of substance abuse is higher than in the general population for all of these substances in spite of the fact that such abuse is associated with poorer outcomes, exacerbation of positive symptoms, increased hospitalization, and increased frequency of homelessness. This increased propensity to abuse a variety of substances regardless of consequences suggests that there may be a disregulation of reward systems in...

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.

Nonnutrient Dietary Components

Non-nutrient substances, i.e. those other than carbohydrates, fats and proteins, are present as minor components of foods and may have an effect on DIT examples of non-nutrient substances include caffeine, spices, and nicotine. A thermogenic stimulating effect has been found in green tea, attributed to its caffeine and catechin polyphenols content. Since the latter is capable of inhibiting the enzyme that degrades noradrenaline (catechol-o-methyl transferase) and caffeine inhibits transcellular phos-phodiesterases (enzymes that break down nora-

Aberrant Cav1 Expression Complexity and Context

In contrast to studies of Cav-1 ' that revealed its potential tumor-suppressor activities, recently published study results showed that Cav-1 ' TRAMP (transgenic mouse prostate) mice demonstrate significantly fewer primary tumors and lesions than Cav-1*'* TRAMP mice do 101 . Additional studies showed that transgenic mice with targeted overexpression of Cav-1 in prostatic epithelial cells using the short probasin (PB) promoter (i.e., PBcav-1 mice) demonstrated prostatic hyperplasia 96 , In addition, secreted Cav-1 from prostatic epithelial cells in PBcav-1 mice created a local microenvironment that permitted tumor growth and increased serum Cav-1 that was associated with increased experimental PCa lung metastasis activities. These results are consistent with those of numerous studies that have documented Cav-1 overexpression in PCa tissues 75, 105, 108, 109 and other malignancies, including esophageal squamous carcinoma 34, 45 , oral carcinoma 35 , papillary carcinoma of the thyroid 38...

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...

Rate of decline in lung function

1 An accelerated decline in lung function. In their classic paper that followed 800 London office staff with serial measures of FEV1 over 8years, Fletcher et al. 38 demonstrated that there is a range of FEV1 decline per year from almost nil to over 100mL per year. They suggested that those with a rapid decline were susceptible smokers. The average decline was 18mL greater in a smoker than in a non-smoker, i.e. 54 mL vs. 36mL year. Some non-smokers showed a rapid decline in function, indicating that there are factors other than smoking to be considered, but there were many more rapid decliners amongst the smokers and it is only those with very rapid declines (i.e. of 70-100 mL per year) who can lose the 3L or more of lung function that places them in the FEV11-litre category that is seen with hospital admissions of patients in their sixties. The US Lung Health Study 39 observed 4000 patients with mild COPD over 5 years with and without an anticholinergic bronchodilator. While the drug...

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.

Etiology and Pathogenesis 361 Etiology

Besides intense sun exposure, exposure to other environmental carcinogens begins or intensifies during this age period tobacco use, recreational drug use, alcohol use, and sexually transmitted disease. It is unlikely, however, that cancers resulting from these exposures occur during young adulthood. They are much more likely to occur later in life.

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.

Studies in MS and Other Conditions

Aromatherapy has been studied in a few other unrelated conditions. Small studies on older people with dementia have produced mixed results. Inhalation of black pepper extract may decrease the craving for cigarettes. People with a form of baldness called alopecia areata may benefit from scalp massage using a mixture of thyme, rosemary, lavender, and cedar-wood oils.

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.

Preparation for Quitting

The physician should then provide the patient with some basic didactic information about quitting smoking. (1) Smoking represents an addiction to nicotine. Therefore smoking cessation must be undertaken as seriously as one would approach any other drug addiction. Willpower alone is insufficient. The patient must make quitting smoking his her top priority. (2) The goal should be total tobacco abstinence after the quit date. (3) The patient can expect to experience unpleasant nicotine withdrawal symptoms (e.g. mood disturbance, insomnia, irritability, 3. Anticipate challenges to the planned quit attempt (including nicotine withdrawal symptoms), particularly during the critical first few weeks difficulty concentrating, increased appetite and weight gain). For most individuals, these symptoms peak within a few days of quitting and dissipate within 1 or 2 weeks. (4) The physician can help the patient identify high-risk or dangerous situations. These are events, internal states, or...

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,...

CASE 4 Thyroid Storm Case Description

A 25-yr-old woman presented to her physician two yr previously with weight loss, palpitations, and tremulousness. She was diagnosed with hyperthyroidism due to Graves' disease and started on therapy with an antithyroid drug. Because of a variety of circumstances, including an inability to afford the medication, she became increasingly symptomatic. Over the next two yr, she lost approximately 40-50 lbs, and developed significant proximal muscle weakness. When referred to the Endocrine Clinic, she was severely debilitated. The patient had no other medical problems. There was a positive family history of thyroid disease her mother had had an overactive thyroid treated surgically many years earlier. She smoked two packs of cigarettes daily and was unemployed.

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.

Historical Perspectives

Evidence that chemicals can induce cancer in humans has been accumulating since the sixteenth century (reviewed in Reference 7). In 1567, Paracelsus described a ''wasting disease of miners'' and proposed that exposure to something in the mined ores caused the condition. A similar condition was described in 1926 in Saxony and was later identified as the ''lung cancer of the Schneeberg mines.'' It was realized much later that the cause of this was probably exposure to radon. Nevertheless, Paraclesus could probably be called ''the father of occupational carcinogenesis. It is Bernadini Ramazzini, however, who published a systematic account of work-related diseases in 1700, who is more logically considered the founder of occupational medicine.7

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...

Multiplicity and ligand specificity

Which are bioactivated byAOX (orXOR). AOXalso plays an important role in the detoxification of potentially reactive iminium ions that can be generated by P450 or MAO, often from cyclic tertiary amines, e.g., nicotine.40 Menadione, isovanillin, and raloxifene are useful diagnostic inhibitors of AOX.65

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 role of nutritional factors in the susceptibility to COPD

It is possible that smokers who develop COPD have dietary deficiencies in the nutritional elements mentioned above. However, this hypothesis is not supported by longitudinal studies 68 and would not explain the whole problem, since there are so many confounding factors between diet and cigarette smoking (alcohol intake, etc.).

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,...

The Functional Impact of Cancer Cachexia

Many of the consequences of cachexia are likely to impact on patient function but as yet this has not been studied in detail. There is, however, a considerable body of knowledge about the importance of weight loss in relation to clinical end-points and treatment variables. Scott 37 studied patients with inoperable non-small-cell lung cancer -about 40 had at least 5 weight loss and almost 80 an elevated CRP. Weight-losing patients had a significantly lower KPS and overall QoL and greater fatigue and pain. An elevated CRP was independently associated with increased fatigue. In patients with advanced gastrointestinal (GI) cancer receiving palliative chemotherapy, Persson 38 showed that those who were losing weight had a reduced global QoL. In addition, on multi-variate analysis, poor performance status and weight loss were independently related to decreased survival and a lower probability of responding to treatment. In a one-month study of 24 patients with lung cancer, Sarna 42 used the...

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 .

Endosomes And Lysosomes

The internal matrix space of mitochondria contains enzymes that metabolize pyruvate and fatty acids, generating acetyl CoA. This space also contains enzymes that oxidize acetyl CoA. The end products of these enzymatic reactions include nicotine adenine dinucleotide hydride (NADH) and CO2. NADH is a form of nicotine adenine dinucleotide (NAD) with the addition of two electrons and is a major carrier and source of electrons for energy generation in the mitochondria. CO2 is a waste product, which is released into the blood and removed from the lung and kidney. The internal matrix also contains mito-chondrial DNA, ribosomes, tRNA, and enzymes necessary for regulating the expression of mitochondrial genes.

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.

Conclusions and the future

Ultimately the future of combined modality therapy looks bright for several of the major tumor sites. The role of gemcitabine in combination with radiation remains to be determined in many malignancies largely because trials have progressed slowly because of the initial clinical experience with this combination. Oncologists will hopefully have learned from the initial worrisome experience in lung cancer that proper phase I trials designed with an understanding of the interaction between radiation and the drug in question really need to be undertaken prior to starting novel therapies. The current series of ongoing trials will help determine the ultimate utility of the gemcitabine and radiation combination. It is hoped that the results of preclinical studies showing the potency of gemcitabine's radiosensitizing properties will be realized while normal tissue toxicities can be minimized.

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.

Epidemiology of Reproductive Toxicology

Antimicrobials, antiemetics, theophylline, caffeine, ethanol, and nicotine. From 15 to 25 of pregnant women report licit drug use (ethanol > nicotine), or illicit drug use (marijuana > cocaine > heroin), or have positive urine drug screens during pregnancy. Analgesics, vitamins, iron, antibiotics, theoph-ylline, and psychotropic medications account for 50 to 80 of all reported toxic ingestions by pregnant women.

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...

Implementation of Treatment

Daily massage is feasible if indicated from a therapeutic view (22). A RCT on smoking in 20 subjects found less anxiety and less cigarettes smoked in the group who used daily self-massage (22). Ideally, the use of massage therapy will include psychological parents persons with a history of positive interaction with the individual with epilepsy. Treatment designs utilizing laypersons as massage givers must consider that (as confirmed by video-EEGs) the quality of nonmanual interactions may also influence seizure control (22-25).

Toxic Optic Neuropathies Definition

Ethambutol and other antitubercular drugs, cytostatic agents, heavy metals, hexachlorophene, and methanol can all cause a toxic optic neuropathy (also see Chap. 17). The first priority is to identify the offending agent and then to block further exposure. Specific measures that follow are determined by the nature of the toxin. The most common syndrome of toxic damage to the optic nerve chiasm is that of tobacco-alcohol amblyopia. It is thought that the toxin in question is cyanide, which is present in trace quantities in tobacco smoke. Interventional therapy with oral multivitamins (e.g., vitamin B complex) and intramuscular injections of hydroxycobalamine (the decyanated form of vitamin B12) can reverse the visual loss in the early stages of the disease. These vitamins are thought to chelate trace levels of cyanide and detoxify the affected tissues. Some individuals may be more at risk than others are, based on the composition of their mitochondrial DNA and variations in the...

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...

Inflammatory Biomarkers and Clinical Utility

A more optimistic position would argue that residual risk indicated by inflammatory biomarkers in an optimally managed patient could provide impetus for intensification of lifestyle measures to ameliorate the individual's inflammatory profile. Weight loss, dietary interventions, smoking cessation, and regular physical activity may all mitigate inflammation beyond pharmacotherapy. Statins have received the greatest attention as pharmacological modifiers of inflammatory biomarkers. However, increasing evidence supports the possibility that other classes of medications may likewise modulate inflammation. Although aspirin has not consistently reduced levels of CRP, emerging evidence suggests that fibric acid derivatives, thiazolidinediones, and metformin can reduce such levels. The fibric acid derivatives can limit inflammation by activating peroxisome proliferator activated receptor-a (PPAR-a). The thiazolidinediones (e.g., the glitazone class of insulin...

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

Treatment of Graves Disease

When managing the problems of active Graves' disease, the following measures are known to be of benefit maintenance of a euthyroid state, avoidance of cigarette smoking (very important), use of topical hydrating agents (with or without preservatives, as needed), and nonsteroidal anti-inflammatory drugs. These are largely supportive therapy, allowing time to pass and inflammatory activity to subside, while protecting vision in the meantime. This is adequate for a majority of cases. Infrequently, one encounters cases of fulminant inflammatory disease that threaten destruction of the eye through extreme exposure of the ocular surface and formation of corneal ulcers, or by compression of the optic nerve, which can destroy vision to the point of no light perception. The use of orbital irradiation and or surgical decompression should be saved for these very dangerous, high-risk cases. High doses of oral corticosteroids, such as 1 mg kg of body weight of prednisone, can be used

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...

Therapeutic interventions

Conclusive evidence that lowering hsCRP levels leads to a reduction in clinical cardiovascular events in primary prevention settings is not available. Nevertheless, many behavioral and pharmacological interventions that reduce cardiovascular event rates are associated with lower hsCRP levels. Behavioral interventions in this category include smoking cessation, weight loss, increased physical activity, and dietary modification (see ref. 6 for a review). Pharmacological interventions are reviewed in the following sections. Because a patient's compliance with recommended interventions depends in part on his or her perception of absolute disease risk and because the addition of hsCRP testing to existing risk algorithms provides an improved prediction tool, a major rationale for hsCRP screening is to help motivate at-risk individuals to adopt healthier lifestyles and to comply with prescribed drug therapies.

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.

Preoperative radiation therapy

Several early investigations explored preoperative RT. In a comprehensive review, it was concluded that preoperative RT improves resectability and local control (40,41). Preoperative RT regimens provide pathologic complete response in 15-45 of patients, but with increased operative complications (doses above 45 Gy). Randomized trials have failed to show a survival benefit when preoperative radiation was compared to surgery alone, but many of the trials are fairly old and modern staging techniques were not used. A more recent randomized phase II trial of the Lung Cancer Study Group (LCSG 881) gave preoperative RT of 44 Gy to patients with pathologically proven IIIA disease, yielding only a 12 mo median survival and pathologic complete response (CR) in only 1 33 patients (42). Thus, despite more modern methods, results of preoperative RT and surgery do not appear to increase survival.

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.

Cardiovascular System

Transient hypertension is noted in nearly 50 of alcoholics undergoing detoxification and is related to quantity of drinking and severity of other withdrawal symptoms. Epidemiological studies have demonstrated that alcohol elevates blood pressure independently of age, body weight, or cigarette smoking (Klatsky, Friedman, & Armstrong, 1986). A 10-year follow-up study found even moderate intake of alcohol (< 23 grams day) significantly increased the risk for hypertension in men, independent of age and body mass index. The risk of hypertension was increased for women, but not significantly, when age and body mass index were controlled (Ohmori et al., 2002).

CASE 3 Acute Hyperkalemia Case Description

Her past medical history is notable for obesity, recurrent urinary tract infections, and COPD. There was no history of hypertension. Her current medications include albuterol (inhaled), long-acting glipizide, ibuprofen as needed, and trimethaprim sulfamethoxa-zole as prophylaxis for recurrent urinary tract infections. She has no known allergies to any medication. There is a prior history of tobacco use, last noted 20 yr ago. Her family history is notable for diabetes mellitus and hypothyroidism.

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,...

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