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1.  Risk of lymphedema after mastectomy – potential benefit of applying ACOSOG Z0011 protocol to mastectomy patients 
Axillary lymph node dissection (ALND) and radiation therapy (RT) are commonly recommended for mastectomy patients with positive sentinel lymph node biopsy (SLNB). Effective alternatives to ALND that reduce lymphedema risk are needed. We evaluated rates of lymphedema in mastectomy patients who received SLNB with RT, compared to ALND with or without RT.
627 breast cancer patients who underwent 664 mastectomies between 2005–2013 were prospectively screened for lymphedema, median 22.8 months follow-up (range 3.0–86.9). Each mastectomy was categorized as: SLNB-no RT, SLNB+RT, ALND-no RT, or ALND+RT. RT included chest wall +/− nodal radiation. Perometer arm volume measurements were obtained pre- and post-operatively. Lymphedema was defined as ≥10% arm volume increase. Kaplan-Meier and Cox regression analyses were performed to determine lymphedema rates and risk factors.
Of 664 mastectomies, 52% (343/664) were SLNB-no RT, 5% (34/664) SLNB+RT, 9% (58/664) ALND-no RT, and 34% (229/664) ALND+RT. The two-year cumulative lymphedema incidence was 10.0% (95% CI: 2.6–34.4%) for SLNB+RT compared with 19.3% (95% CI: 10.8–33.1%) for ALND-no RT, and 30.1% (95% CI: 23.7–37.8%) for ALND+RT. The lowest cumulative incidence was 2.19% (95% CI: 0.88%–5.40%) for SLNB-no RT. By multivariate analysis, factors significantly associated with increased lymphedema risk included RT (p=0.0017), ALND (p=0.0001), greater number of lymph nodes removed (p=0.0006), no reconstruction (p=0.0418), higher BMI (p<0.0001) and older age (p=0.0021).
Avoiding completion ALND and instead receiving SLNB with RT may decrease lymphedema risk in patients requiring mastectomy. Future trials should investigate the safety of applying the ACOSOG Z0011 protocol to mastectomy patients.
PMCID: PMC4011490  PMID: 24500108
Mastectomy; Lymphedema; Quality of Life; Radiation Therapy; Sentinel Lymph Node Biopsy
2.  Effect of Training on Inspiratory Load Compensation in Weaned and Unweaned Mechanically Ventilated ICU Patients 
Respiratory care  2013;59(1):22-31.
While inspiratory muscle weakness is common in prolonged mechanical ventilation, inspiratory muscle strength training (IMST) can facilitate strengthening and ventilator weaning. However, the inspiratory load compensation (ILC) responses to threshold loads are not well characterized in patients. We retrospectively compared ILC responses according to the clinical outcomes of IMST (ie, maximum inspiratory pressure [PImax], weaning outcome), in difficult-to-wean ICU patients.
Sixteen tracheostomized subjects (10 weaned, 6 unweaned) from a previous clinical trial underwent IMST 5 days/week, at the highest tolerated load, in conjunction with daily, progressive spontaneous breathing trials. PImax and ILC with a 10 cm H2O load were compared in the subjects before and after IMST. Changes in ILC performance were further characterized (5, 10, 15 cm H2O loads) in the trained subjects who weaned.
Demographics, respiratory mechanics, and initial PImax (52 ± 26 cm H2O vs 42 ± 13 cm H2O) did not significantly differ between the groups. Upon enrollment, PImax significantly correlated with flow ILC responses with the 10 cm H2O load (r = 0.64, P = .008). After IMST, PImax significantly increased in the entire sample (P = .03). Both before and after IMST, subjects who weaned generated greater flow and volume ILC than subjects who failed to wean. Additionally, ILC flow, tidal volume, and duty cycle increased upon ventilator weaning, at loads of 5, 10, and 15 cm H2O.
Flow ILC at a threshold load of 10 cm H2O in ventilated, tracheostomized subjects positively correlated with PImax. Although PImax improved in both groups, the flow and volume ILC responses of the weaned subjects were more robust, both before and after IMST. The results suggest that ILC response is different in weaned and unweaned subjects, reflecting dynamic inspiratory muscular efforts that could be influential in weaning.
PMCID: PMC4157996  PMID: 23764858
respiratory failure; respiratory muscle training; respiratory muscles; ventilator weaning
3.  Intrinsic Transient Tracheal Occlusion Training and Myogenic Remodeling of Rodent Parasternal Intercostal Fibers 
It is recognized that diaphragm muscle plasticity occurs with mechanical overloads, yet less is known regarding synergistic parasternal intercostal muscle fiber remodeling. We conducted overload training with intrinsic transient tracheal occlusion (ITTO) exercises in conscious animals. We hypothesized ITTO would yield significant fiber hypertrophy and myogenic activation that would parallel diaphragm fiber remodeling. Sprague-Dawley rats underwent placement of a tracheal cuff and were randomly assigned to receive daily ten-minute sessions of conscious ITTO or observation (SHAM) over two weeks. After training, fiber morphology, myosin heavy chain isoform composition, cross-sectional area, proportion of Pax7-positive nuclei, and presence of embryonic myosin (eMHC) were quantified. Type IIx/b fibers were 20% larger after ITTO training than with SHAM training (ITTO: 4431±676 μm2, SHAM: 3689±400 μm2, p<0.05), and type I fibers were more prevalent after ITTO (p<0.01). Expression of Pax7 was increased in ITTO parasternals and diaphragm (p<0.05). In contrast, the proportion of eMHC-positive fibers was increased only in ITTO parasternals (1.2 (3.4-0.6)%, SHAM: 0 (0.6-0%, p<0.05). Although diaphragm and parasternal type II fibers hypertrophy to a similar degree, myogenic remodeling appears to differ between the two muscles.
PMCID: PMC4269303  PMID: 25509059
4.  Mechanical ventilation, diaphragm weakness and weaning: A rehabilitation perspective 
Respiratory physiology & neurobiology  2013;189(2):10.1016/j.resp.2013.05.012.
Most patients are easily liberated from mechanical ventilation (MV) following resolution of respiratory failure and a successful trial of spontaneous breathing, but about 25% of patients experience difficult weaning. MV use leads to cellular changes and weakness, which has been linked to weaning difficulties and has been labeled ventilator induced diaphragm dysfunction (VIDD). Aggravating factors in human studies with prolonged weaning include malnutrition, chronic electrolyte abnormalities, hyperglycemia, excessive resistive and elastic loads, corticosteroids, muscle relaxant exposure, sepsis and compromised cardiac function. Numerous animal studies have investigated the effects of MV on diaphragm function. Virtually all of these studies have concluded that MV use rapidly leads to VIDD and have identified cellular and molecular mechanisms of VIDD. Molecular and functional studies on the effects of MV on the human diaphragm have largely confirmed the animal results and identified potential treatment strategies. Only recently have potential VIDD treatments been tested in humans, including pharmacologic interventions and diaphragm “training”. A limited number of human studies have found that specific diaphragm training can increase respiratory muscle strength in FTW patients and facilitate weaning, but larger, multicenter trials are needed.
PMCID: PMC3808482  PMID: 23692928
ventilator weaning; ventilator induced diaphragm dysfunction; diaphragm strength training
5.  Adeno-Associated Virus–Mediated Gene Therapy for Metabolic Myopathy 
Human Gene Therapy  2013;24(11):928-936.
Metabolic myopathies are a diverse group of rare diseases in which impaired breakdown of stored energy leads to profound muscle dysfunction ranging from exercise intolerance to severe muscle wasting. Metabolic myopathies are largely caused by functional deficiency of a single gene and are generally subcategorized into three major types of metabolic disease: mitochondrial, lipid, or glycogen. Treatment varies greatly depending on the biochemical nature of the disease, and unfortunately no definitive treatments exist for metabolic myopathy. Since this group of diseases is inherited, gene therapy is being explored as an approach to personalized medical treatment. Adeno-associated virus–based vectors in particular have shown to be promising in the treatment of several forms of metabolic myopathy. This review will discuss the most recent advances in gene therapy efforts for the treatment of metabolic myopathies.
PMCID: PMC3814817  PMID: 24164240
6.  The respiratory neuromuscular system in Pompe disease☆ 
Pompe disease is due to mutations in the gene encoding the lysosomal enzyme acid α-glucosidase (GAA). Absence of functional GAA typically results in cardiorespiratory failure in the first year; reduced GAA activity is associated with progressive respiratory failure later in life. While skeletal muscle pathology contributes to respiratory insufficiency in Pompe disease, emerging evidence indicates that respiratory neuron dysfunction is also a significant part of dysfunction in motor units. Animal models show profound glycogen accumulation in spinal and medullary respiratory neurons and altered neural activity. Tissues from Pompe patients show central nervous system glycogen accumulation and motoneuron pathology. A neural mechanism raises considerations about the current clinical approach of enzyme replacement since the recombinant protein does not cross the blood-brain-barrier. Indeed, clinical data suggest that enzyme replacement therapy delays symptom progression, but many patients eventually require ventilatory assistance, especially during sleep. We propose that treatments which restore GAA activity to respiratory muscles, neurons and networks will be required to fully correct ventilatory insufficiency in Pompe disease.
PMCID: PMC4083814  PMID: 23797185
Pompe; Respiratory; Motoneurons; Plasticity; Therapy; Pathology
7.  Hemocompatibility of Polymeric Nanostructured Surfaces 
Tissue integration is an important property when inducing transplant tolerance, however, the hemocompatibility of the biomaterial surface also plays an important role in the ultimate success of the implant. Therefore, in order to induce transplant tolerance, it is critical to understand the interaction of blood components with the material surfaces. In this study, we have investigated the adsorption of key blood serum proteins, in vitro adhesion and activation of platelets and clotting kinetics of whole blood on flat polycaprolactone (PCL) surfaces, nanowire (NW) surfaces and nanofiber (NF) surfaces. Previous studies have shown that polymeric nanostructured surfaces improve cell adhesion, proliferation and viability; however it is unclear how these polymeric nanostructured surfaces interact with the blood and its components. Protein adsorption results indicate that while there were no significant differences in total albumin adsorption on PCL, NW and NF surfaces, NW surfaces had higher total fibrinogen and immunoglobulin-G adsorption compared to NF and PCL surfaces. In contrast, NF surfaces had higher surface FIB and IgG adsorption compared to PCL and NW surfaces. Platelet adhesion and viability studies show more adhesion and clustering of platelets on the NF surfaces as compared to PCL and NW surfaces. Platelet activation studies reveal that NW surfaces have the highest percentage of unactivated platelets, whereas NF surfaces have the highest percentage of fully activated platelets. Whole blood clotting results indicate that NW surfaces maintain an increased amount of free hemoglobin during the clotting process compared to PCL and NF surface, indicating less clotting and slower rate of clotting on their surfaces.
PMCID: PMC3713522  PMID: 23848447
Hemocompatibility; nanowire surfaces; nanofiber surfaces; platelets
Psycho-oncology  2008;17(8):831-843.
Prophylactic mastectomy (PM) offers 90% or greater reduction in risk of breast cancer to women at increased hereditary risk. Nonetheless, acceptance in North America has been low (0–36%). Most women report reduced cancer worry post-operatively, but up to 25–50% of women electing surgery also report psychological distress and/or difficulty adapting following PM. Psychological consultation to aid decision-making and improve post-surgical coping isn’t routinely offered. This retrospective, cross-sectional study explored, quantitatively and qualitatively, interest in and acceptability of psychological consultation for issues related to PM among 108 women who had undergone or were considering surgery. Of the 71 women who had undergone PM, more than half felt pre-surgical psychological consultation was advisable and nearly 2/3 felt post-surgical psychological consultation would be helpful. All 37 women (100%) currently considering PM believed psychological consultation would aid decision-making and preparation for surgery.
Narratives from the interviews illustrate the nature and intensity of the need for psychological support and describe preferences for the role of the psychologist. Suggestions are offered for the integration of psychological services for women deciding about or adapting to PM.
PMCID: PMC4133134  PMID: 18636423
9.  Defining a threshold for intervention in breast cancer-related lymphedema: What level of arm volume increase predicts progression? 
Evaluate arm volume measurements and clinico-pathologic characteristics of breast cancer patients to define a threshold for intervention in breast cancer-related lymphedema.
We prospectively performed arm volume measurements on breast cancer patients using a Perometer. Arm measurements were performed pre- and post-operatively, and change in arm volume was quantified using a relative volume change (RVC) equation. Patient and treatment risk factors were evaluated. Cox proportional hazards models with time-dependent covariates for RVC were used to evaluate whether RVC elevations of ≥3%-<5% or ≥5%-<10% occurring ≤3 months or >3 months after surgery were associated with progression to ≥10% RVC.
1173 patients met eligibility criteria with a median of 27 months post-operative follow-up.The cumulative incidence of ≥10% RVC at 24 months was 5.26% (95% CI: 4.01% – 6.88%). By multivariable analysis, a measurement of ≥5-<10% RVC occurring >3 months after surgery was significantly associated with an increased risk of progression to ≥10% RVC (HR: 2.97, p<0.0001), but a measurement of ≥3-<5% RVC during the same time period was not statistically significantly associated (HR: 1.55, p=0.10). Other significant risk factors included a measurement ≤3 months after surgery with RVC of ≥3–<5% (p=0.007), ≥5–<10% (p<0.0001), or ≥10% (p=0.023), axillary lymph node dissection (ALND) (p<0.0001), and higher BMI at diagnosis (p=0.0028). Type of breast surgery, age, number of positive or number of lymph nodes removed, nodal radiation, chemotherapy, and hormonal therapy were not significant (p>0.05).
Breast cancer patients who experience a relative arm volume increase of ≥3%-<5% occurring >3 months after surgery do not have a statistically significant increase in risk of progression to ≥10%, a common lymphedema criterion . Our data supports utilization of a ≥5-<10% threshold for close monitoring or intervention, warranting further assessment. Additional risk factors for progression to ≥10% include ALND, higher BMI, and post-operative arm volume elevation.
PMCID: PMC3788652  PMID: 23912961
Lymphedema; Quality of Life; Compression Therapy; Threshold; Early Intervention
10.  Lumpectomy Plus Tamoxifen With or Without Irradiation in Women Age 70 Years or Older With Early Breast Cancer: Long-Term Follow-Up of CALGB 9343 
Journal of Clinical Oncology  2013;31(19):2382-2387.
To determine whether there is a benefit to adjuvant radiation therapy after breast-conserving surgery and tamoxifen in women age ≥ 70 years with early-stage breast cancer.
Patients and Methods
Between July 1994 and February 1999, 636 women (age ≥ 70 years) who had clinical stage I (T1N0M0 according to TNM classification) estrogen receptor (ER) –positive breast carcinoma treated by lumpectomy were randomly assigned to receive tamoxifen plus radiation therapy (TamRT; 317 women) or tamoxifen alone (Tam; 319 women). Primary end points were time to local or regional recurrence, frequency of mastectomy, breast cancer–specific survival, time to distant metastasis, and overall survival (OS).
Median follow-up for treated patients is now 12.6 years. At 10 years, 98% of patients receiving TamRT (95% CI, 96% to 99%) compared with 90% of those receiving Tam (95% CI, 85% to 93%) were free from local and regional recurrences. There were no significant differences in time to mastectomy, time to distant metastasis, breast cancer–specific survival, or OS between the two groups. Ten-year OS was 67% (95% CI, 62% to 72%) and 66% (95% CI, 61% to 71%) in the TamRT and Tam groups, respectively.
With long-term follow-up, the previously observed small improvement in locoregional recurrence with the addition of radiation therapy remains. However, this does not translate into an advantage in OS, distant disease-free survival, or breast preservation. Depending on the value placed on local recurrence, Tam remains a reasonable option for women age ≥ 70 years with ER-positive early-stage breast cancer.
PMCID: PMC3691356  PMID: 23690420
11.  Phase I/II Trial of Adeno-Associated Virus–Mediated Alpha-Glucosidase Gene Therapy to the Diaphragm for Chronic Respiratory Failure in Pompe Disease: Initial Safety and Ventilatory Outcomes 
Human Gene Therapy  2013;24(6):630-640.
Pompe disease is an inherited neuromuscular disease caused by deficiency of lysosomal acid alpha-glucosidase (GAA) leading to glycogen accumulation in muscle and motoneurons. Cardiopulmonary failure in infancy leads to early mortality, and GAA enzyme replacement therapy (ERT) results in improved survival, reduction of cardiac hypertrophy, and developmental gains. However, many children have progressive ventilatory insufficiency and need additional support. Preclinical work shows that gene transfer restores phrenic neural activity and corrects ventilatory deficits. Here we present 180-day safety and ventilatory outcomes for five ventilator-dependent children in a phase I/II clinical trial of AAV-mediated GAA gene therapy (rAAV1-hGAA) following intradiaphragmatic delivery. We assessed whether rAAV1-hGAA results in acceptable safety outcomes and detectable functional changes, using general safety measures, immunological studies, and pulmonary functional testing. All subjects required chronic, full-time mechanical ventilation because of respiratory failure that was unresponsive to both ERT and preoperative muscle-conditioning exercises. After receiving a dose of either 1×1012 vg (n=3) or 5×1012 vg (n=2) of rAAV1-hGAA, the subjects' unassisted tidal volume was significantly larger (median [interquartile range] 28.8% increase [15.2–35.2], p<0.05). Further, most patients tolerated appreciably longer periods of unassisted breathing (425% increase [103–851], p=0.08). Gene transfer did not improve maximal inspiratory pressure. Expected levels of circulating antibodies and no T-cell-mediated immune responses to the vector (capsids) were observed. One subject demonstrated a slight increase in anti-GAA antibody that was not considered clinically significant. These results indicate that rAAV1-hGAA was safe and may lead to modest improvements in volitional ventilatory performance measures. Evaluation of the next five patients will determine whether earlier intervention can further enhance the functional benefit.
Smith and colleagues present 180-day safety and ventilatory outcomes for five ventilator-dependent children in a phase 1/2 clinical trial of adeno-associated viral (AAV) vector-mediated gene therapy for lysosomal acid α-glucosidase (GAA) deficiency (rAAV1-hGAA) after intradiaphragmatic delivery. rAAV1-hGAA treatment was safe and may lead to modest improvements in volitional ventilatory performance measures.
PMCID: PMC3689178  PMID: 23570273
12.  Genomic Confirmation of Hybridisation and Recent Inbreeding in a Vector-Isolated Leishmania Population 
PLoS Genetics  2014;10(1):e1004092.
Although asexual reproduction via clonal propagation has been proposed as the principal reproductive mechanism across parasitic protozoa of the Leishmania genus, sexual recombination has long been suspected, based on hybrid marker profiles detected in field isolates from different geographical locations. The recent experimental demonstration of a sexual cycle in Leishmania within sand flies has confirmed the occurrence of hybridisation, but knowledge of the parasite life cycle in the wild still remains limited. Here, we use whole genome sequencing to investigate the frequency of sexual reproduction in Leishmania, by sequencing the genomes of 11 Leishmania infantum isolates from sand flies and 1 patient isolate in a focus of cutaneous leishmaniasis in the Çukurova province of southeast Turkey. This is the first genome-wide examination of a vector-isolated population of Leishmania parasites. A genome-wide pattern of patchy heterozygosity and SNP density was observed both within individual strains and across the whole group. Comparisons with other Leishmania donovani complex genome sequences suggest that these isolates are derived from a single cross of two diverse strains with subsequent recombination within the population. This interpretation is supported by a statistical model of the genomic variability for each strain compared to the L. infantum reference genome strain as well as genome-wide scans for recombination within the population. Further analysis of these heterozygous blocks indicates that the two parents were phylogenetically distinct. Patterns of linkage disequilibrium indicate that this population reproduced primarily clonally following the original hybridisation event, but that some recombination also occurred. This observation allowed us to estimate the relative rates of sexual and asexual reproduction within this population, to our knowledge the first quantitative estimate of these events during the Leishmania life cycle.
Author Summary
Sexual reproduction is predicted to be a rare event in Leishmania parasites, as evidenced by detection of rare parasite hybrids in natural populations using molecular methods. Recently, a sexual cycle has been detected experimentally in parasites within the sand fly vector (that transmits this pathogenic microorganism to mammalian species including man, causing human leishmaniasis). In this study, we have used whole genome sequencing to investigate genetic variation at the highest level of resolution in Leishmania parasites isolated from sand flies in a defined focus of leishmaniasis in southeast Turkey. Using a range of analytical tools, we show that variation in these parasites arose following a single cross between two diverse strains and subsequent recombination between the progeny, despite mainly clonal reproduction in the parasite population. We have thus been able to derive quantitative estimates of the relative rates of sexual and asexual reproduction during the Leishmania life cycle for the first time, information that will be critical to our understanding of the epidemiology and evolution of this genus.
PMCID: PMC3894156  PMID: 24453988
13.  Extracellular matrix synthesis in vascular disease: hypertension, and atherosclerosis 
Journal of Biomedical Research  2013;28(1):25-39.
Extracellular matrix (ECM) within the vascular network provides both a structural and regulatory role. The ECM is a dynamic composite of multiple proteins that form structures connecting cells within the network. Blood vessels are distended by blood pressure and, therefore, require ECM components with elasticity yet with enough tensile strength to resist rupture. The ECM is involved in conducting mechanical signals to cells. Most importantly, ECM regulates cellular function through chemical signaling by controlling activation and bioavailability of the growth factors. Cells respond to ECM by remodeling their microenvironment which becomes dysregulated in vascular diseases such hypertension, restenosis and atherosclerosis. This review examines the cellular and ECM components of vessels, with specific emphasis on the regulation of collagen type I and implications in vascular disease.
PMCID: PMC3904172  PMID: 24474961
extracellular matrix; vascular disease
14.  An improved genetic system for bioengineering buoyant gas vesicle nanoparticles from Haloarchaea 
BMC Biotechnology  2013;13:112.
Gas vesicles are hollow, buoyant organelles bounded by a thin and extremely stable protein membrane. They are coded by a cluster of gvp genes in the halophilic archaeon, Halobacterium sp. NRC-1. Using an expression vector containing the entire gvp gene cluster, gas vesicle nanoparticles (GVNPs) have been successfully bioengineered for antigen display by constructing gene fusions between the gvpC gene and coding sequences from bacterial and viral pathogens.
To improve and streamline the genetic system for bioengineering of GVNPs, we first constructed a strain of Halobacterium sp. NRC-1 deleted solely for the gvpC gene. The deleted strain contained smaller, more spindle-shaped nanoparticles observable by transmission electron microscopy, confirming a shape-determining role for GvpC in gas vesicle biogenesis. Next, we constructed expression plasmids containing N-terminal coding portions or the complete gvpC gene. After introducing the expression plasmids into the Halobacterium sp. NRC-1 ΔgvpC strain, GvpC protein and variants were localized to the GVNPs by Western blotting analysis and their effects on increasing the size and shape of nanoparticles established by electron microscopy. Finally, a synthetic gene coding for Gaussia princeps luciferase was fused to the gvpC gene fragments on expression plasmids, resulting in an enzymatically active GvpC-luciferase fusion protein bound to the buoyant nanoparticles from Halobacterium.
GvpC protein and its N-terminal fragments expressed from plasmid constructs complemented a Halobacterium sp. NRC-1 ΔgvpC strain and bound to buoyant GVNPs. Fusion of the luciferase reporter gene from Gaussia princeps to the gvpC gene derivatives in expression plasmids produced GVNPs with enzymatically active luciferase bound. These results establish a significantly improved genetic system for displaying foreign proteins on Halobacterium gas vesicles and extend the bioengineering potential of these novel nanoparticles to catalytically active enzymes.
PMCID: PMC3878110  PMID: 24359319
Vaccine; Halophiles; Archaea; Luciferase
15.  The accuracy of surrogate decision makers: informed consent in hypothetical acute stroke scenarios 
Over one third of stroke patients have cognitive or language deficits such that they require surrogate consent for acute stroke treatment or enrollment into acute stroke trials. Little is known about the agreement of stroke patients and surrogates in this time-sensitive decision-making process. We sought to determine patient and surrogate agreement in 4 hypothetical acute stroke scenarios.
We performed face to face interviews with ED patients at an academic teaching hospital from June to August 2011. Patients and the surrogates they designated were asked to make decisions regarding 4 hypothetical stroke scenarios: 2 were treatment decisions; 2 involved enrollment into a clinical trial. Percent agreement was calculated as measures of surrogate predictive ability.
A total of 200 patient/surrogate pairs were interviewed. Overall patient/surrogate percent agreement was 76.5%. Agreement for clinical scenarios ranged from 87% to 96% but dropped to 49%-74% for research scenarios.
Surrogates accurately predict patient preferences for standard acute stroke treatments. However, the accuracy decreases when predicting research participation suggesting that the degree of surrogate agreement is dependent on the type of decision being made. Further research is needed to more thoroughly characterize surrogate decision-making in acute stroke situations.
PMCID: PMC4225766  PMID: 24219014
Acute stroke; Cerebrovascular accident; Drug trials; Emergency medicine; Stroke care; Thrombolysis; TPA; Surrogate consent
16.  External Beam Accelerated Partial-Breast Irradiation Using 32 Gy in 8 Twice-Daily Fractions: Five-Year Results of a Prospective Study 
External-beam accelerated partial breast irradiation (APBI) is an increasingly popular technique following treatment of patients for early-stage breast cancer with conventional breast-conserving therapy. Here we present 5-year results of a prospective trial.
From 10/2003 through 11/2005, 98 evaluable patients with Stage I breast cancer were enrolled on the first dose-step (32 Gy delivered in 8 twice-daily fractions) of a prospective, multi-institutional, dose-escalation clinical trial of three-dimensional conformal external-beam APBI (3D-APBI).
The median age was 61 years; the median tumor size was 0.8 cm; 89% of tumors were estrogen receptor positive; 10% had a triple-negative phenotype; and 1% had a HER-2-positive subtype. Median follow-up was 71 months (range, 2–88 months; interquartile range 64–75 months).
Five patients developed IBTR, for a 5-year actuarial IBTR rate of 5% (95% confidence interval, 1–10%). Three of these occurred in patients with triple-negative disease and 2 in non-triple-negative patients, for 5-year actuarial IBTR rates of 33% (0–57%) and 2% (0–6%; p<0.0001), respectively. On multivariate analysis, triple-negative phenotype was the only predictor of IBTR, with borderline statistical significance after adjusting for tumor grade (p=0.0537).
Overall outcomes were excellent, particularly for patients with estrogen receptor positive disease. Patients in this study with triple-negative breast cancer had a significantly higher IBTR rate than patients with other receptor phenotypes when treated with 3D-APBI. Larger, prospective 3D-APBI clinical trials should continue evaluating the effect of hormone receptor phenotype on IBTR rates.
PMCID: PMC3455124  PMID: 22652104
1. Breast cancer; 2. Triple-negative; 3. 3D conformal; 4. Prospective trial; 5. PBI
17.  Accelerated Partial Breast Irradiation With Low-Dose-Rate Interstitial Implant Brachytherapy After Wide Local Excision: 12-Year Outcomes From a Prospective Trial 
To evaluate the long-term toxicity, cosmesis, and local control of accelerated partial breast irradiation with implant brachytherapy after wide local excision for Stage T1N0 breast cancer (BCa).
Materials and Methods
Between 1997 and 2001, 50 patients with Stage T1N0M0 BCa were treated in a Phase I–II protocol using low-dose-rate accelerated partial breast irradiation with implant brachytherapy after wide local excision and lymph node surgery. The total dose was escalated in three groups: 50 Gy (n = 20), 55 Gy (n = 17), and 60 Gy (n = 13). Patient- and physician-assessed breast cosmesis, patient satisfaction, toxicity, mammographic abnormalities, repeat biopsies, and disease status were prospectively evaluated at each visit. Kendall’s tau (τβ) and logistic regression analyses were used to correlate outcomes with dose, implant volume, patient age, and systemic therapy.
The median follow-up period was 11.2 years (range, 4–14). The patient satisfaction rate was 67%, 67% reported good-excellent cosmesis, and 54% had moderate-severe fibrosis. Higher dose was correlated with worse cosmetic outcome (τβ 0.6, p < .0001), lower patient satisfaction (τβ 0.5, p < .001), and worse fibrosis (τβ 0.4, p = .0024). Of the 50 patients, 35% had fat necrosis and 34% developed telangiectasias ≥1 cm2. Grade 3–4 late skin and subcutaneous toxicities were seen in 4 patients (9%) and 6 patients (13%), respectively, and both correlated with higher dose (τβ 0.3–0.5, p ≤ .01). One patient had Grade 4 skin ulceration and fat necrosis requiring surgery. Mammographic abnormalities were seen in 32% of the patients, and 30% underwent repeat biopsy, of which 73% were benign. Six patients had ipsilateral breast recurrence: five elsewhere in the breast, and one at the implant site. One patient died of metastatic BCa after recurrence. The 12-year actuarial local control, recurrence-free survival, and overall survival rate was 85% (95% confidence interval, 70–97%), 72% (95% confidence interval, 54–86%), and 87% (95% confidence interval, 73–99%), respectively.
Low-dose-rate accelerated partial breast irradiation with implant brachytherapy provides acceptable local control in select early-stage BCa patients. However, treatment-related toxicity and cosmetic complications were significant with longer follow-up and at higher doses.
PMCID: PMC3786258  PMID: 22099046
Accelerated partial breast irradiation; Implant brachytherapy; Early-stage breast cancer; Low-dose-rate; Long-term cosmesis
Postmastectomy radiation therapy (PMRT) can reduce locoregional recurrences (LRR) in high-risk patients, but its role in the treatment of lymph node negative (LN−) breast cancer remains unclear. The aim of this study was to identify a subgroup of T1-T2 breast cancer patients with LN− who might benefit from PMRT.
Methods and Materials
We retrospectively reviewed 1,136 node-negative T1-T2 breast cancer cases treated with mastectomy without PMRT at the Massachusetts General Hospital between 1980 and 2004. We estimated cumulative incidence rates for LRR overall and in specific subgroups, and used Cox proportional hazards models to identify potential risk factors.
Median follow-up was 9 years. The 10-year cumulative incidence of LRR was 5.2% (95% CI: 3.9–6.7%). Chest wall was the most common (73%) site of LRR. Tumor size, margin, patient age, systemic therapy, and lymphovascular invasion (LVI) were significantly associated with LRR on multivariate analysis. These five variables were subsequently used as risk factors for stratified analysis. The 10-year cumulative incidence of LRR for patients with no risk factors was 2.0% (95% CI: 0.5–5.2%), whereas the incidence for patients with three or more risk factors was 19.7% (95% CI: 12.2–28.6%).
It has been suggested that patients with T1-T2N0 breast cancer who undergo mastectomy represent a favorable group for which PMRT renders little benefit. However, this study suggests that select patients with multiple risk factors including LVI, tumor size ≥2 cm, close or positive margin, age ≤50, and no systemic therapy are at higher risk of LRR and may benefit from PMRT.
PMCID: PMC3722592  PMID: 21420245
Breast cancer; Mastectomy; Postmastectomy radiation; Risk factors; Locoregional recurrence
19.  Repeatability of aerobic capacity measurements in Parkinson Disease 
Maximal or peak aerobic capacity (VO2peak) during a maximal effort graded exercise test (GXT) is considered by many to be the “gold standard” outcome for assessing the impact of exercise training on cardiorespiratory fitness. The reliability of this measure in Parkinson Disease (PD) has not been established, where the degree of motor impairment can vary greatly and is influenced by medications. This study examined the reliability of VO2peak during maximal effort GXT in subjects with PD.
Seventy healthy middle-aged and older subjects with PD, Hoehn and Yahr stage 1.5 to 3 underwent a screening/acclimatization maximal effort treadmill test followed by 2 additional maximal effort treadmill tests with repeated measurements of VO2peak. A third VO2peak test was performed in a subset of 21 subjects.
The mean VO2peak measurement was 2.4% higher in the second test compared to the first test (21.42 ± 4.3 ml/kg/min versus 21.93 ± 4.50 ml/kg/min, mean ± SD, p=0.03). The intraclass correlation coefficients (ICC) for VO2peak expressed either as ml/kg/min or L/min was highly reliable, with ICC of 0.90 and 0.94 respectively. The maximum heart rate (ICC of 0.91), and final speed achieved during the tests (ICC of 0.94) were also highly reliable, with the respiratory quotient (RQ) being the least reliable of the parameters measured (ICC of 0.65).
Our results demonstrate that measurement of VO2peak is reliable and repeatable in subjects with mild to moderate PD, thereby validating use of this parameter for assessing the effects of exercise interventions on cardiorespiratory fitness.
PMCID: PMC3701959  PMID: 21606869
graded exercise test; reliability; cardiorespiratory fitness; maximal oxygen uptake; Parkinson Disease
20.  Correction: Chronic Intrinsic Transient Tracheal Occlusion Elicits Diaphragmatic Muscle Fiber Remodeling in Conscious Rodents 
PLoS ONE  2013;8(5):10.1371/annotation/4d84ef28-da1b-4dba-9df6-e8f2ec51cced.
PMCID: PMC3660615
21.  Inspiratory Muscle Training in a Child with Nemaline Myopathy and Organ Transplantation 
To report the use of inspiratory muscle strength training (IMST) to treat repeated ventilatory insufficiency in a child with nemaline myopathy (NM) who underwent cardiac and renal transplantation.
Case report.
Pediatric intensive care unit of a tertiary care university teaching hospital.
IMST was provided five days weekly for two weeks, accompanied by progressive weaning from non-invasive ventilation.
Measurements and Main Results
Maximal inspiratory pressure (MIP) increased from −36.7 cm H2O to −77.8 cm H2O, accompanied by improved inspiratory flow, volume, pressure activation and power. During the training period, the patient weaned from continuous non-invasive ventilatory assist to her pre-operative level of ventilatory function.
Inspiratory muscle training may be a beneficial component of care for children with NM who experience acute ventilatory insufficiency.
PMCID: PMC3633211  PMID: 20407395
Myopathy, nemaline; Respiratory insufficiency; Muscle weakness; Respiratory muscles; Strength training; Organ transplantation
22.  Basal Subtype of Invasive Breast Cancer is Associated with a Higher Risk of True Recurrence after Conventional Breast-Conserving Therapy 
To determine whether breast cancer subtype is associated with patterns of ipsilateral breast tumor recurrence (IBTR), either true recurrence (TR) or elsewhere local recurrence (ELR), among women with pT1-T2 invasive breast cancer (IBC) who receive breast-conserving therapy (BCT)
Methods and Materials
From 1/1998 to 12/2003, 1223 women with pT1-T2N0-3 IBC were treated with BCT (lumpectomy + whole breast radiation). Ninety percent of patients received adjuvant systemic therapy, but none received trastuzumab. Biologic subtype was approximated using estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2): luminal A (ER+ or PR+ and HER-2-), luminal B (ER+ or PR+ and HER-2+), HER-2 (ER- and PR- and HER-2+), and basal (ER- and PR- and HER-2-). Imaging, pathology and operative reports were reviewed by two physicians independently, including an attending breast radiologist. Readers were blinded to subtype and outcome. TR was defined as IBTR within the same quadrant and within three centimeters of the primary tumor. All others were ELR.
At median follow-up of 70 months, 24 patients developed IBTR (5-year cumulative incidence 1.6%), including 15 TR and 9 ELR. At 5 years, basal (4.4%) and HER-2 (9%) subtypes had a significantly higher incidence of TR compared with luminal B (1.2%) and luminal A (0.2%) subtypes (p<0.0001). On multivariate analysis, basal subtype (HR 4.8, p=0.01), younger age at diagnosis (HR 0.97, p=0.05), and increasing tumor size (HR 2.1. p=0.04) were independent predictors of TR. Only younger age (HR 0.95, p=0.01) significantly predicted for ELR.
Basal and HER2 subtypes are significantly associated with higher rates of TR among women with pT1-T2 IBC after BCT. Younger age predicts for both TR and ELR. Strategies to reduce TR in basal breast cancers, such as increased boost doses, concomitant radiation and chemotherapy, or targeted therapy agents, should be explored.
PMCID: PMC3161144  PMID: 21601377
breast cancer; biologic subtype; basal; triple negative; local recurrence; true recurrence; elsewhere recurrence
23.  Sentinel lymph node biopsy at the time of mastectomy does not increase the risk of lymphedema: implications for prophylactic surgery 
Women diagnosed with or at high risk for breast cancer increasingly choose prophylactic mastectomy. It is unknown if adding sentinel lymph node biopsy (SLNB) to prophylactic mastectomy increases the risk of lymphedema. We sought to determine the risk of lymphedema after mastectomy with and without nodal evaluation. 117 patients who underwent bilateral mastectomy were prospectively screened for lymphedema. Perometer arm measurements were used to calculate weight-adjusted arm volume change at each follow-up. Of 234 mastectomies performed, 15.8 % (37/234) had no axillary surgery, 63.7 % (149/234) had SLNB, and 20.5 % (48/234) had axillary lymph node dissection (ALND). 88.0 % (103/117) of patients completed the LEFT-BC questionnaire evaluating symptoms associated with lymphedema. Multivariate analysis was used to assess clinical characteristics associated with increased weight-adjusted arm volume and patient-reported lymphedema symptoms. SLNB at the time of mastectomy did not result in an increased mean weight-adjusted arm volume compared to mastectomy without axillary surgery (p = 0.76). Mastectomy with ALND was associated with a significantly greater mean weight-adjusted arm volume change compared to mastectomy with SLNB (p < 0.0001) and without axillary surgery (p = 0.0028). Patients who underwent mastectomy with ALND more commonly reported symptoms associated with lymphedema compared to those with SLNB or no axillary surgery (p < 0.0001). Patients who underwent mastectomy with SLNB or no axillary surgery reported similar lymphedema symptoms. Addition of SLNB to mastectomy is not associated with a significant increase in measured or self-reported lymphedema rates. Therefore, SLNB may be performed at the time of prophylactic mastectomy without an increased risk of lymphedema.
PMCID: PMC3563357  PMID: 22941538
Prophylactic mastectomy; Breast cancer-related lymphedema; Sentinel lymph node biopsy; Bilateral mastectomy; Arm swelling
24.  Functional Analysis of Leishmania Cyclopropane Fatty Acid Synthetase 
PLoS ONE  2012;7(12):e51300.
The single gene encoding cyclopropane fatty acid synthetase (CFAS) is present in Leishmania infantum, L. mexicana and L. braziliensis but absent from L. major, a causative agent of cutaneous leishmaniasis. In L. infantum, usually causative agent of visceral leishmaniasis, the CFAS gene is transcribed in both insect (extracellular) and host (intracellular) stages of the parasite life cycle. Tagged CFAS protein is stably detected in intracellular L. infantum but only during the early log phase of extracellular growth, when it shows partial localisation to the endoplasmic reticulum. Lipid analyses of L. infantum wild type, CFAS null and complemented parasites detect a low abundance CFAS-dependent C19Δ fatty acid, characteristic of a cyclopropanated species, in wild type and add-back cells. Sub-cellular fractionation studies locate the C19Δ fatty acid to both ER and plasma membrane-enriched fractions. This fatty acid is not detectable in wild type L. major, although expression of the L. infantum CFAS gene in L. major generates cyclopropanated fatty acids, indicating that the substrate for this modification is present in L. major, despite the absence of the modifying enzyme. Loss of the L. infantum CFAS gene does not affect extracellular parasite growth, phagocytosis or early survival in macrophages. However, while endocytosis is also unaffected in the extracellular CFAS nulls, membrane transporter activity is defective and the null parasites are more resistant to oxidative stress. Following infection in vivo, L. infantum CFAS nulls exhibit lower parasite burdens in both the liver and spleen of susceptible hosts but it has not been possible to complement this phenotype, suggesting that loss of C19Δ fatty acid may lead to irreversible changes in cell physiology that cannot be rescued by re-expression. Aberrant cyclopropanation in L. major decreases parasite virulence but does not influence parasite tissue tropism.
PMCID: PMC3519623  PMID: 23251490
25.  Genome-Wide Screen Identifies Drug-Induced Regulation of the Gene Giant Axonal Neuropathy (Gan) in a Mouse Model of Antiretroviral-Induced Painful Peripheral Neuropathy 
Painful peripheral neuropathy is a debilitating complication of the treatment of HIV with nucleoside reverse transcriptase inhibitors (NRTIs). Patients are living longer with these drugs; however many develop excruciating, unremitting, and often treatment-limiting neuropathy that is resistant to conventional pain management therapies. Improving patient comfort and quality of life is paramount and depends on a clearer understanding of this devastating side effect. The mechanisms underlying the development of NRTI-induced neuropathy, however, remain unclear. Using a mouse model of NRTI-induced neuropathy, the authors conducted an unbiased whole-genome microarray screen to identify molecular targets in the spinal dorsal horn, which is the location where integration of ascending sensory transmission and descending modulatory effects occur. Analysis of the microarray data identified a change in the gene giant axonal neuropathy 1 (Gan1). Mutation of this gene has been linked to the development of giant axonal neuropathy (GAN), a rare autosomal recessive condition characterized by a progressive sensorimotor neuropathy. Gan1 has not been previously linked to nerve pathologies in other populations. In this study, downregulation of the Gan1 gene and the gene protein product, gigaxonin, was validated via quantitative polymerase chain reaction ([qPCR] gene expression) and Western blot analyses (protein level). Our report is the first to suggest that Gan1 might be a novel molecular target in the development of NRTI-induced peripheral neuropathy with implications for new therapeutic approaches to preventing or reducing a significant side effect of HIV treatment.
PMCID: PMC3513273  PMID: 19398414
microarray; painful peripheral neuropathy; chronic pain; gigaxonin; giant axonal neuropathy; HIV/AIDS; HAART; NRTI

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