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.

Immunologic and virologic response after tetanus toxoid booster among HIV-1- and HIV-2-infected Senegalese individuals.

Twelve HIV-1-infected, nine HIV-2-infected patients and eight HIV-negative subjects were given a 40IU booster dose of tetanus toxoid (TT). Blood was collected on days 0, 7 and 30 after immunization. Changes in HIV-1 or HIV-2 RNA load were evaluated by nested PCR. TT-IgG antibody levels were quantified by ELISA. CD4 cell counts as well as activation, memory and maturation markers of T lymphocyte subsets were determined by flow cytometry. The induction of apoptosis was investigated using 7-aminoactinomycin D (AAD) and propidium iodide (PI) staining. Proliferative responses to TT and pokeweed mitogen (PWM) were determined by the level of [(3)H] thymidine incorporation. Seven and 30 days after immunization, there was no detectable increase in HIV-1 or HIV-2 plasma load. There were also no changes in CD4 cell counts, CD69, HLA-DR and memory CD45RO or naive CD45RA antigens. Immunization did not increase the spontaneous apoptosis of peripheral blood mononuclear cells (PBMCs), CD4+ and CD8+ T cells subsets neither in controls nor in HIV-infected patients. Similarly, apoptosis induced in vitro by PWM or by the specific TT recall antigen did not vary during the study period. The proliferative response to PWM and to the TT recall antigen was decreased both in HIV-1- and HIV-2-infected patients compared to HIV-negative controls. Immunization significantly increased the TT-IgG levels in healthy controls and in HIV-infected patients. However, the anti-TT-IgG response, as measured by the fold-increase index between days 0 and 30, was significantly higher in healthy controls than in HIV-1- (P=0.036) and HIV-2-infected patients (P=0.003). In conclusion, we found no deleterious immunologic or virologic effect was detected in healthy HIV-1- and HIV-2-infected individuals after antigenic challenge with a TT booster. However, the response to TT vaccination was lower in HIV-1- and in HIV-2-infected individuals than in healthy HIV-negative controls.

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.

Low plasma human immunodeficiency virus type 2 viral load is independent of proviral load: low virus production in vivo.

Levels of virus in the plasma are closely related to the pathogenicity of human immunodeficiency virus type 1 (HIV-1). HIV-2 is much less pathogenic than HIV-1, and infection with HIV-2 leads to significantly lower plasma viral load. To identify the source of this difference, we measured both viral RNA and proviral DNA in matched samples from 34 HIV-2-infected individuals. Nearly half had undetectable viral RNA loads (<100 copies/ml), but levels of proviral DNA were relatively high and confirmed that quantities of provirus in HIV-1 and HIV-2 infection were similar. Overall, HIV-2 proviral DNA load did not correlate with viral RNA load, and higher viral RNA load was associated with increased production of plasma virus from the proviral template. These results suggest that low viral load in HIV-2 infection is due to decreased rates of viral production, rather than differences in target cell infectivity.

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.

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.

Lower human immunodeficiency virus (HIV) type 2 viral load reflects the difference in pathogenicity of HIV-1 and HIV-2.

Human immunodeficiency virus type 2 (HIV-2) is less pathogenic than HIV type 1 (HIV-1), but the mechanisms underlying this difference have not been defined. We developed an internally controlled quantitative reverse transcriptase-polymerase chain reaction to measure HIV-2 viral load and determined levels of plasma virus in a cohort of registered commercial sex workers in Dakar, Senegal. The assay has a lower limit of detection of 100 copies/mL and is linear over 4 logs. HIV-2 viral RNA was detectable in 56% of all samples tested; the median load was 141 copies/mL. Levels of viral RNA in the plasma were inversely related to CD4+ cell counts. HIV-2 and HIV-1 viral loads were compared among the seroincident women in the cohort; the median viral load was 30x lower in the HIV-2-infected women (P<.001, Wilcoxon rank sum test), irrespective of the length of time infected. This suggests that plasma viremia is linked to the differences in the pathogenicity of the 2 viruses.

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.

Relation between HIV-2 proviral load and CD4+ lymphocyte count differs in monotypic and dual HIV infections.

OBJECTIVE: To explore and compare the relations between proviral DNA load and CD4+ lymphocyte counts in both HIV-2 monotypic and HIV dual infection. STUDY DESIGN/METHODS: In Dakar, Senegal, where the HIV-1 and HIV-2 epidemics overlap, serum and peripheral blood mononuclear cell (PBMC) DNA samples were collected from registered female sex workers and hospitalized patients. Sera were evaluated for reactivity to antigens of HIV-1 and HIV-2 by immunoblot; dual reactivity was confirmed with recombinant envelope peptides for HIV-1 and HIV-2. These samples were then subjected to HIV-1 and HIV-2 proviral DNA polymerase chain reaction (PCR). To evaluate the HIV-2 cellular proviral DNA loads, a quantitative competitive PCR (QC-PCR) was developed using nested primers to amplify the gag region of HIV-2. This assay used an internal competitor generated by inserting 25 bp in the first-round PCR target sequence. T-lymphocyte subset counts were estimated by flow cytometry for both HIV-2 monotypic and dually infected persons. RESULTS: 35 HIV-2-infected and 33 dually seroreactive samples were evaluated in this study. The CD4+ lymphocyte counts were similar in both groups, with mean values of 449 +/- 390 cells/mm3 for the HIV-2 monotypic infected persons and 476 +/- 308 cells/mm3 among the dually infected persons. However, the median proviral loads differed significantly, with those in the HIV-2 group ranging from 63.2 to 669.8 copies/10(5) CD4+ cells and demonstrating an inverse correlation with CD4+ lymphocyte count. The HIV dually infected persons showed less variation in viral load, ranging from 9.9 to 43.3 copies/10(5) CD4+ cells. Among the HIV dually infected persons, low HIV-2 proviral load was correlated with low CD4+ lymphocyte counts. CONCLUSIONS: The HIV-2 proviral loads in HIV dually infected persons were significantly lower than those in HIV-2 monotypically infected individuals (P < .0001), despite comparable CD4+ lymphocyte counts. These results suggest that different HIV-2 proviral dynamics prevail in HIV dual infection.

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.

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.

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.

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.

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.

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.

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.

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.

Readiness: observations and comments from a medical team deployment.

The evolving strategy of the United States in dealing with the changing world order calls for a force structure capable of fighting and winning two nearly simultaneous major regional conflicts and conducting a range of other military operations. Readiness is a key factor in this new strategy. Consequently, major paradigm shifts are occurring within the Air Force Medical Service. Maintaining current and accurate medical records on personnel to meet deployment requirements is a significant challenge. Historically, time and resources are consumed determining the deployability of troops prior to a deployment. This adds to the cost of doing business and increases the time required to clear the deploying team, even though there is an established process to avoid these very problems. The experience of a recent medical team deployment to Bosnia is discussed. Future directions given the implementation of TRI-CARE, the Preventive Health Assessment Program, and the Strategic Health Resourcing Plan are also considered.

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.

Cellulitis versus positive purified protein derivative? A case report and review of the literature.

The tuberculin skin test is one of the most widely used diagnostic aids ever developed and remains the only technique of detecting Mycobacterium tuberculosis infection other than actually culturing the organism. False-positives are an acknowledged problem, especially among health care workers (HCW), in whom rescreening can raise more questions than answers. A HCW presented with a severe response to an annual screening test and was retested 6 weeks later with normal results (non-reactive). Causes of false-positives (not including cross-reactivity) are discussed. Readers of the purified protein derivative reaction need to consider alternative explanations for a significant response than infection with tuberculosis, given the medical history and nature of response.