Temsirolimus in Daily Use: Results of a Prospective Multicentre Noninterventional Study of Patients with Metastatic Kidney Cancer

Background

Temsirolimus (TEMSR) was approved for treating advanced renal cell carcinoma (RCC) in 2007. Based on the data from a single phase 3 trial, it is recommended explicitly as first-line therapy for patients with a poor clinical prognosis.

Objective

The aim of this prospective multicentre trial (STARTOR) was to examine the effectiveness of TEMSR in daily clinical practice with a broader indication in the treatment of metastatic RCC.

Design, setting, and participants

Metastatic RCC patients treated with 25 mg of TEMSR weekly were submitted to a prospective systematic evaluation and follow-up in 87 German centres between January 2008 and October 2011 using standardised procedures.

Outcome measurements and statistical analysis

All data were centrally analysed by an independent clinical research organisation.

Results and limitations

This interim analysis of the STARTOR study included 386 patients. The observed toxicity was tolerable, the median dose intensity was 91% (interquartile range: 79–100%), and the median treatment duration was 20.1 wk (95% confidence interval [CI], 17.0–23.3 wk). Clinical benefit was seen in 157 patients (40.7%); the median progression-free and overall survival were 4.9 mo (95% CI, 4.2–5.6) and 11.6 mo (95% CI, 9.3–13.9), respectively. The effectiveness of TEMSR did not differ significantly in relation to the patient's age, histologic RCC subtype, or line of treatment. The major limitations were the noninterventional study design, limited information about Memorial Sloan-Kettering Cancer Center risk factors and detailed toxicity, and the lack of central radiologic review.

Conclusions

TEMSR is an effective and largely well-tolerated treatment alternative for metastatic RCC patients in daily clinical practice, irrespective of the patient's age, histologic RCC subtype, or line of treatment.     

婴儿抚触研究进展

从婴儿抚触的概念、生理机制、作用、要求、方法、影响实施的因素等多个方面，综述了婴儿抚触的研究进展。     

Clinical and Radiographic Outcomes of Traumatized Immature Permanent Necrotic Teeth after Revascularization/Revitalization Therapy

Introduction

Revascularization treatment is rapidly becoming an accepted treatment alternative for the management of endodontic pathology in immature permanent teeth with necrotic dental pulps. However, the success and timing of clinical resolution of symptoms, and radiographic outcomes of interest, such as continued hard tissue deposition within the root, are largely unknown.

Methods

In this prospective cohort study, 20 teeth were treated with a standardized revascularization treatment protocol and monitored for clinical and radiographic changes for 1 year. Standardized radiographs were collected at regular intervals, and radiographic changes were quantified.

Results

All 20 treated teeth survived during the 12-month follow-up period, and all 20 also met the clinical criteria for success at 12 months. As a group, the treated teeth showed a statistically significant increase in radiographic root width and length and a decrease in apical diameter, although the changes in many cases were quite small (such that the clinical significance is unclear). The within-case percent change in apical diameter after 3 months was 16% and had increased to 79% by 12 months, with 55% (11/20) showing complete apical closure. The within-case percent change in root length averaged less than 1% at 3 months and increased to 5% at 12 months. The within-case percent change in root thickness averaged 3% at 3 months and 21% at 12 months.

Conclusions

Although clinical success was highly predictable with this procedure, clinically meaningful radiographic root thickening and lengthening are less predictable after 1-year of follow-up. Apical closure is the most consistent radiographic finding.     

Multiple types of motives don't multiply the motivation of West Point cadets

Although people often assume that multiple motives for doing something will be more powerful and effective than a single motive, research suggests that different types of motives for the same action sometimes compete. More specifically, research suggests that instrumental motives, which are extrinsic to the activities at hand, can weaken internal motives, which are intrinsic to the activities at hand. We tested whether holding both instrumental and internal motives yields negative outcomes in a field context in which various motives occur naturally and long-term educational and career outcomes are at stake. We assessed the impact of the motives of over 10,000 West Point cadets over the period of a decade on whether they would become commissioned officers, extend their officer service beyond the minimum required period, and be selected for early career promotions. For each outcome, motivation internal to military service itself predicted positive outcomes; a relationship that was negatively affected when instrumental motives were also in evidence. These results suggest that holding multiple motives damages persistence and performance in educational and occupational contexts over long periods of time.Philosophers and psychologists have long distinguished among various types of motives to engage in particular activities. Some motives are internal or intrinsic to the activities themselves. The artist is motivated to create a great painting. The scientist is motivated to produce a major discovery. The gardener is motivated to grow a bountiful garden. In each case, the desired consequence matters; the artist, the scientist, and the gardener are not just dabbling. In each case, the activities leading to that consequence may involve hardship and struggle. And in each case, the desired outcome is intimately, intrinsically connected to the activity itself. The artist will not hire someone else to make the painting, nor will the gardener hire someone else to create a beautiful garden. In contrast to these kinds of internal motives, people are often guided by what might be called instrumental motives, where the relation between the motive and the activity is largely arbitrary (i.e., the motive bears no intrinsic relation to the activity itself). The scientist may want to earn a good salary, to get promoted, and to win awards. Whereas there are many paths to high salaries, promotions, and recognition, there is only one path to scientific discovery—doing science.Researchers have studied the relation between what we are calling “internal” and “instrumental” motives for more than 40 y. Typically, past research has designated these different types of motives as “intrinsic” and “extrinsic” (1). However, there is an ambiguity to the terms “intrinsic” and “extrinsic” in that they might refer to the actor (e.g., “he is intrinsically motivated”) or to the task (e.g., “drawing is an intrinsically motivated activity”). In addition, the term “intrinsic motivation” often conveys the idea that the activity in question is pleasant or fun (2). We prefer the terms “internal” and “instrumental” to make clearer that the relation being described is between the activity (not the person) and the motive, and also to make clear that internally motivated activities need not be undertaken for the inherent pleasure they bring (2, 3).What happens to the performance of demanding, effortful activities when internal and instrumental motives are combined? Logic would suggest that if you have one reason for doing something, having two or more reasons to do the same thing would be even better, rendering motivation more tenacious, follow-through stronger, and outcomes better. Schools and workplaces are full of systems that attempt to tap people’s internal motives to act (e.g., because engaging in the activity is the moral, interesting, or meaningful thing to do), while also providing rewards intended to spark instrumental motives to pursue the same acts (e.g., grades, bonuses, promotions, and so forth). Tapping internal motives and the instrumental motives assumed to result from rewards seems to be a foolproof way to engage the full spectrum of motivational levers that lead people to act. However, in a direct challenge to this assumption, social science research suggests that far from boosting motivation, holding instrumental motives can undermine whatever internal motives may have been operating, leading to drops in overall motivation, persistence, and performance (4–6). In short, this work suggests that salient instrumental incentives trigger instrumental motives, acting to undermine motivation that would otherwise be based in the value and reward of doing the activity or engaging in the act for the sake of objectives that are intimately connected to the act itself. This effect, labeled the “motivational crowding out effect” by economists (7) and the “overjustification effect” by psychologists (6), has been demonstrated across a range of experimental contexts (4). In the present study, rather than focusing on the impact of rewards on motives, we assess motives that already exist to understand their interactive effects on a series of long-term outcomes.The general structure of this body of research consists of laboratory and field experiments in which internal motivation is either established or assumed, followed by the introduction of instrumental rewards or inducements to an experimental group, and the comparison of outcomes of this group and a control group. The robustness of this effect has been generally accepted [but is still the subject of debate (6, 8, 9)]; indeed, recent research has found a possible neural basis for the “undermining effect” of instrumental rewards on internal motivation (10).Although it is possible to demonstrate the negative impact of instrumental rewards on activity-specific motivation, existing research typically introduces instrumental rewards as exogenous “shocks” to the system. However, in the real world, rather than suddenly being presented with rewards for actions in which they were already engaging, individuals carry an assortment of motives into any course of action they pursue: a mixture of activity-specific and instrumental motives in various combinations and at varying strengths (11). Whereas the typical experimental paradigm has demonstrated the relationship between internal and instrumental motivation in controlled settings through the introduction of instrumental rewards, longitudinal field research on the relative and interactive impact of various kinds and levels of motives on meaningful outcomes over time has been relatively lacking. Furthermore, examining the impact of the set and strength of motives that propel people to launch a course of action—joining the military, entering a university, becoming a volunteer—on the outcomes they later experience provides a test of naturally co-occurring motives on behavior. Additionally, as we will demonstrate, tests of the impact of different kinds of motives on outcomes occurring in real-world contexts need not depend on the introduction and withdrawal of instrumental rewards (as in experimental studies), but instead on the measurement of the strength of various kinds of motives that launched the course of action from the start.Prior work, mostly led by Deci and Ryan (2, 3), has demonstrated the ample benefits of intrinsic motivation or, at the very least, extrinsic motivation that has been internalized (what they call “autonomous motivation” in contrast to “controlled motivation,” which reflects compliance with others’ desires or external regulations), for well-being and a host of outcomes in education and health contexts. This research has treated motivation as a property of self-determination and has had a powerful impact on how social scientists understand and study motivation in a variety of contexts. However, in three important ways, our work takes a different approach to the impact of motives on outcomes, one that complements Deci and Ryan’s seminal research. First, although their approach to motivation considers whether motivation is intrinsic or extrinsic to the self (e.g., “I’m doing this because it’s natural to me” vs. “because I’ll feel badly if I don’t/others will criticize me if I don’t”) (3), our focus is on whether the motives people hold are internal or external to the activity (e.g., the scientist who pursues science to produce a discovery vs. to earn a salary or win awards). This distinction matters, because the theory of motivation presented by Deci and Ryan concerns identity, or how much of one’s motivation emanates from one’s psychological needs and sense of self (1) as opposed to other forces.Second, Deci and Ryan reserve “intrinsic” motivation as a label for only those activities that are undertaken for the inherent satisfaction they bring to the self, free from influence of what one’s parents, teachers, managers, or others think should be done or what one feels one should do (what they call “controlled motivation”), even if those reasons become somewhat or fully internalized (what they call “autonomous motivation”). Although this disqualifies most activities from ever being truly intrinsically motivated, “internal” motivation represents a broader category, one that we use here. It focuses on the relation between the outcomes pursued and the activity itself, rather than on relations between the activity and one’s self-definition or values (3).Furthermore, the outcomes that are assessed in experimental studies in this realm typically occur over a period of minutes, hours, or weeks rather than longer lengths of time, as occur in actual educational or workplace settings. Specifically, the ability of instrumental motives to effectively undermine the positive influence of internal motives on engagement in a course of action has not been demonstrated in a real-world context in which the outcomes have the potential to shape individual education and career trajectories and, more broadly, to shape public institutions. Even less is known about the impact of holding additional types of motives at varying levels of strength in these realms.There is some research that may provide clues. Researchers have reported the negative impact of holding multiple motives on individuals’ experience of a course of action they have voluntarily undertaken, demonstrating that holding multiple motives yields more stress and less satisfaction with the activity at hand (12). Other research in educational contexts that has differentiated between autonomous and controlled motivation (3) suggests that autonomous motivation predicts stronger persistence and better performance (13, 14), whereas controlled motivation predicts lower engagement and performance (15, 16). Furthermore, students experiencing high levels of both autonomous and controlled motivation have lower GPAs and procrastinate more than those with high levels of autonomous motivation and low levels of controlled motivation (17). Similarly, evidence from workplaces suggests that employees experiencing high levels of both autonomous and controlled motivation are poorer performers, even when their levels of initiative are high (18). Although these studies focus on the relationship between motivation inherent in the individual rather than for the activity at hand, the pattern is instructive: motivation that stems from sources external to the self undermines key outcomes.Clarifying the relation between different types of motives is of great practical significance. Whether called instrumental, controlled, or extrinsic (2, 3), some level of motivation from sources external to the activity itself is likely to occur in anyone undertaking a paid activity, which includes essentially every working adult. Because most people must work to make a living, instrumental consequences are ever present, and instrumental motives are likely present; thus, understanding the ways in which the strength of these motives vary and interact with motives internal to the activity is essential if we are to create work environments in which people work effectively and energetically.In the present study, we hypothesized that having strong internally based motives for undertaking a course of action will be associated with stronger persistence and better performance, but when these internally based motives are accompanied by strong instrumentally based motives, outcomes will be worse across a range of indicators of persistence and performance. We tested our hypotheses with data drawn from nine classes of West Point cadets at the start of their education, linking the strength of their various motives for attending West Point with outcomes that reflect their persistence and quality as military personnel between 4 and 14 y later. Although others have established the importance of grit for making it through West Point (19), the impact of cadets’ motives on this and later career outcomes is not yet understood.Specifically, we conducted analyses of data drawn from 11,320 cadets from nine consecutive entering classes of West Point cadets (the classes of 1997–2006). Data from the class of 2003 were dropped, as the survey instrument used that year used response categories that did not align with the questions for the items pertaining to cadets’ motives for attending West Point. We assessed the impact of cadets’ motives for attending West Point on the likelihood that they would successfully complete their studies and become commissioned officers, remain military officers beyond the mandatory 5-y period of service required following graduation, and be selected for consideration for early promotion during their 5 y of mandatory service.