Weekly paclitaxel with trastuzumab and pertuzumab in patients with HER2-overexpressing metastatic breast cancer: overall survival and updated progression-free survival results from a phase II study.

We previously reported progression-free survival (PFS) results on a phase II trial of weekly paclitaxel, trastuzumab, and pertuzumab in patients with human epidermal growth factor receptor 2(HER2)-positive metastatic breast cancer (MBC) treated in the first- and second-line setting. Here, we report results for overall survival (OS) and updated PFS after an additional year of follow-up. Patients with HER2-positive MBC with 0-1 prior treatment were eligible. Treatment consisted of paclitaxel (80 mg/m(2)) weekly, and trastuzumab (loading dose 8 mg/kg â†’ 6 mg/kg) and pertuzumab (loading dose 840 mg â†’ 420 mg) every 3 weeks, all given intravenously. Primary endpoint was 6-month PFS. Secondary endpoints included median PFS, 6-month and median OS. Evaluable patients received at least one full dose of treatment. From January 2011 to December 2013, 69 patients were enrolled: 51 (74 %) and 18 (26 %) treated in first- and second-line metastatic settings, respectively. As of July 1, 2015, the median follow-up was 33 months (range 3-49 months; 67 patients were evaluable for efficacy). The median OS was 44 months (95 % CI 37.5-NR) overall and 44 months (95 % CI 38.3-NR) and 37.5 months (95 % CI 30.3-NR) for patients with 0 and 1 prior metastatic treatment, respectively; 6-month OS was 98 % (95 % CI 90-1). The 6-month PFS was 86 % (95 % CI 75-93) overall and 89 % (95 % CI 76-95) and 78 % (95 % CI 51-91) for patients with 0 and 1 prior therapy, respectively; and median PFS was 21.4 months (95 % CI 14.1-NR) overall and 25.7 months (95 % CI 14.1-NR) and 16.9 months (95 % CI 8.5-NR) for patients with 0-1 prior treatment, respectively. Treatment was well tolerated. Updated analysis demonstrates that weekly paclitaxel, when added to trastuzumab and pertuzumab, is associated with a favorable OS and PFS and offers an alternative to docetaxel-based therapy. http://www.ClinicalTrials.gov NCT0127604.

Robust HIV type 2 cellular immune response measured by a modified anthrax toxin-based enzyme-linked immunospot assay.

Evaluation of immune mechanisms responsible for control of viral replication is critical to understanding HIV-2 attenuated biological characteristics in pathogenesis and transmission. Evaluation of the cellular immune response is often based on labor-intensive techniques that limit the scope of most studies performed. A simple and rapid anthrax toxin-based ELISPOT method to assess HIV-2 cellular immune response was developed. The modified anthrax toxin-based antigen presentation process performed better than a recombinant vaccinia system and the ELISPOT method significantly enhanced the ease and simplicity of the assay. Using this method, a robust HIV-2 cellular immune response directed toward the p26 core protein was exhibited in 21 of 24 (87.5%) infected women, and all 8 seronegative subjects were negative in both assays. Cellular immune responses were associated with low HIV-2 viral load. This simple and rapid modified anthrax toxin-based ELISPOT method allowed us to demonstrate, strong cellular immune responses that may be critical determinants in the HIV-2 attenuated phenotype.

Antibodies to the HIV type 2 core protein p26 and Vpx: association with disease progression.

A longitudinal cohort study was conducted to define the prevalence and temporal pattern of antibody response to the HIV-2 virion-associated proteins p26gag and Vpx. One hundred and forty-one asymptomatic HIV-2-infected women were enrolled, and followed for up to 11 years. Eighty-one percent of the subjects had antibodies to p26, and 51% to Vpx; response to these two antigens was not correlated. The response to both proteins was determined early in infection, and remained stable over time. The absence of antibodies to p26 was a highly significant predictor of CDC category IV HIV-related disease (p < 0.01) in both univariate and multivariate analysis. Antibody response to Vpx alone was not associated with disease progression. However, those individuals lacking anti-p26 antibodies, and with anti-Vpx antibodies, were six times more likely to be classified as CDC category IV by the end of the study (p < 0.01). This represents the first identification of virus-specific serological markers for HIV-2-related disease progression.

Case study: ego-dystonic anger attacks in mothers of young children.

Parental anger can have detrimental effects on children and can contribute to physical abuse. Ego-dystonic anger attacks are an underrecognized psychiatric symptom that occurs in associated with depression, with other psychiatric disorders, and in the absence of comorbid disorders. They are characterized by overwhelming anger and autonomic arousal occurring upon provocation viewed as trivial by the individual, and they respond well to treatment with serotonergic antidepressants. Consequently, they represent a readily treatable problem. Four cases of anger attacks in mothers of young children are described to illustrate the importance of recognizing and treating anger attacks.

Thoughts of harming infants in depressed and nondepressed mothers.

BACKGROUND: Thoughts of harming the infant and other disturbing cognitions are frequently described in anecdotal reports on postpartum depression. These cognitions have not been examined empirically. METHODS: 100 clinically depressed mothers with a child under 3 years were evaluated and compared to a control group of 46 nondepressed mothers. RESULTS: 41% of depressed mothers compared to 7% of control mothers admitted to thoughts of harming their infant. Fear of being alone with the infant and inability to care for the infant were assessed only in depressed mothers and occurred less frequently. More than half of depressed mothers had problems in one of these three areas. CONCLUSIONS: Thoughts of harming the infant are common in depressed mothers. Demographic variables, psychosocial stressors and psychiatric variables do not help predict which mothers are likely to experience thoughts of harm or fear of being alone with the infant. These cognitive and affective disturbances may be one pathway by which maternal depression affects infants. LIMITATIONS: The control group was not given the full diagnostic interview. Consequently, the groups were not selected by identical procedures. Also fear of being alone with the infant and difficulty caring for the infant were not assessed in the control group.

Improving readiness and fitness of the active military force through occupational medicine tenets.

The United States Military deploys its forces with minimal lead time. These forces must be medically qualified and physically fit for any locale and mission scenario. Historically, up to half of the force identified for deployment at any given time were not medically qualified. Matching individuals to specific occupations using validated medical and physical performance standards is an occupational medicine tenet that increases the effectiveness and efficiency of the workforce. To establish a cost-effective, valid medical program ensuring a fit and ready force, the military must: (1) develop validated physical fitness/occupational standards; (2) consolidate one fitness standard for males/females on the basis of workload requirements; (3) eliminate differing age standards; (4) provide statistically relevant medical screening, testing for health maintenance, and fitness for duty; and (5) mandate one joint medical standard for all military services.

Incorporating occupational medicine methodology into military fitness for duty and readiness issues.

The need for the U.S. Air Force (USAF) to know its personnel's fitness for duty and readiness status is one of the most significant criteria for determining their ability to complete the missions assigned to them. This is especially critical in the current milieu of increasing deployments. However, the USAF has a very limited program to meet this need. Occupation Medicine has had extensive experience in determining job requirements, assessing individuals, and monitoring performance over time. Further integrating Occupational Medicine methodology and the current state of scientific knowledge on physical performance is advocated to improve the USAF's ability to have a fit and ready force able to meet its burgeoning mission. This paper reviews the literature with the following recommendations: a) assess the physical fitness of the force given future demands due to readiness taskings and if necessary mandate individual and unit exercise and provide time for these activities; b) eliminate the weight management and cycle ergometry programs; c) establish physical fitness standards appropriate for each job as well as for initial entry into the USAF, these standards should incorporate ongoing testing, evaluation, and training; d) body fat should be treated only as a medical condition and not as an image standard; and e) establish case management teams to optimize the identification, treatment, return to duty and medical boarding of personnel with injuries or subpar performance.

Validity of using non-pilot subjects to represent pilots in a sustained acceleration environment.

BACKGROUND: A preliminary study determined the similarities between the personality of military pilots (transport and fighter) and centrifuge subjects using the Edwards Personal Preference Schedule (EPPS). Past, similar personality studies have shown differences between military fighter vs. transport pilots, and general population vs. male and female general aviators. To use subjects in lieu of pilots in the centrifuge, they must represent the pilot characteristics of interest, for both ethical and scientific reasons. With the increase in measuring performance metrics (e.g., reaction time, tracking tasks, missile evasion) during centrifuge testing, any factor effecting performance must be explored. It is unknown whether personality effects performance. METHODS: Cluster analysis of 36 pilot and subject personality tests consisted of the Partitioning Around Medoids (PAM) program by Leonard Kaufman and Peter Rousseeuw (10) and Ward's method/K-MEANS clustering (CSS:STATISTICA). RESULTS: The clusters generated by the 36 pilots and subjects did not match the Retzlaff and Gibertini (21) clusters. Two clusters were preferred over three, and while the values of the personality variables Dominance, Exhibition, and Aggression (DOM, EXH, AGG) were similar, the pilot membership did not coincide. Subjects had basically the same cluster characteristics as pilots and did not alter the pilot cluster composition characteristics when clustered together. Females did not appear to differ from the males in the cluster analysis. Clustering did not differentiate between fighter and transport pilots using the chosen variables. CONCLUSION: These preliminary results support the hypothesis that there are no major differences in personality between fighter pilots, transport pilots, or centrifuge subjects using the EPPS.

Are human subject volunteers still players in aeromedical research as we enter the 21st century?

The U.S. Air Force has enjoyed the luxury of having dedicated human volunteer subjects for sustained and impact acceleration research for over 50 yr. However, with today's world economy and budgetary cutbacks, this may no longer be a viable option. The onslaught of advanced medical technology, combined with an increasing performance envelope for aircraft and their ejection systems, have created an environment where the validity of research data and the ethics of human-use research are being challenged. Now is an opportune time to reevaluate the way human-use aeromedical research is conducted. The validity of using nonpilots in lieu of pilots in aeromedical research is discussed in light of the following: a) the increased emphasis on performance metrics within sustained acceleration; b) the matching of human subjects (nonpilots) to pilots in the appropriate attributes to ensure validity of data; c) degree of medical screening required given the ethics of human-use research and concerns of pilots; and d) the challenge of evaluating the "value added" of new technology for medical screening. It is concluded that volunteer panels should be maintained with nonpilots matched with pilots physically and psychologically such that operational performance characteristics are similar. Medical screening should be similar so that research data from subjects can be applied to the target population (pilots). Longitudinal data collection (e.g., spinal X-rays) on pilots would also be of great value as a basis for studying the occupational hazards of flying.

Unequal narrowing of the visual field in a +Gz environment.

Anecdotally, the existence of individuals who experience an unequal loss of peripheral vision (left versus right) under sustained +Gz acceleration is well known. However, there is little mention or explanation of the etiology in the literature. Only recently has there been a surge of interest in this phenomenon. The operational significance is more important. The most common interpretations for this phenomenon are unequal arterial pressure between the left and right blood supplies to the retina (ophthalmic artery, its branch to the retina, the central retinal arteries, the circle of Willis, and the internal carotid artery), and a difference in the intraocular pressure. Two case histories of unequal peripheral light loss (PLL) are discussed. It is possible for a pilot not to be aware of his or her full sequence of PLL and, in an operational environment, lose half the visual field and not realize it. We need more controlled studies to define unequal PLL and to ensure valid centrifuge subject data.

Individual differences and subgroups within populations: the shopping bag approach.

The aerospace medical research community needs to consider the individual as something other than a statistical entity. The cumulative effects of performance enhancers that are collectively ignored, secondary to statistical analysis of populations, can be significant for individuals. By considering the individual, all aspects of whatever makes humans unique need to be integrated into research. One suggested remedy to the problem of subordination of the individual to the population mean/standard deviation is the use of a "shopping bag" approach. In this approach, each individual may select those performance enhancers that work best for him or her (based on controlled studies). Acceleration protection devices are used as an example. The impact of this philosophy can be readily seen in human factor design strategy as well as in the interpretation of human research data.

Gender and effect of impact acceleration on neck motion.

BACKGROUND: With the opening of the fighter cockpit to women, it became imperative to expand the current database of responses of females to both sustained and impact acceleration environments. With less upper-body strength (lean body mass) than men, it was hypothesized that women would not brace their heads as effectively against the loads occurring during high G-loading in flight and during impact and escape. This scenario creates increased potential for injury, exacerbated by the changing center of gravity and weight of helmets due to technological advances (e.g., night vision, head-up displays, etc.). METHODS: The main objective of this experimental effort was measuring the ability of subjects of both sexes to brace against an impact acceleration of -6.5 Gx or +4.0 Gy. An attempt was made to identify a correlation between such ability, static strength measurements, anthropometric measurements, or any combination thereof. RESULTS: No correlation was found between any of the static strength or anthropomorphic parameters and the amplitude of head motion. The isometric strength measurements correlated well with the size, weight, and neck circumference of the subjects, but none of these proved useful in predicting head displacement. However, there was a strong relationship between neck force exerted just before impact and head motion in the -Gx study, and somewhat less correlation for the +Gy impacts. CONCLUSION: It is useful to estimate resistance to impact by measuring neck strength, but only under conditions where the subject is highly motivated.

Human subject research at Armstrong Laboratory, 1973-93: medical and musculoskeletal disqualifications.

The reasons for disqualification of human subjects from 1973-93 at Armstrong Laboratory, formerly the Harry G. Armstrong Aeromedical Research Laboratory (AAMRL), are presented for both sustained and impact acceleration panels. Evaluations for both medical and spinal anomalies were accomplished. The rationale for each disqualification is discussed, demonstrating the variability in each panel physician's clinical judgment in the context of personal bias, the ethical framework surrounding the use of human volunteers, and the existing research milieu.

Human subject screening: a dynamic process.

INTRODUCTION: The history of disqualified (DQ) subjects from 1973-1993 at Armstrong Laboratory, Wright Patterson AFB, is presented for both sustained and impact acceleration panels. METHODS: Candidate and subject medical records were reviewed for screening results, recommendation for panel duty, and any follow-up medical findings. The generation and interpretation of the medical screening criteria and DQ rates are discussed. MEDICAL SCREENING CRITERIA: The mechanisms for change, those factors influencing change, and the interpretation of the screening criteria for Armstrong Laboratory's acceleration panels determine the panel's composition, which is reflected in the DQ rates. RESULTS: The centrifuge had a 5% (7/132) disqualification (DQ) rate from 1973-93 with 29% (2/7) due to musculoskeletal and 71% (5/7) for medical reasons. All were DQ during 1973-88. The impact panel had a DQ rate of 18% (36/195) with 71% (24/34) DQ due to musculoskeletal and 29% (10/34) for medical reasons. Only 28% (10/36) were DQ during 1973-88, while during 1989-93, 72% (26/36) were DQ. CONCLUSIONS: The differences in DQ rates between the centrifuge and impact facility were due to the variability or conservatism of individual physicians, interpretation of the medical screening criteria, and the type of research being done. These factors effect the composition of the human subject panels. This determines to which target population the research data can be applied. If the subjects do not represent pilots due to inappropriate screening, then there is no benefit from the research and, therefore, there can be no risk incurred by the subjects.

Factors influencing aeromedical decision-making: operational versus research environments.

The aeromedical research and operational flying communities have at least one common goal; ensuring the optimum combination of mission performance and safety for the aircrew. This is a continual challenge as aerospace technology leaps ahead while the human factor remains relatively constant. However, several issues interfere with the smooth interaction between these communities: 1) perceptions that the research and operational communities have towards human subjects and pilots respectively; 2) the legal and ethical considerations involved in exposing individuals to risk; and 3) the ever-present personality dynamics involved in any decision-making process (e.g., returning individuals to a centrifuge panel or flying duty after a medically disqualifying incident). All of these factors influence decisions made in both communities, and how they interact with each other. It is a dynamic process that varies between countries, individual services (e.g., Navy vs Air Force), and even between different geographical locations within the same service.

Comparison of acceleration subjects to other populations: spinal anomaly distribution.

Two Armstrong Laboratory (AL) human volunteer subject panels (sustained and impact acceleration) at Wright Patterson AFB, OH, were compared to each other and to other samples of different populations in terms of spinal anomalies. These sample populations were obtained from the scientific literature: French, Norwegian, Netherlands, and U.S. pilots; U.S. Air Force (AF) and Navy subjects, and from representative "normal" civilian populations, and then compared using the proportion parameters for various spinal anomalies. There were only a few common parameters between the two panels and between each panel compared with the foreign military, human subjects, and "normal" population. However, there were two to six times as many similar spinal anomaly incidence rates between the AL panels and the U.S. pilot sample. It was reassuring that the AL subject panels used in AF acceleration research have more in common with AF pilots than other populations in regards to spinal anomalies, even though the pilot sample may not be representative of the true pilot population. Recommendations are to establish a common reference point in nomenclature and description of spinal anomalies (modeled after the French) and to start collecting spinal radiographs on all U.S. pilots. These radiographs would not be for screening but for establishing a database following the occupational pathology of flying. This data would also facilitate comparisons with research acceleration panels, as well as with foreign air forces. Informed decisions can then be made regarding screening criteria for the future as aircraft and ejection seat performance envelopes continue to expand.

Unexplained unilateral vision loss during centrifugation.

Vision loss during a centrifuge run is an expected occurrence given the G-profile, physical fitness of the subject, expected visual endpoint [central light loss (CLL) or peripheral light loss (PLL)] of the experimental protocol, and the cyclic nature of the anti-G straining maneuver (AGSM). During a relatively low level G exposure, a subject experienced a unilateral loss of vision that did not resolve spontaneously upon removal of the G load. An extensive medical workup did not reveal any medical explanation for the vision loss.

Ethics in human experimentation: examples in aeromedical research.

The existence of ethical standards directing how humans are utilized in clinical and human-use research have a significant impact on the conduct and outcome of aeromedical research. The validity of the data generated by human research is a direct result of the application of these ethical guidelines. The risk/benefit ratio evaluation can terminate a project even before its initiation. New technology, individual beliefs, and a changing society will continue to guarantee controversy over how human subjects should be screened and evaluated as well as how research should utilize them. Ethical guidelines are not cast in stone. Their interpretation is influenced by new experimental results, the individual researcher, the intended subject, the composition of human use committees, and the social environment. How we address new and old concerns alike will dictate the research environment of the future.

Ethics in human experimentation: historical perspectives.

Ethics has received renewed attention recently as evidenced by recent revelations of experimentation on Eskimos during the 1950s and a new President vowing to raise ethical standards of conduct within government. There is also an ongoing, intense scrutiny of past radiation-exposure experiments with all of its possible ethical violations. This paper is a modest attempt to familiarize the reader with some of the historical development of ethics in human-use research. Debate concerning the use of humans as subjects of medical and behavioral experimentation has a long and distinguished history going back at least 2,000 years. A short historical review reveals that ethical behavior exhibits a pendulum action between the extremes of protection of humans at all costs and the attainment of scientific knowledge at all costs. Only by knowing the historical foundation of ethics can one understand the current issues surrounding human experimentation.

Impact on USAF tuberculosis detection and control program given a low facility tuberculosis prevalence rate.

Isoniazid prophylaxis is a major part of the U.S. Air Force tuberculosis (TB) screening program and is closely tied to the efforts to eliminate TB. If a facility has a low prevalence rate of TB and there is no sound epidemiological evidence to rule out a false-positive TB skin test, a higher threshold for what constitutes a positive reaction in a given population may be appropriate. Criteria for preventive treatment in Air Force Instruction 48-115, para 3.4.2 and 3.4.5, should be expanded to incorporate the positive-predictive rate of the tuberculin skin test as recommended by the Centers for Disease Control and Prevention.