By E. Grobock. Loyola University, Chicago.
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 order 20mg tadalis sx otc erectile dysfunction song, node- responder bias purchase tadalis sx 20 mg visa impotence specialists,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. Despite the signiﬁcant reduction in smoking, Because of the unique biological features of small- especially among the male population since the cell lung cancer (SCLC), its staging and treatment Textbook of Clinical Trials. Green 2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5 160 TEXTBOOK OF CLINICAL TRIALS differ radically from the other three types of lung the TNM staging. Besides histological classiﬁcation, lung can- A staging system entirely different from that cer is also classiﬁed according to the Tumour, for NSCLC is used for patients with small-cell Node and Metastasis (TNM) staging and the carcinoma of the lung. The TNM is clinically categorised into two stages: limited staging system is applied primarily to NSCLC and extensive.
It does not follow that they are doing it in the most effective way (see false feedback loop) cheap 20mg tadalis sx free shipping erectile dysfunction causes emotional. Proofreading This is the task of reading a piece of writing that is about to be published tadalis sx 20mg visa erectile dysfunction treatment natural in india, and identifying any errors that may have crept in during the writing and editing processes. The mistake that authors sometimes make is believing this is an opportunity for them to improve what they have written. It is too late for that, and any attempts to overturn previous technical editing will be distracting and dangerous – risking more serious mistakes. Find yourself a quiet corner so that you can give the proof your full attention. Watch particularly for four types: • misspellings of names of people or their titles; • numbers that are inconsistent within the copy (i. Some say that you should read each proof twice, once for major errors and another for minor ones of spelling and punctuation. Others recommend reading backwards, so that you do not become distracted by the meaning. If possible, enlist the help of other readers: a fresh pair of eyes is far more likely to spot errors that you put there in the first place. Some people are better than others at proofreading: if you do find someone good at the task, cherish them. Propaganda A derogatory term used to dismiss a piece of writing that we believe upholds a viewpoint with which we do not 104 PROPAGANDA agree. When we speak we make use of a wide range of visual cues, such as eye contact and stifled yawns, to help us adjust to our audience and put our message across. When we write, we lose sight of the audience, and spend large amounts of time putting on (an unnecessary) posh overcoat. Whenever you come across a particularly impenetrable piece of prose that you have written, apply the pub test: how would you have explained this to your target reader, face to face? This invariably produces a sentence that is simpler and easier to understand. Once this has been agreed, all kinds of other arrangements have to be made, such as reserving time on the printing press, and summoning extra staff to help with the distribution. Postponing these arrangements is tiresome and costly, which is why we need deadlines. Publication planning Many pharmaceutical organizations now spend time and money working out what papers they need to have published where and by when. But it is usually less bad than many people think (see false feedback loop). But these articles are often badly written and hard to read, few take-home messages seem to get through (see CF Kellett et al. Poor recall performance of journal-browsing doctors, Lancet August 17, 1996), and it can take years for findings to be trans- lated into action. In fact the evidence of market research (and commercial success) shows that these publications, which are written in simpler English, are well read and acted upon. This leaves anyone writing for doctors having to choose: do they follow the style of the journal, and risk being ignored, or follow the style of the medical newspaper, and risk being undervalued? Punctuation Marks that make our writing easier to read (see colons; commas; dashes; exclamation marks; full stops; hyphens; quotation marks; semicolons). Puns Using a word with two meanings and making people smile (or even laugh a little). Beware overuse: The write stuff (as a headline on articles about writing courses) has become a tedious cliché. Putting on the posh overcoat It is hard to escape the feeling that when we write we need to impress (see English teachers). There are clear exceptions – when writing for doctors who believe that writing is of value only when they have to struggle over its meaning. On these occasions you should write to impress (see political writing), but do not expect readers to act on what you have written (see Pulse paradox). As a general principle, only start with a question, or put one in the title or headline, if it is clearly the policy of your target publication to do so (see evidence-based writing). Interviewees favour them, because it gives them control; readers tend to switch off. Quiet You do not need to put aside large tracts of time in order to write. Find out what they want you to talk about, who the audience will be, and what they really are trying to achieve.
The amount of heteronymous facilitation of of stroke patients (Aymard et al trusted 20mg tadalis sx erectile dysfunction pills wiki. Each horizontal bar represents one subject and the hatched terminals in patients with spinal cord lesions columns show the mean and 1 SEM in the three populations discount tadalis sx 20mg with mastercard erectile dysfunction pills cost. Modiﬁed In contrast with results obtained in the lower limb of from Faist et al. If the corticospinal control was normally exerted exaggerated on the affected side of most hemiplegic tonically, corticospinal lesions would be expected patients, there was no evidence for decreased pre- to produce a decrease in presynaptic inhibition of synaptic inhibition of Ia terminals on soleus, even in Ia terminals on FCR and an increase in presynaptic patients with a lesion in the territory of the anterior inhibition of Ia terminals on soleus. This would hemiplegia in the absence of any other evidence to imply that the organisation of the cortical control of suggest spasticity or motor impairment. However, this view is not supported by evidence from parkinsonian patients (p. A decrease in presynaptic inhibition of Ia terminals may not be responsible for the stretch reﬂex exag- geration which characterises spasticity measured at Spinal cord lesions rest,butthelackofcontrolofPADinterneuronesdur- Whatever the lesion in the spinal cord, presynap- ing motor tasks could still contribute to the motor tic inhibition is decreased on Ia terminals of the disability of these patients. This cannot be due to the interruption during both voluntary movement and gait. It voluntary contraction thereforeprobablyresultsfrominterruptionofother descending pathways which help maintain a tonic In spastic multiple sclerosis patients, presynaptic level of presynaptic inhibition of Ia terminals in nor- inhibition of homonymous soleus Ia terminals was mal subjects under resting conditions (e. Modulation of the soleus H reﬂex of patients Studies in patients 371 with spinal cord injuries has been examined during (1994) also found no reduction of the radial-induced treadmill walking (Yang, Stein & James, 1991). The D1 inhibition of the FCR H reﬂex at ISIs around mostcommonpatternobservedwasalackofHreﬂex 20 ms. The eronymous tendon tap is reduced in parkinsonian responsible abnormality is probably lack of mod- patients, all of whom were taking dopaminergic ulation of presynaptic inhibition of soleus Ia ter- medication (Roberts et al. In normal subjects, there is a profound mod- tionship has been found between the amount of ulationofthequadricepstendonjerkthroughoutthe presynaptic inhibition so assessed and various clin- step cycle, with the reﬂex peaking in early stance ical variables: rigidity in limb studied, Webster rat- and then decreasing progressively until almost abol- ing, duration of disease, duration of dopaminergic ished during the swing phase. There was no correlation between the ferences reﬂect differences in the modulation of decreaseinpresynapticinhibitionandgradeofrigid- presynaptic inhibition of Ia terminals on quadriceps ity or disease severity on the Hoehn and Yahr scale, motoneurones. This suggests that a descending pathway mous vibration produces complex effects which controls tonic presynaptic inhibition of Ia terminals are difﬁcult to interpret (see Chapter 12,p. Theﬁndingofsimilarresults Changes in radial-induced D1 inhibition of the forbothsidesinasymmetricalpatientsindicatesthat FCR H reﬂex the abnormality does not correlate with the degree Decreased presynaptic inhibition of FCR of rigidity. Only the late inhibition at ISIs of 70–100 ms was found to be reduced in the patients explored The co-contraction of agonists and antagonists typ- by Tsai, Chen & Lu (1997), and Nakashima et al. Radial-induced inhibition of the FCR H terminals, the late phase may involve long-loop reﬂex has been investigated in patients with differ- inhibitory connections to the brainstem (spino- ent types of dystonia: simple occupational cramp bulbo-spinal) or even the cerebral cortex (Huang (i. Theconsistentﬁndingisthat ECRtendonelicitsatransientinhibitionoftheongo- thesecondphaseoftheradial-inducedD1inhibition ing ECR EMG activity. It has been argued that this of the FCR H reﬂex was decreased in all types of dys- suppression is due to slowly conducting afferents tonia. Themoreseverethedystoniathemoremarked from the tendon (possibly group III) activating pre- was the decrease in presynaptic inhibition. The latter ﬁnding could reﬂect decreased gests that the CNS dysfunction underlying dystonia presynaptic inhibition of Ia terminals, but this con- causesaspeciﬁcchangeinthedescendingcontrolof clusion needs to be conﬁrmed by techniques assess- PAD interneurones. Itisalsointerestingthatasimilar ing presynaptic inhibition more speciﬁcally. This is in keeping with the ﬁnding that abnor- Conclusions malities of the hand representation in sensory cor- tex are more obvious in the hemisphere driving the Role of changes in presynaptic inhibition non-dystonic limb, even though they are correlated of Ia terminals in normal motor control to the severity of the dystonic limb motor impair- ment (Meunier et al. Changes in presynaptic inhibition of Ia terminals mayhavelittleeffectonthereﬂexresponsetoabrupt stretch. Instead, the role of changes in the presynap- Differential effect of repetitive TMS (rTMS) tic gating during motor tasks probably lies in the on the second and late phases of radial-induced modulation of physiological feedback from primary depression of the FCR H reﬂex endings, i. This corticospinal drive produces a decrease in presy- result supports the hypothesis that, while the naptic inhibition of Ia terminals to motoneurones Resume´ ´ 373 responsible for the movement. This ensures that the spasticity or motor impairment in the correspond- full feedback excitatory support from primary mus- ing muscle(s). However, the absence of modulation cle spindle endings is available to active motoneu- ofpresynapticinhibitionofIaterminalstosoleusand rones. Inparallel,presynapticinhibitionisenhanced quadriceps motoneurones probably contributes to onheteronymousIaterminalsoninactivemotoneu- the stiff gait of these patients. Duringvoluntaryco-contractionofankleﬂexorsand extensors and during active standing, presynaptic Dystonia inhibition of Ia terminals of ankle muscles is The CNS dysfunction underlying dystonia causes increased. This probably contributes to the depres- a decrease in presynaptic inhibition of forearm Ia sion of reciprocal Ia inhibition required for co- terminals. Thedecreaseinpresynapticinhibitionofquadriceps Ia terminals during active standing and in the early ´ ´ Resume part of the stance phase of gait ensures that excita- tory Ia feedback is available to provide a safety factor Background from animal experiments to the quadriceps contraction, when it must support much of the body weight. At the end of the stance Presynaptic inhibition of Ia terminals is accom- phase of gait, presynaptic inhibition of soleus Ia ter- panied by primary afferent depolarisation (PAD) minals is markedly increased, to help limit the acti- and reduces the size of monosynaptic Ia EPSPs vationofankleextensormotoneuronesandallowthe in motoneurones without change in the motoneu- body to move forward. Presynaptic inhibition is a potent mechanism since, in the acute spinal cat, it can completely suppress the monosynaptic reﬂex. It Changes in presynaptic inhibition has a long central delay (∼5 ms) and a long dura- and pathophysiology of movement tion (300–400 ms).
Generally safe tadalis sx 20 mg testosterone associations with erectile dysfunction diabetes and the metabolic syndrome, since the ities of dose-limiting toxicities are respectively number of Phase II agents that can be tested 0 tadalis sx 20mg for sale erectile dysfunction at age 30. However, as and European investigators for the conduct of Simon33 pointed out, it is rarely advantageous to 110 TEXTBOOK OF CLINICAL TRIALS go beyond two stages. Two excellent references PHASE III DESIGN with regard to Phase II design are Simon33 and 34 33 These studies typically ask a randomised question Shuster The designs of Simon stop at the ﬁrst about either survival or event-free survival (the stage only if lack of activity is demonstrated. Intent-to-treat is the analysis of choice the relative scarcity of patients with recurrent for efﬁcacy, with other analysis done as sec- disease, designs that stop early for either lack of ondary supportive inference. The response would be event-free survival from the randomi- rate of the new study is statistically compared sation date. Makuch and Phase III studies are typically designed assum- Simon35 have provided methods to determine ing either proportional hazards or the cure model the sample size requirements for these studies. Randomised Phase II Comparison Nearly all Phase III childhood cancer trials are run either as two-armed studies or as 2 × 2 fac- Due to a limited availability of patients, it is torial studies. It is rare that sufﬁcient numbers of exceedingly rare that a randomised comparison paediatric cancer patients are available to conduct of a new agent to a control is feasible in a three-armed studies, except perhaps in ALL, the paediatric Phase II study. The programme EAST38 A qualitative interaction between treatments A can be used for designs that allow for both and B would occur if a standard regimen plus A early acceptance and early rejection of the null is superior to the standard regimen alone, but the hypothesis that the new treatment is equivalent standard plus A plus B is inferior to the standard to the control treatment. For example, if a study is to randomise In paediatric oncology, with limited patient leukaemia patients to receive or not receive regi- numbers, only one or two cooperative Phase II menA,designedtohaveanimpactontheCNS, trials are conducted with each new agent, and while at the same time to receive or not receive all malignancies refractory to standard therapy regimen B, designed to have an impact on mar- are typically combined into a single paediatric row remission, a factorial design would seem Phase II trial, usually stratiﬁed by histology. Essentially, we can run two studies surprisingly, Phase II trials of novel multiagent for the price of one. If the two interventions have regimens provide greater evidence of activity much in common, this would be a contraindi- than single agent Phase II trials and offer cation for a factorial design. This can take the form of biologic studies, late effects, or zero or even harmful. These studies Phase III studies done in cooperative groups are designed on a case-by-case basis. Cases are deﬁned as patients failing at planned intervals for efﬁcacy, until it releases a protocol (typically a relapse) and controls the study to the study committee. These studies can be can occur no sooner than the earlier of (1) all done using sequential designs, typically two- subjects have completed the planned intervention stage designs. Other typical studies might look or (2) the study was closed early and a new at cognitive impairment (multivariate analysis intervention is needed for patients on one or of variance of neuropsychological variables), both arms. Any release prior to the planned date acute toxicity of a speciﬁed type (typical Chi- of ﬁnal analysis requires approval of the board. ETHICAL AND OTHER SPECIAL Negative questions are often posed for paedi- CONSIDERATIONS AFFECTING CONDUCT atric cancer. For such studies, a very high cure OF TRIALS IN CHILDREN WITH CANCER rate of at least 85% has been shown possible on a conventional regimen. To vulnerable population of research subjects, often answer such questions with conﬁdence requires grouped with other special classes, like the large numbers, and it is rare that even the entire mentally retarded, mentally ill and prisoners. For example, if a to all research involving children as subjects disease has a historical 4-year remission rate of which are covered by Subpart D of Part 46 of 90%, and an accrual rate of 200 patients per year, Title 45 of the Code of Federal Regulations a randomised study would take 6 years of accrual (45 CFR 46), requiring that institutional review (10-year duration) to have 95% power to detect boards (IRBS) give consideration to the degree a degradation to 85% under reduced therapy at of risk, the beneﬁt to child subjects, the nature p = 0. While the beneﬁts of reduced therapy Subsequent to the promulgation of the original may be obvious, such studies carry considerable rules, adopted in 1983 and modiﬁed in 1991, risk and must be carefully monitored for early there has been nearly continuous debate and evidence that the reduction in therapy is unsafe controversy surrounding safeguards for all human and is associated with an inferior outcome. Federal NIH policies promul- a major research university in which human gated in 1998 were aimed at increasing the par- subjects were not protected, adverse events had ticipation of children in research so that adequate not been reported and ﬁnancial conﬂicts of data would be developed to support the treatment interest were involved, served to trigger several for disorders affecting adults which also affect new federal initiatives to further strengthen children, and rules mandated that children (i. As a result, the which impact the conduct of paediatric trials, ethical and regulatory framework within which there are also practical problems associated with paediatric cancer clinical trials are conducted, clinical cancer research in children. Due to an now and in the future, will continue to evolve, understandably greater concern for long-term and investigators must remain abreast. The frequency and severity of late the acute or delayed effects of cancer treatment effects also tend to progress with time off treat- on the growing child. For example, Lipshultz to enroll children in clinical trials as a result et al. International collabora- multivariate analysis showed that female sex and tion will probably be required in a substantial higher cumulative dose of doxorubicin were asso- segment of cancer types in order to obtain suf- ciated with depressed contractility, that there was ﬁcient patient numbers to conduct randomised an association between younger age at diagnosis trials. Enlightened partnerships between industry and reduced left ventricular wall thickness and and academia, with the assistance of the FDA and increased afterload, and that the prevalence and NCI, will be needed for efﬁcient development of severity of abnormalities increased with longer new agents. Tradi- of late effects of childhood cancer, the greatest tionally the ﬁeld involved paediatric haematolo- challenge being data collection. Today, diagnostic imagers, bench scien- OF CHILDHOOD CANCER RESEARCH tists, geneticists, pharmacists, clinical psychol- ogists, health economists and others also play signiﬁcant roles in the research. In the future, Despite the progress of the last half century there other ﬁelds of expertise will surely need to be remain a number of challenges in childhood can- added to the team. The focus of research in certain patient sub- disciplinary team and prompt referral of patients sets with very high cure rates will be on quality to paediatric cancer centres participating in clini- of life endpoints. For example, retinoblastoma is cal trials will be critical to achieving future goals curable in nearly 100% of cases, so preservation of reﬁning and improving therapy. Cancer Incidence and Survival among Children and Ado- hood cancer will be developed which would be lescents: United States SEER Program 1975–1995.
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