Phase I dose-escalation trial of tucatinib in combination with trastuzumab in patients with HER2-positive breast cancer brain metastases.

BACKGROUND: Brain metastases are frequent in HER2-positive breast cancer. ONT-380 (tucatinib) is a potent selective inhibitor of HER2 with intracranial activity in preclinical models. PATIENTS AND METHODS: This was a phase I study of tucatinib with trastuzumab, without chemotherapy, in patients with progressive, measurable HER2-positive brain metastases. The study tested two schedules of tucatinib: cohort A was twice daily and cohort B was once daily. The primary objective was determination of the maximum tolerated dose (MTD). Secondary end points included objective response (intracranial and extracranial) using modified RECIST and clinical benefit rate (CBR). RESULTS: Overall, 41 patients were enrolled (cohort A, n = 22; cohort B, n = 19). Patients had a median of two prior treatments for metastatic breast cancer and 83% had progressed after prior brain radiation. The MTD of tucatinib for cohort A was 300 mg twice daily and for cohort B was 750 mg once daily. The most common dose-limiting toxicities included thrombocytopenia and aspartate transaminase/alanine aminotransferase elevation. Grade 3/4 aspartate transaminase/alanine aminotransferase elevation occurred in nine of 41 patients (22%). Intracranial responses were observed in two of 17 (12%) patients in cohort A and one of 17 (6%) patients in cohort B treated at the MTD. In cohort A, CBR at 16 weeks was 35% (n = 6). In cohort B, CBR at 16 weeks was 53% (n = 9). Of 15 patients overall who experienced clinical benefit, 12 (80%) had received prior neratinib and/or lapatinib. Median progression-free survival for cohorts A and B was 3.4 and 4.1 months, respectively. CONCLUSION: The combination of tucatinib and trastuzumab is tolerable and demonstrated preliminary evidence of efficacy in patients with HER2-positive brain metastases. CLINICAL TRIAL REGISTRATION: NCT01921335.

Rank order of sarcoma susceptibility among mouse strains reverses with low concentrations of carcinogen.

Ten mouse strains in which aryl hydrocarbon hydroxylase can be induced, or F1 hybrids of these strains, were ranked according to their sarcoma susceptibility when exposed to a high concentration (5 percent) of the chemical carcinogen 3-methylcholanthrene. This rank order was reversed when the concentration of 3-methylcholanthrene was reduced to 0.05 percent.

Oncogenes in radioresistant, noncancerous skin fibroblasts from a cancer-prone family.

Li-Fraumeni syndrome is manifested in a variety of neoplasms that are transmitted in a dominantly inherited pattern. The noncancerous skin fibroblasts of family members exhibit a unique characteristic of being resistant to the killing effect of ionizing radiation. A three- to eightfold elevation in expression of c-myc and an apparent activation of c-raf-1 gene have been observed in these noncancerous skin fibroblasts. These results may provide insight into the heritable defect underlying the familial predisposition to a variety of cancers.

Congenital oligonephropathy: The fetal flaw in essential hypertension?

In 1988, Brenner, Garcia and Anderson advanced the hypothesis that the nephron endowment at birth is inversely related to the risk of developing essential hypertension in later life. This novel perspective on the origins of essential hypertension was taken from the viewpoint that the development and maintenance of hypertension must involve a renal factor favoring sodium retention, thereby preventing pressure-induced natriuresis from restoring blood pressure toward normal levels. Since nephron numbers in the normal population range from 300,000 to 1,100,000 or more, it was reasoned that a congenital shortfall in nephron endowment itself could be the renal risk factor for hypertension: demographic groups in whom hypertension is unusually prevalent tend to have smaller kidneys, implying fewer nephrons, and some inbred hypertensive rat strains have, on average, fewer nephrons than their respective normotensive counterparts. Recent independent observations in humans, relating low birth weight to both increased risk of hypertension in later life and the formation of fewer nephrons at birth, lend support to this nephron number hypothesis. Moreover, independent experimental studies in rodents suggest that maternal protein intake during gestation is directly related to the numbers of nephrons formed, and when protein intake is restricted, the offspring develop hypertension in maturity. The concept that nephron numbers may be programmed during gestation, as these observations imply, is discussed in relation to the potential advantages and disadvantages of such a mechanism for the next generation. Parallels are drawn with the relationship of low birth weight to pancreatic beta cell development and maturity-onset diabetes. We suggest that the programming of fewer nephrons at birth may provide a fitting and overlooked explanation for the eventual development of hypertension in those of low birth weight.

Endorsement of formal leaders: an integrative model.

This experiment develops an integrative, path-analytic model for the endorsement accorded formal leaders. The model contains four independent variables reflecting aspects of group structure (i.e., group success-failure, the payoff distribution, the degree of support by others members for the leader, and the vulnerability of the leader). Also included are two intervening variables reflecting perceptual processes (attributed competence and attributed fairness), and one dependent variable endorsement). The results indicate that endorsement is greater when the group's success is high, when the payoff distribution is flat rather than hierarchial, and when the leader is not vulnerable to removal from office. Other support had no significant impact on endorsement. Analyses further demonstrate that the effect of success-failure on endorsement is mediated by attributed competence, while the effect of the payoff distributed is mediated by attributed fairness. These results suggest that moral and task evaluations are distinct bases of endorsement.

Acid phosphatase activity of chondroclasts from Fusarium-induced tibial dyschondroplastic cartilage.

Tibial dyschondroplasia was induced in broiler chickens by oral administration of fusarochromanone, the toxic component of Fusarium equiseti. In two experiments, the activity of acid phosphatase in chondroclasts was assessed histochemically. Chicks were examined at 7, 14, 21, and 28 days of treatment in Expt. 1 and at 2, 4, and 6 days of treatment in Expt. 2. The staining for acid phosphatase was consistently lower in fusarochromanone-treated chicks after 2 days of treatment than in age-matched controls, and the onset of this difference corresponded to the onset of lesions. However, the decrease in acid phosphatase staining intensity was significant only at day 21 in Expt. 1 and at day 6 in Expt. 2. The deficiency of acid phosphatase in chondroclasts was judged to be of insufficient magnitude to account for the accumulation of growth plate cartilage that characterizes tibial dyschondroplasia.

Quality circles after the fad.

On the face of it, it makes sense, If you want to involve your employees more in decision making and shift the organization toward a more participative culture, starting suggestion groups called quality circles seems to be a risk-free way to begin. Having studied many quality circles in different organizations, the authors of this article conclude that quality circles have their distinct advantages but that they have inherent in their design numbers of factors that often lead them to self-destruct. Quality circles are also said to be a poor forerunner for more participative approaches to management. Changing a quality circle into an institutionalized participative structure involves making many changes in important features of the organization that do not naturally flow from the implementation of a circle program. The authors describe the stages that quality circles go through, discuss the various threats they must survive, and then outline the most effective uses that managers can make of them.

Appraising boardroom performance.

Rare is the company that does not periodically review the performance of its staff, business units, and suppliers. But rare, as well, is the company that does such a review of one of its most important contributors--its board of directors. Reviewing a board's performance is not an easy proposition: it has to be done by the members themselves, people who generally have many other responsibilities and whose time is always at a premium. But done properly, appraisals can help boards become more effective by clarifying individual and collective responsibilities. They can help improve the working relationship between a company's board and its senior management. They can help ensure a healthy balance of power between the board and the CEO. And, once in place, an appraisal process is difficult to dismantle, making it harder for a new CEO to dominate a board or avoid being held accountable for poor performance. Done properly is the key here, though. Done incorrectly, board appraisals can degenerate into self-serving evaluations or unpleasant, time-wasting exercises. Worse, they can evolve into rigid mechanical processes that discourage innovation. In fact, all of the approaches the authors observed in two years of research were incomplete. The authors have therefore drawn on the strengths of several different approaches to synthesize a best-practice process that is both rigorous and comprehensive.

Quality of work life: perspectives and directions.

The values that quality of work life (QWL) has brought to the workplace are in danger of being lost, say authors Nadler and Lawler; to avert this danger, they debunk several "definitions" of the concept that miss the point, give it a precise definition, and spell out ways to use it successfully. They delineate six factors that they believe separate more successful from less successful QWL efforts. The first success factor is a perception of need--that is, in successful efforts organization members actually perceive a problem. Second, the problem is salient to the organization. Third, a structure for participation is created. Fourth, rewards are provided both for the processes and for the outcomes of QWL activities. Fifth, multiple levels of management are involved. And, finally, QWL involves all organization members in a way that avoids "we-they" rivalries. With these factors in mind, the authors conclude that three major components of QWL efforts must be managed well if they are to succeed: (1) development of projects at different levels; (2) changes in management systems and structure; and (3) changes in senior management behavior--that is, if the QWL effort is to be credible to organization members, there must be some specific, tangible QWL activity in which senior managers participate.

Gainsharing: a few questions, and fewer answers.

Gainsharing is an important organization development intervention, yet many of the basic questions have not been answered. This paper addresses these questions by developing a conceptual model and using the model to review the case study literature on gainsharing . The plans varied in terms of structural factors, implementation factors, and situational factors, and a majority were successful. Gainsharing impact was found in five key areas: organizational effectiveness, individual quality of work life, ideas and innovation, labor-management cooperation, and pay. Relevant research is briefly reviewed and several unanswered questions are identified for future research.

The immune basis of dosage-induced reversal of the rank-order of strain susceptibility to MCA.

Even AHH-inducible mouse strains vary in their susceptibilities to MCA sarcomagenesis. Previous work showed that the rank-order of strain susceptibility depended upon the dosage of MCA; the strain most susceptible to a high dose became the least susceptible to a low one and vice versa. We now confirm our previous findings and test the hypothesis that the reversal, with dosage, of the rank-order of relative strain-susceptibility has an immunological basis. This was tested in two ways: by examining the effect of immunosuppression on strain-susceptibility to sarcomagenesis and by transplanting parental bone marrow into irradiated F1 hybrid to see if the relative MCA-susceptibility characteristics of the parental donors could be transferred. The results of both studies suggest that the rank-order-reversal phenomenon is caused, at least in part, by differences in the immunological reactivities of the strains. Inasmuch as immunosuppression inhibited the response of the C3 mice to a high dose of carcinogen, but facilitated carcinogenesis among the B6, the level of innate immune capacity most conducive to high-dose carcinogenesis is apparently intermediate between the levels of these two strains.

Macrophage content and immunogenicity of C57BL/6J and BALB/cByJ methylcholanthrene-induced sarcomas.

A total of 33 methylcholanthrene-induced sarcomas, growing in C57BL/6J or BALB/cByJ mice, were tested for their immunogenicity and for their relative macrophage content. No relationship was demonstrated between these two characteristics. These results suggest that the direct correlation between macrophage content and immunogenicity demonstrated in rat tumor model systems may not hold for other systems.

Influence of immune status of host on immunogenicity of tumors induced with two doses of methylcholanthrene.

Previous studies by Prehn demonstrated a direct correlation between the dose of carcinogen used for tumor induction and the immunogenicity of the resulting tumors. The purpose of the present study was to determine the role of the host's immune response and the influence of the carcinogen on immune function in this relationship. For that reason, a comparison was made of the immunogenicities of tumors induced with two doses of carcinogen in immunologically normal mice and in mice immunodepressed by adult thymectomy and irradiation. If the direct relationship between dose and immunogenicity demonstrated in normal mice was due to the degree of immunosuppression produced by the carcinogen, this correlation should not be apparent in mice already immunosuppressed. Although there was some increase in the immunogenicity of tumors induced in the immunosuppressed mice, the same relationship between carcinogen dose and immunogenicity was observed in both groups of mice. These results indicate that the degree of immunogenicity of tumors induced with both high and low doses of carcinogen was influenced by immunoselection, but in addition another, non-immunologic factor was significant in the relationship between carcinogen dose and immunogenicity.

The empowerment of service workers: what, why, how, and when.

In recent years, businesses have rushed to adopt an empowerment approach to service delivery in which employees face customers "free of rulebooks," encouraged to do whatever is necessary to satisfy them. But that approach may not be right for everyone. Bowen and Lawler look at the benefits and costs of empowering employees, the range of management practices that empower employees to varying degrees, and key business characteristics that affect the choice of approaches. Managers need to make sure that there is a good fit between their organizational needs and their approach to frontline employees.