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By I. Gorok. Cleveland State University. 2018.

The most widely utilised Several primary prevention trials to prevent manoeuvre is that of withdrawal cheap 200 mg celecoxib overnight delivery. If the effect dementia or AD have been initiated with most induced by the drug is purely symptomatic generic celecoxib 200mg on line, even utilising an enrichment strategy 200 mg celecoxib amex. An alternative clinical manoeuvre women with a family history of AD ran- to demonstrate the same effect would be a domised to HRT or placebo order celecoxib 200 mg with mastercard. Gingko study–3000 normal elderly subjects the group is started on drug and half started on (age >75) treated with Ginkgo or placebo cheap celecoxib 200mg without prescription. In addition to various trial manoeuvres, the PRIMARY, SECONDARY AND TERTIARY demonstration of a structural change within the TREATMENTS brain could be used to support a structural effect for a therapeutic agent. For example, in a rate Treatment of existing symptoms represents ter- of decline trial, the maintenance of hippocampal tiary treatment and is representative of all of volume or the maintenance of a synaptic num- the currently approved drugs for AD. Secondary ber, as demonstrated on an imaging study, would treatment refers to treatment when minimal but serve as a direct demonstration that a pharma- not full-blown disease is present. This is best cological agent produced a difference in brain exemplified by the treatment of patients with MCI structure. Randomised start and randomised withdrawal it might be reflected in higher homovanillic acid drug and looking for improvement. In reality, this levels in the cerebrospinal fluid after drug with- manoeuvre is often carried out in the clinic with drawal at the end of the treatment period. For AD, simple withdrawal of the agent, retesting, rein- a clear-cut biochemical marker does not yet exist. While still useful, the lack of a blinded N-OF-ONE DESIGN crossover to placebo limits the interpretation of the results of this manoeuvre. This manoeuvre is not particularly useful for drug development but is often used in the clinical set- ting to determine continued response to drug. ETHICAL ISSUES An example of an N-of-one design in an ide- alised setting would be to answer the question of At present, available drugs to treat AD are symp- whether or not a patient on a cognitive-enhancing tomatic. Several agents are currently approved agent, such as a cholinesterase inhibitor, is still and before enrolling patients in any clinical trial, responding to drug. This question is an impor- disclosure and discussion of these agents with the tant one since AD patients continue to decline patient and their caregiver is necessary. After one or two years on tion, vitamin E and selegiline have been reported treatment, the clinician is faced with the decision to delay the time to endpoints in moderately as to whether or not to continue treatment. The results of the vitamin an idealised version, a patient could be blindly E study also need to be discussed with patients crossed over to placebo to examine for a with- before enrolling them in clinical trials since the drawal effect. If the patient was on a symp- use of both cholinesterase inhibitors and vitamin tomatic treatment and continuing to respond, a E is currently the standard of care in the US. This manoeuvre could then regarding the ethics of placebo-controlled tri- be followed by blindly restarting the patient on als. Arch Neurol (1976) 33: on studies or by demonstrating equivalence of 217–18. In addition, patients are free to not enter hypoxia in senile dementia and other abiotrophies. Necropsy evidence of central cholinergic deficits cern that comparator studies may result in the in senile dementia. George-Hyslop PH, Tanzi RE, Polinsky PJ, agent and the true effect size in the approved et al. Gene dose of apolipoprotein E type 4 allele and a placebo-controlled trial. Allgem Z Psychiatr-Gerich Med man R, Bick KL, Sisodia SS, eds, Alzheimer Dis- (1907) 64: 146–8. The associa- disease: a case–control study of an Italian popu- tion between quantitative measures of dementia lation. A double-blind, heimer and morbus Pic: a genetic, clinical, and placebo-controlled multicenter study of tacrine for patho-anatomical study. Philadelphia: Lippincott Williams Patterns of decline in the Lewy body variant & Wilkins (1999) 188–203.

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In contrast 100 mg celecoxib overnight delivery, unselected the large sample size and high costs associated normal subjects over the age of 65 develop AD 38 with this strategy buy celecoxib 200 mg visa, enrichment strategies should at a rate of only 1% per year cheap celecoxib 100mg on-line. These include enrolling: older conversion has allowed for the development of subjects purchase 200 mg celecoxib visa, subjects with a positive family history clinical trials of a reasonable size using the MCI of AD buy generic celecoxib 200mg, and subjects at risk because of the pres- patient population. Several primary pre- trials is the time to development of clinically vention trials for AD are currently preparing to diagnosable AD analysed with survival analysis. Several such trials have been initiated recently A second strategy would be to find subjects who examining the effects of vitamin E, cholinesterase are already randomised to compounds of interest inhibitors and NSAIDs to delay the time to the in trials for other indications to which cognitive development of AD in patients with MCI. However, to hormone replacement therapy (HRT) to deter- after the age of 65, the prevalence doubles mine the effects of these agents on coronary approximately every five years reaching an artery disease and osteoporotic fractures. Cog- average prevalence of over 30% by 90 years nitive endpoints have now been added to this of age. A third approach would be to ran- of the disease by five years would result in a domise to drug treatment a non-demented popula- 50% reduction of prevalence in one generation. If individuals are entered into a study entirely Thus, primary prevention would yield the greatest on the basis of age, a large sample size will cost benefit. For example, for individuals at occur 20–30 years before the clinical expres- a mean age of 75 who have normal cognition sion of disease. With such low incidence, even these large Treatments that slow progression in AD may samples will yield only 150 cases of dementia produce underlying structural change within the in the untreated group. One could logically reason that if treatment incidence of AD by 50%, 75 cases would exist in caused slowing of the rate of decline, it may the treated group. To allow for losses to follow-up have a permanent underlying effect on the brain. These sample sizes would only allow for that an underlying brain structural effect has an 80% probability of detecting a 30% increase occurred. The most widely utilised Several primary prevention trials to prevent manoeuvre is that of withdrawal. If the effect dementia or AD have been initiated with most induced by the drug is purely symptomatic, even utilising an enrichment strategy. An alternative clinical manoeuvre women with a family history of AD ran- to demonstrate the same effect would be a domised to HRT or placebo. Gingko study–3000 normal elderly subjects the group is started on drug and half started on (age >75) treated with Ginkgo or placebo. In addition to various trial manoeuvres, the PRIMARY, SECONDARY AND TERTIARY demonstration of a structural change within the TREATMENTS brain could be used to support a structural effect for a therapeutic agent. For example, in a rate Treatment of existing symptoms represents ter- of decline trial, the maintenance of hippocampal tiary treatment and is representative of all of volume or the maintenance of a synaptic num- the currently approved drugs for AD. Secondary ber, as demonstrated on an imaging study, would treatment refers to treatment when minimal but serve as a direct demonstration that a pharma- not full-blown disease is present. This is best cological agent produced a difference in brain exemplified by the treatment of patients with MCI structure. Randomised start and randomised withdrawal it might be reflected in higher homovanillic acid drug and looking for improvement. In reality, this levels in the cerebrospinal fluid after drug with- manoeuvre is often carried out in the clinic with drawal at the end of the treatment period. For AD, simple withdrawal of the agent, retesting, rein- a clear-cut biochemical marker does not yet exist. While still useful, the lack of a blinded N-OF-ONE DESIGN crossover to placebo limits the interpretation of the results of this manoeuvre. This manoeuvre is not particularly useful for drug development but is often used in the clinical set- ting to determine continued response to drug. ETHICAL ISSUES An example of an N-of-one design in an ide- alised setting would be to answer the question of At present, available drugs to treat AD are symp- whether or not a patient on a cognitive-enhancing tomatic. Several agents are currently approved agent, such as a cholinesterase inhibitor, is still and before enrolling patients in any clinical trial, responding to drug. This question is an impor- disclosure and discussion of these agents with the tant one since AD patients continue to decline patient and their caregiver is necessary. After one or two years on tion, vitamin E and selegiline have been reported treatment, the clinician is faced with the decision to delay the time to endpoints in moderately as to whether or not to continue treatment. The results of the vitamin an idealised version, a patient could be blindly E study also need to be discussed with patients crossed over to placebo to examine for a with- before enrolling them in clinical trials since the drawal effect. If the patient was on a symp- use of both cholinesterase inhibitors and vitamin tomatic treatment and continuing to respond, a E is currently the standard of care in the US.

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It is likely that the GMK vaccine acted perhaps even a detrimental effect buy celecoxib 100mg lowest price, from adjuvant essentially as placebo and the study provided interferon buy celecoxib 100 mg with mastercard. But we do not know this (a total of 31 out of 280 eligible patients effective 200mg celecoxib, or for certain order celecoxib 100 mg overnight delivery. As the dramatic survival difference 11%) and an imbalance in a major prognostic between E1684 and E1690 observation patients factor (ulceration of the primary tumour) biasing amply illustrates purchase celecoxib 100mg with amex,13 comparison of patient out- the results in favour of the observation arm. Even assuming that the analyses cor- analysis of E1694 showed the greatest interferon rected for the inherent responder versus non- over vaccine benefit for the subset of thick, node- responder bias,20 the results still cannot be used 15 negative patients. As pointed out subset analysis indicated a different group as in numerous publications, response to treatment obtaining the most benefit from high-dose inter- could simply serve as a selection mechanism feron: the subset with one single positive node wherein responders represented a better progno- in E1684; the subset with two to three positive sis group. One may contend that it is difficult to nodes in E1690; and the node-negative subset MELANOMA 157 in E1694. The authors properly suggested that, of a far more homogeneous patient population taken together, there was no indication of prefer- than any prior clinical trial, potentially enhancing ential treatment effect in any one subset. Unfortunately, this trial errors stemming from multiple testing, post hoc is likely to be small compared to the most recent subset analyses suffer both high false-positive Intergroup trials and, regardless of the results, it and high false-negative rates. The combined evidence indicates profound, and the burden they place on clinical that, for high-risk melanoma patients, treatment trialists is clear: design and analyse our trials of high-dose interferon prolongs relapse-free carefully to have the greatest probability of a survival. REFERENCES There are many reasons why high-dose inter- feron has not been uniformly embraced by physi- cians and patients around the world, even though 1. Pro- it is the only adjuvant therapy yet shown to have gnostic factors analysis of 17,600 melanoma patients: validation of the American Joint Com- any sustained impact on relapse-free survival. J Clin When the three trials are looked at in the light Oncol (2001) 19: 3622–34. Narrow excision (1- differences are more plausibly regarded as under- cm margin): a safe procedure for thin cutaneous standable variations reflecting trial design and melanoma. Long-term analysis, combined with the fluctuations inher- results of a multi-institutional randomized trial ent in human clinical trials conducted over time comparing prognostic factors and surgical results in similar yet subtly different patient populations. Only one current clinical trial, basins in melanoma patients undergoing sentinel the Sunbelt Melanoma Trial, is comparing one node biopsy. The role of elective lymph node dissection in melanoma: rationale, results, and This study includes only patients with a single controversies. Immediate or delayed dissection 158 TEXTBOOK OF CLINICAL TRIALS of regional nodes in patients with melanoma of 14. J Clin of intraoperative lymphatic mapping for early Oncol (1994) 12: 1036–44. Vali- High-dose interferon alfa-2b significantly prolongs dation of the accuracy of intraoperative lymphatic relapse-free and overall survival compared with mapping and sentinel lymphadenectomy for early- the GM2-KLH/QS-21 vaccine in patients with stage melanoma: a multicenter trial. Multicen- resected stage IIB–III melanoma: results of ter Selective Lymphadenectomy Trial Group. Multi-institutional melanoma lymphatic preferences for adjuvant interferon alfa-2b treat- mapping experience: the prognostic value of ment. J Clin Oncol (1999) 17: High-dose interferon alfa-2b does not diminish 976–83. Adjuvant therapy for patients with resected melanoma: results of the melanoma. Multi-institutional melanoma vac- Cooperative Oncology Group trial EST 1684. McMasters KM, Sondak VK, Lotze MT, Ross lity-of-life – adjusted survival analysis of inter- MI. Recent advances in melanoma staging and feron alfa-2b adjuvant treatment of high-risk therapy. A pooled High- and low-dose interferon alfa-2b in high-risk analysis of ECOG and Intergroup trials of adjuvant melanoma: first analysis of Intergroup trial E1690/ high-dose interferon for melanoma. SCHILLER AND KYUNGMANN KIM Departments of 1Medicine and 2Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI 53792, USA INTRODUCTION late 1970s, the incidence of lung cancer is still ris- ing because of long latency and a steady increase Carcinoma of the lung and bronchus is estimated in smoking among the female population. As a conse- next four leading cancers, colon, breast, prostate quence, the smoking-related public health problem and pancreas, all combined. Cigarette smoking is attributed as related cancer incidence and death, as well as the cause of 80% to 90% of lung cancer cases, with other diseases such as cardiovascular and other the risk for lung cancer among smokers being 20 pulmonary diseases, appears to be in smoking to 30 times that among non-smokers. Other risk cessation and prevention of taking up the smok- factors include exposure to asbestos and radon. Asbestos exposure, known to cause malignant mesothelioma, increases the risk for lung cancer, CLASSIFICATIONS especially among smokers. There are limited data on molecular and genetic profile as a risk factor, Lung cancer consists of four major histological and familial predisposition to lung cancer.

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Notwithstand- ate tendon directly: percussion on a bony protu- ing buy celecoxib 200mg, the rising phase of the electrically evoked EPSP berance will result in a vibration wave that trav- is briefer than might be expected given the opportu- els along the bone exciting muscle spindles in nity for dispersion of the volley created by the long nearby muscles and celecoxib 200mg visa, in subjects with brisk ten- conduction pathway (much longer than in the cat) purchase 100mg celecoxib with visa, don jerks generic celecoxib 100 mg with amex, may produce tendon jerks in multiple theslowerconductionvelocitiesofgroupIaafferents muscles throughout the limb – the phenomenon of −1 (maximally∼60–70ms inthelowerlimb order 100mg celecoxib with amex,i. The muscle spin- −1 of Ia conduction velocities (∼60–70 m s down to dle is not the only receptor responsive to ten- −1 ∼48 m s ; see Chapter 7,pp. It has been don percussion, even when the mechanical stimu- suggested that group Ib afferents curtail the electri- lus is delivered carefully only to the appropriate callyevokedEPSPandthattheHreflexcanbealtered muscle: sensitive muscle and cutaneous receptors by altering transmission across the Ib inhibitory throughout the limb, even those in antagonists, may interneurone, a situation not equally applicable be excited and the extent of this will be dependent to the tendon jerk (Burke, Gandevia & McKeon, only on effective transmission of the mechanical 1984). There is now direct experimental support stimulus (Burke, Gandevia & McKeon, 1983; Ribot- for this suggestion (Marchand-Pauvert et al. Hreflex Conclusions On the other hand, a 1-ms current pulse will excite axons only once, producing a more synchronised The tendon jerk and the H reflex are both dependent afferent volley, but one that involves group Ib as on the monosynaptic excitation from homonymous well as group Ia afferents. In addition, the stimu- Ia afferents, but they differ in so many other respects latednerveusuallyinnervatesmanymuscles:e. Underlying principle In the cat, Matthews & Rushworth (1957a,b) demon- Presynaptic inhibition of Ia terminals strated that it is possible to block efferents This is more effective on the afferent volley of the H using local anaesthetic applied directly to the reflex than on that eliciting the tendon jerk (Morita nerve because they are smaller than efferents. Rushworth (1960) then showed that injections of Methodology 119 dilute procaine into the motor point reduced both Acceptable techniques spasticity and rigidity, an effect attributed, not unreasonably, to efferent blockade (however, Microneurography see below). Microelectrode Situation in human subjects The first definitive reports of microneurography were publishedbyVallbo&Hagbarth(1968)oncuta- The situation in human subjects is quite differ- neous afferents and Hagbarth & Vallbo (1968)on ent from the controlled experimental circumstances muscle afferents. The basic technique has not rather than smaller axons, and this will also be changed greatly since then, and adequate descrip- so when the injection is into the motor point. The ents and efferents and, theoretically at least, reflex traditional microelectrode is a monopolar tungsten depression could result from loss of small afferent electrode with a shaft diameter of ∼200 m, insu- inputs rather than loss of fusimotor function. Loss lated to the tip, with an optimal impedance in situ of of the tendon jerk but preservation of near-normal ∼100–150 k for single unit recordings and perhaps strength does not constitute an adequate control for ∼50 k for multi-unit recordings. Some authorities the integrity of motor axons because consider- preferconcentricneedleelectrodeswithorwithouta able denervation is required before the triceps surae bevelled tip, but the electrode has a wider shaft and, muscles become weak to clinical testing. Finally, inpractice,thereisprobablylittleadvantageoverthe microneurographic studies have shown that, in gen- traditional electrode. It is likely that greater involvement of effer- into an appropriate nerve fascicle. In most labora- ents occurs during the recovery from a complete tories this is facilitated by delivering weak electrical local anaesthetic block than during its induction, stimuli through the electrode to produce radiating but this remains to be proven. Pressure blocks seem cutaneousparaesthesiae(whentryingtohomeinon to produce a more reliable sequence of axon block, a fascicle innervating skin) or a twitch contraction of large before small, possibly because their temporal the innervated muscle (when focussing on a fasci- development can be controlled, at least in part, by cle innervating muscle). When in situ,itwas supported without rigid fixation at one end by its connecting lead and at the other by the skin and subcutaneous tissue. Its position was adjusted within the nerve until the tip penetrated the desired nerve fascicle. Minor adjustments were made to bring the desired neural activity into focus. Note that the microelectrode has a shaft diameter of ∼200 m and that the largest axons have a diameter of ∼20 m. The target muscle was identified by the responses to intraneural electrical stimulation and the responses to passive and active movements of the digits. The ending increased its discharge during extension and passive abduction (not shown) at the fourth metacarpophalangeal joint, the responses to stretch and shortening being essentially static. This is preferable to external fix- to differentiate muscle spindle afferents from Golgi ation because movement by the subject cannot be tendonorganafferentsincludetheclassicalresponse avoided,andexternalfixationthenleadstoelectrode to a twitch contraction of the receptor-bearing mus- dislodgement. Even so, the stability of the recording cle (unloading with spindles: Figs. The twitch contractions can be pro- duced by stimuli delivered through the recording Identification microelectrode, transiently switching off the record- If arecording is obtained from a single axon it is ing to do so (McKeon & Burke, 1980;Burke, Aniss & necessary to identify the axon as an afferent and Gandevia, 1987)orbyusing external stimuli to thentocharacteriseitsresponsetovariousstimuliin the nerve trunk (e. This can be times ambiguous, possibly because of the above- time-consuming,andoftenrecordingsfrompartially mentioned fascial interconnections between nearby or completely identified afferents are lost before motor units and the spindle (see Burke, Aniss & Methodology 121 Fig. Note that an early discharge occurs before torque starts to rise (associated with the volley, cf. In both (c ) and (d ) the movement of the ankle joint is shown in the lower trace, but for simplicity, the goniometer record for the primary ending has been omitted. In (d) the imposed movements for the two endings were very similar, but not quite identical in amplitude, so that occasionally the discharge of the primary ending appears slightly out of phase. Both primary and secondary 122 Muscle spindles and fusimotor drive (b) (a) (c) (d) (e) f ) Fig. The effects of isometric voluntary contractions on background discharge rate of a secondary ending in extensor digitorum longus.

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