Allogeneic hematopoietic cell transplantation for metastatic breast cancer

We reviewed 66 women with poor-risk metastatic breast cancer from 15 centers to describe the efficacy of allogeneic hematopoietic cell transplantation (HCT). Median follow-up for survivors was 40 months (range, 3-64). A total of 39 patients (59%) received myeloablative and 27 (41%) reduced-intensity conditioning (RIC) regimens. More patients in the RIC group had poor pretransplant performance status (63 vs 26%, P=0.002). RIC group developed less chronic GVHD (8 vs 36% at 1 year, P=0.003). Treatment-related mortality rates were lower with RIC (7 vs 29% at 100 days, P=0.03). A total of 9 of 33 patients (27%) who underwent immune manipulation for persistent or progressive disease had disease control, suggesting a graft-vs-tumor (GVT) effect. Progression-free survival (PFS) at 1 year was 23% with myeloablative conditioning and 8% with RIC (P=0.09). Women who developed acute GVHD after an RIC regimen had lower risks of relapse or progression than those who did not (relative risk, 3.05: P=0.03), consistent with a GVT effect, but this did not affect PFS. These findings support the need for preclinical and clinical studies that facilitate targeted adoptive immunotherapy for breast cancer to explore the benefit of a GVT effect in breast cancer.     

Long-term outcome after allogeneic hematopoietic stem cell transplantation for advanced stage acute myeloblastic leukemia: a retrospective study of 379 patients reported to the Société Française de Greffe de Moelle (SFGM)

To assess the place of allogeneic hematopoietic stem cell transplantation (HSCT) in the advanced stage of acute myeloid leukemia (AML), we retrospectively analyzed 379 consecutive patients who underwent allogeneic HSCT for advanced AML. The median follow-up of the entire cohort was 7.5 years. Sixty-nine patients (18%) were transplanted with primary resistant disease. Three hundred and ten (82%) were relapsed patients, 94 (30%) of whom were in untreated relapse, 67 (22%) in refractory relapse and 149 (48%) in 2nd or 3rd complete remission at time of transplantation. The 5-year probabilities of overall survival (OS), disease-free survival (DFS), and transplant-related mortality (TRM) were 22 +/- 4%, 20 +/- 4%, 45 +/- 6%, respectively. In multivariate analysis, we demonstrated the favorable impact on OS, DFS and TRM of two factors over which we have no control (age <15 years, complete remission achievement) and three factors over which we have some control (female donor, acute and chronic graft-versus-host disease). The results of this study suggest that the graft-versus-leukemia effect is important in advanced AML and that new HSCT modalities are needed for some patients with this indication.     

The dismal outcome in patients with acute leukaemia who relapse after an autograft is improved if a second autograft or a matched allograft is performed. Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

All patients receiving autografts for acute leukaemia in remission between 1 January 1981 and 31 December 1996 and reported to the European Group for Blood and Marrow Transplantation and had a relapse, were included. The patients underwent an allograft (n = 90, group A), were treated with chemotherapy (n = 2584, group B) or received a second autograft (n = 74, group C). The 2-year survival after relapse was 32 +/- 5%, 11 +/- 1% and 42 +/- 6% in groups A, B and C, respectively. In group A, those with an HLA-A, -B and -DR compatible related or unrelated donor had a 2-year survival of 37 +/- 7% compared to 13 +/- 8% for those receiving a graft from an HLA mismatched donor (n = 20). The following factors were associated with better survival in multivariate analyses: an interval from first autograft to relapse >5 months (P < 0.00001), a first autograft performed later than 1991 (P < 0.00001), patient age below 26 years (median, P < 0.002), group B vs HLA mismatches from group A (P = 0.002), group C vs group B (P < 0.005), patients who were not treated with total body irradiation at first autograft (P < 0.02) and patients in first remission at first autograft (P = 0.02). To conclude, the poor outcome in these patients was improved if a second autograft was feasible (P < 0.005), or if an HLA-matched allograft was performed (NS). Bone Marrow Transplantation (2000).     

Secretory immunoglobulin A: well beyond immune exclusion at mucosal surfaces

At mucosal surfaces, secretory IgA (SIgA) antibodies serve as the first line of defense against microorganisms through a mechanism called immune exclusion that prevents interaction of neutralized antigens with the epithelium. In addition, SIgA plays a role in the immune balance of the epithelial barrier through selective adhesion to M cells in intestinal Peyer’s patches. This mediates the transepithelial retro-transport of the antibody and associated antigens from the intestinal lumen to underlying gut-associated organized lymphoid tissue. In Peyer’s patches, SIgA-based immune complexes are internalized by underlying antigen-presenting cells, leaving the antigen with masked epitopes, a form that limits the risk of overwhelming the local immune protection system with danger signals. This translates into the onset of mucosal and systemic responses associated with production of anti-inflammatory cytokines and limited activation of antigen-presenting cells. In the gastrointestinal tract, SIgA exhibits thus properties of a neutralizing agent (immune exclusion) and of an immunopotentiator inducing effector immune responses in a noninflammatory context favorable to preserve local homeostasis.     

Recommendations for Responsible Development and Application of Neurotechnologies

Advancements in novel neurotechnologies, such as brain computer interfaces (BCI) and neuromodulatory devices such as deep brain stimulators (DBS), will have profound implications for society and human rights. While these technologies are improving the diagnosis and treatment of mental and neurological diseases, they can also alter individual agency and estrange those using neurotechnologies from their sense of self, challenging basic notions of what it means to be human. As an international coalition of interdisciplinary scholars and practitioners, we examine these challenges and make recommendations to mitigate negative consequences that could arise from the unregulated development or application of novel neurotechnologies. We explore potential ethical challenges in four key areas: identity and agency, privacy, bias, and enhancement. To address them, we propose (1) democratic and inclusive summits to establish globally-coordinated ethical and societal guidelines for neurotechnology development and application, (2) new measures, including “Neurorights,” for data privacy, security, and consent to empower neurotechnology users’ control over their data, (3) new methods of identifying and preventing bias, and (4) the adoption of public guidelines for safe and equitable distribution of neurotechnological devices.

     

Insulin resistance is a poor predictor of type 2 diabetes in individuals with no family history of disease

In normoglycemic offspring of two type 2 diabetic parents, low insulin sensitivity (S(I)) and low insulin-independent glucose effectiveness (S(G)) predict the development of diabetes one to two decades later. To determine whether low S(I), low S(G,) or low acute insulin response to glucose are predictive of diabetes in a population at low genetic risk for disease, 181 normoglycemic individuals with no family history of diabetes (FH-) and 150 normoglycemic offspring of two type 2 diabetic parents (FH+) underwent i.v. glucose tolerance testing (IVGTT) between the years 1964-82. During 25 +/- 6 years follow-up, comprising 2,758 person years, the FH- cohort (54 +/- 9 years) had an age-adjusted incidence rate of type 2 diabetes of 1.8 per 1,000 person years, similar to that in other population-based studies, but significantly lower than 16.7 for the FH+ cohort. Even when the two study populations were subdivided by initial values of S(I) and S(G) derived from IVGTT's performed at study entry, there was a 10- to 20-fold difference in age-adjusted incidence rates for diabetes in the FH- vs. FH+ individuals with low S(I) and low S(G). The acute insulin response to glucose was not predictive of the development of diabetes when considered independently or when assessed as a function of S(I), i.e., the glucose disposition index. These data demonstrate that low glucose disposal rates are robustly associated with the development of diabetes in the FH+ individuals, but insulin resistance per se is not sufficient for the development of diabetes in individuals without family history of disease and strongly suggest a familial factor, not detectable in our current measures of the dynamic responses of glucose or insulin to an IVGTT is an important risk factor for type 2 diabetes. Low S(I) and low S(G), both measures of glucose disposal, interact with this putative familial factor to result in a high risk of type 2 diabetes in the FH+ individuals, but not in the FH- individuals.     

Increased presence of anti-HLA antibodies early after allogeneic granulocyte colony-stimulating factor-mobilized peripheral blood hematopoietic stem cell transplantation compared with bone marrow transplantation

We have recently shown that the use of allogeneic granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood hematopoietic stem cell transplantation (PBHSCT), as compared with bone marrow transplantation (BMT), is associated with increased titers of antibodies (Abs) directed against red blood cell ABO antigens. To further evaluate the influence of a G-CSF-mobilized PBHSCT graft on alloimmune Ab responses, we examined the frequency of anti-HLA Abs after transplantation in the setting of the same randomized study, comparing PBHSCT with BMT in adults. Anti-HLA Ab presence was determined by complement-dependent cytotoxicity assay (CDC) and flow cytometry in the recipient before and 30 days after transplantation as well as in the donor before graft donation. The use of PBHSCT was significantly associated with increased detection of anti-HLA immunoglobulin G (IgG) Abs early after transplantation as evidenced by flow cytometry (11 of 24 versus 4 of 27 transplant recipients, P =.03) and, less so, by CDC (5 of 24 versus 1 of 27 transplant recipients, P =.09). The difference between PBHSCT and BMT was further heightened when analysis was restricted to anti-HLA IgG Ab-negative donor/recipient pairs. In such a setting, early anti-HLA Ab was never detected after BMT but was repeatedly detected after PBHSCT (flow cytometry, 6 of 18 versus 0 of 17 transplant recipients, P =.02; CDC, 4 of 23 versus 0 of 26 transplant recipients, P =.04). Importantly, the PBHSCT-associated increase in anti-HLA Ab detection was observed despite a reduction in the median number of platelet-transfusion episodes per patient in PBHSC transplant versus BM transplant recipients (3 platelet-transfusion episodes [range, 1-21] in PBHSCT group vs 6 platelet-transfusion episodes [range, 3-33] in the BMT group; P =.02). In conclusion, this study strongly suggests that G-CSF-mobilized PBHSCT results in an increased incidence of circulating anti-HLA Abs and further confirms that the use of such a graft alters alloimmune Ab responses.     

EFFECTS OF NORMAL AGING ON LOWER EXTREMITY LOADING AND COORDINATION DURING RUNNING IN MALES AND FEMALES

Background

Runners sustain high injury rates. As greater numbers of individuals continue to run past the age of 60, normal physiological changes that occur with aging may further contribute to injuries. Male and female runners demonstrate different mechanics and injury rates. However, whether these mechanics further diverge as runners age and whether or not this potential divergence in mechanics may or may not be associated with a potential for increased injury risk is unknown.

Hypothesis/Purpose

The purpose of this study was to compare measures of loading and lower extremity coupling during running with respect to age and sex. It was hypothesized that males and females would demonstrate increasingly diverging mechanics with increased age.

Methods

Forty‐one subjects were placed in four groups: younger males (n=13), younger females (n=6), older males (n=16), and older females (n=6). Ten running trials were collected and analyzed for each subject. Kinematic data were collected and reconstructed using a nine‐camera motion analysis system and commercial software. Vertical loading rate (VLR), initial (GRF₁) and peak vertical ground reaction force (GRF₂) and lower leg joint coupling were calculated for each subject. Analysis was performed using a 2‐factor ANOVA (sex X age) to determine differences between groups during the stance phase of running.

Results

Compared to younger subjects, older subjects demonstrated higher GRF₁ per body weight (Y: 1.70 (0.19), O: 1.96 (0.23), p < 0.01), higher VLR in body weight/second (Y: 44.17 (6.73), O: 52.76 (8.39), p < 0.01) and lower GRF₂ per body weight (Y: 2.47 (0.18), O: 2.35 (0.18), p=0.04). However, no differences existed between males and females or further diverged in the older subjects. There were no differences between or within groups in joint coupling. Finally, no significant differences were seen between sexes and no interactions were found between any variables in the current study.

Conclusions

Older runners experience greater GRF₁ and VLR and lower GRF₂. These are factors previously associated with tibial loading and stress fractures. Males and females do not differ on these factors suggesting older female runners may be at no greater risk than younger runners or male runners for lower extremity bony injury based on normal mechanics.

Level of Evidence

3     

Increased Medial Longitudinal Arch Mobility,Lower Extremity Kinematics,and Ground Reaction Forces in High-Arched Runners

Context:

Runners with high medial longitudinal arch structure demonstrate unique kinematics and kinetics that may lead to running injuries. The mobility of the midfoot as measured by the change in arch height is also suspected to play a role in lower extremity function during running. The effect of arch mobility in high-arched runners is an important factor in prescribing footwear, training, and rehabilitating the running athlete after injury.

Objective:

To examine the effect of medial longitudinal arch mobility on running kinematics, ground reaction forces, and loading rates in high-arched runners.

Design:

Cross-sectional study.

Setting:

Human movement research laboratory.

Patients or Other Participants:

A total of 104 runners were screened for arch height. Runners were then identified as having high arches if the arch height index was greater than 0.5 SD above the mean. Of the runners with high arches, 11 rigid runners with the lowest arch mobility (R) were compared with 8 mobile runners with the highest arch mobility (M). Arch mobility was determined by calculating the left arch height index in all runners.

Intervention(s):

Three-dimensional motion analysis of running over ground.

Main Outcome Measure(s):

Rearfoot and tibial angular excursions, eversion-to-tibial internal-rotation ratio, vertical ground reaction forces, and the associated loading rates.

Results:

Runners with mobile arches exhibited decreased tibial internal-rotation excursion (mobile: 5.6° ± 2.3° versus rigid: 8.0° ± 3.0°), greater eversion-to-tibial internal-rotation ratio (mobile: 2.1 ± 0.8 versus rigid: 1.5 ± 0.5), decreased second peak vertical ground reaction force values (mobile: 2.3 ± 0.2 × body weight versus rigid: 2.4 ± 0.1 × body weight), and decreased vertical loading rate values (mobile: 55.7 ± 14.1 × body weight/s versus rigid: 65.9 ± 11.4 × body weight/s).

Conclusions:

Based on the results of this study, it appears that runners with high arch structure but differing arch mobility exhibited differences in select lower extremity movement patterns and forces. Future authors should investigate the impact of arch mobility on running-related injuries.Key Words: foot, running injuries, joint coupling

Key Points

• Foot arch mobility played an important role in lower extremity biomechanics during running.
• High-arched rigid runners demonstrated increased vertical loading rates, which are often associated with lower extremity injuries in runners.
• Joint coupling or coordination is influenced by arch mobility. Changes in intersegment coordination can result in the need for compensation and potential overuse at nearby joints.

Differences in lower extremity kinematics and kinetics between runners with high arches (HAs) and low arches (LAs) have received much attention because of the relationship between arch structure and elevated injury risk.^1–4 The prevalence of individuals with HAs in the population has been reported to be as large as 20%.⁵ Runners with HA structure report more heel pain, stress fractures, and other structure-specific injuries.⁶ These injuries may be the result of runners with HAs moving with a stiffer lower extremity and higher loading rates during running.^3,4,7 Although the arch structure has received much attention, there has been little focus on the mobility of the medial longitudinal arch. The relationship between arch structure and mobility is a critical component in understanding how structure, biomechanics, and injury are related in runners with the HA foot type.One specific kinematic factor often associated with foot type is eversion. Eversion is the primary motion at the foot that is responsible for shock attenuation during running.⁸ Eversion is coupled with internal rotation of the tibia and pronation of the foot.² These coupled motions have been defined as the eversion-to-tibial internal-rotation (EV:TIR) ratio.² This relationship is based solely on the structure of the arch and the resting position of the subtalar joint; mobility has not been considered in this relationship.² The EV:TIR relationship has previously been compared between runners with HAs and LAs, demonstrating that HA runners have decreased total eversion excursions and a concurrent increase in tibial internal rotation.^2,9 More specifically, HA individuals demonstrate a lower EV:TIR compared with LA runners.^9,10 Further, a lower EV:TIR has been reported to increase the stress on the knee in HA runners secondary to the relative increase in transverse-plane motion of the tibia.⁹ These findings suggest that the orientation of the arch has an effect on the coupling of the lower extremity further up the kinematic chain and may be a factor associated with knee injury in HA runners.Although arch structure has a clear relationship to lower extremity movement, its effect on lower extremity forces is less conclusive.^{2,3,9,11–13} Differences in the magnitude of the vertical impact peak have not been associated with arch height.³ This may be because at initial contact, the forefoot is not in contact with the ground, which means the shape or mobility of the arch cannot affect the absorption or transfer of forces. Loading occurs at initial contact through the calcaneus and the rear one-third of the foot. At this point, the ground reaction force is transmitted through the heel pad, calcaneus, and talus before moving into the lower leg.¹⁰ The second vertical ground reaction force (VGRF) peak may better represent the effect of arch height and mobility on shock attenuation because the arch is likely to deform under weight. Specifically, a more mobile foot may result in decreased magnitude of the second VGRF peak.High arches are often considered to be rigid because of the relatively vertical rearfoot-to-midfoot axis relationship.^1,14 However, arch mobility has been reported to be independent of the static height of the medial longitudinal arch.^3,11 Decreased mobility of the arch in HA runners has been suggested to relate to an increased need for compliance at other lower extremity joints, such as the knee.⁴ High-arched individuals demonstrate a more supinated position of the foot, which results in decreased pronation throughout the stance phase.^2,9,14 However, a mobile arch or midfoot that compresses under force may result in both midfoot and rearfoot pronation, even in an HA foot. Because of this change in rearfoot pronation and the coupling present in the rearfoot and lower leg, it is likely that an individual with a mobile HA will demonstrate different lower extremity kinematics and kinetics.The purpose of our study was to compare running kinematics and VGRF characteristics between 2 groups of HA runners: those with rigid arches and those with mobile arches. We hypothesized that the EV:TIR ratio would be different between groups, as we suggested arch mobility has a potential effect on rearfoot motion and subsequent coupling. We also hypothesized that the initial loading rate between the groups would be similar because the force at this point is through the rear of the foot, but the second loading rate and maximum VGRF would be decreased in the mobile group.