Showing papers by "Texas Medical Center published in 2013"

Effect of Levosimendan on the Short-Term Clinical Course of Patients With Acutely Decompensated Heart Failure

Abstract: Background This study evaluated the efficacy and safety of levosimendan, a positive inotropic drug with vasodilator effects, given intravenously to patients with acutely decompensated heart failure (ADHF). Methods We performed 2 sequential trials, the first to develop a new measure of efficacy in 100 patients, and the second to use this measure to evaluate levosimendan in an additional 600 patients. Patients admitted with ADHF received placebo or intravenous levosimendan for 24 h in addition to standard treatment. The primary endpoint was a composite that evaluated changes in clinical status during the first 5 days after randomization. Results In the 600-patient trial, more levosimendan than placebo patients (58 vs. 44) were improved at all 3 pre-specified time points (6 h, 24 h, and 5 days), whereas fewer levosimendan patients (58 vs. 82) experienced clinical worsening (p = 0.015 for the difference between the groups). These differences were apparent, despite more frequent intensification of adjunctive therapy in the placebo group (79 vs. 45 patients). Improvements in patient self-assessment and declines in B-type natriuretic peptide levels with levosimendan persisted for 5 days and were associated with reduced length of stay (p = 0.009). Similar findings were present in the 100-patient pilot trial. Levosimendan was associated with more frequent hypotension and cardiac arrhythmias during the infusion period and a numerically higher risk of death across the 2 trials (49 of 350 on a regimen of levosimendan vs. 40 of 350 on a regimen of placebo at 90 days, p = 0.29). Conclusions In patients with ADHF, intravenous levosimendan provided rapid and durable symptomatic relief. As dosed in this trial, levosimendan was associated with an increased risk of adverse cardiovascular events. (Evaluation of Intravenous Levosimendan Efficacy in the Short Term Treatment of Decompensated Chronic Heart Failure; NCT00048425 )

Frequency-specific network connectivity increases underlie accurate spatiotemporal memory retrieval.

Abstract: The medial temporal lobes, prefrontal cortex and parts of parietal cortex form the neural underpinnings of episodic memory, which includes remembering both where and when an event occurred. However, the manner in which these three regions interact during retrieval of spatial and temporal context remains untested. We employed simultaneous electrocorticographical recordings across multilobular regions in patients undergoing seizure monitoring while they retrieved spatial and temporal context associated with an episode, and we used phase synchronization as a measure of network connectivity. Successful memory retrieval was characterized by greater global connectivity compared with incorrect retrieval, with the medial temporal lobe acting as a hub for these interactions. Spatial versus temporal context retrieval resulted in prominent differences in both the spectral and temporal patterns of network interactions. These results emphasize dynamic network interactions as being central to episodic memory retrieval, providing insight into how multiple contexts underlying a single event can be recreated in the same network.

Food sources of energy and nutrients among children in the United States: National Health and Nutrition Examination Survey 2003–2006.

Abstract: Background: Recent detailed analyses of data on dietary sources of energy and nutrients in US children are lacking. The objective of this study was to identify food sources of energy and 28 nutrients for children in the United States. Methods: Analyses of food sources were conducted using a single 24-h recall collected from children 2 to 18 years old (n = 7332) in the 2003–2006 National Health and Nutrition Examination Survey. Sources of nutrients contained in foods were determined using nutrient composition databases. Food grouping included ingredients from disaggregated mixtures. Mean energy and nutrient intakes from the total diet and from each food group were adjusted for the sample design using appropriate weights. Percentages of the total dietary intake that food sources contributed were tabulated by rank order. Results: The two top ranked food/food group sources of energy and nutrients were: energy—milk (7% of energy) and cake/cookies/quick bread/pastry/pie (7%); protein—milk (13.2%) and poultry (12.8%); total carbohydrate—soft drinks/soda (10.5%) and yeast bread/rolls (9.1%); total sugars—soft drinks/soda (19.2%) and yeast breads and rolls (12.7%); added sugars—soft drinks/soda (29.7%) and candy/sugar/sugary foods (18.6%); dietary fiber—fruit (10.4%) and yeast bread/rolls (10.3%); total fat—cheese (9.3%) and crackers/popcorn/pretzels/chips (8.4%); saturated fatty acids—cheese (16.3%) and milk (13.3%); cholesterol—eggs (24.2%) and poultry (13.2%); vitamin D—milk (60.4%) and milk drinks (8.3%); calcium—milk (33.2%) and cheese (19.4%); potassium—milk (18.8%) and fruit juice (8.0%); and sodium—salt (18.5%) and yeast bread and rolls (8.4%). Conclusions: Results suggest that many foods/food groupings consumed by children were energy dense, nutrient poor. Awareness of dietary sources of energy and nutrients can help health professionals design effective strategies to reduce energy consumption and increase the nutrient density of children’s diets.

Independent predictors of enteric fistula and abdominal sepsis after damage control laparotomy: results from the prospective AAST Open Abdomen registry.

Abstract: Importance Enterocutaneous fistula (ECF), enteroatmospheric fistula (EAF), and intra-abdominal sepsis/abscess (IAS) are major challenges for surgeons caring for patients undergoing damage control laparotomy after trauma. Objective To determine independent predictors of ECF, EAF, or IAS in patients undergoing damage control laparotomy after trauma, using the AAST Open Abdomen Registry. Design The AAST Open Abdomen registry of patients with an open abdomen following damage control laparotomy was used to identify patients who developed ECF, EAF, or IAS and to compare these patients with those without these complications. Univariate analyses were performed to compare these groups of patients. Variables from univariate analyses differing at P Setting Fourteen level I trauma centers. Participants A total of 517 patients with an open abdomen following damage control laparotomy. Main outcomes and measures Complication of ECF, EAF, or IAS. Results More patients in the ECF/EAF/IAS group than in the group without these complications underwent bowel resection (63 of 111 patients [57%] vs 133 of 406 patients [33%]; P Conclusions and relevance Large bowel resection, large-volume fluid resuscitation, and an increasing number of abdominal reexplorations were statistically significant predictors of ECF, EAF, or IAS in patients with an open abdomen after damage control laparotomy.

Chronometric Electrical Stimulation of Right Inferior Frontal Cortex Increases Motor Braking

Abstract: The right inferior frontal cortex (rIFC) is important for stopping responses. Recent research shows that it is also activated when response emission is slowed down when stopping is anticipated. This suggests that rIFC also functions as a goal-driven brake. Here, we investigated the causal role of rIFC in goal-driven braking by using computer-controlled, event-related (chronometric), direct electrical stimulation (DES). We compared the effects of rIFC stimulation on trials in which responses were made in the presence versus absence of a stopping-goal (“Maybe Stop” [MS] vs “No Stop” [NS]). We show that DES of rIFC slowed down responses (compared with control-site stimulation) and that rIFC stimulation induced more slowing when motor braking was required (MS) compared with when it was not (NS). Our results strongly support a causal role of a rIFC-based network in inhibitory motor control. Importantly, the results extend this causal role beyond externally driven stopping to goal-driven inhibitory control, which is a richer model of human self-control. These results also provide the first demonstration of double-blind chronometric DES of human prefrontal cortex, and suggest that—in the case of rIFC—this could lead to augmentation of motor braking.

Recursive grid partitioning on a cortical surface model: an optimized technique for the localization of implanted subdural electrodes.

Abstract: Object Precise localization of subdural electrodes (SDEs) is essential for the interpretation of data from intracranial electrocorticography recordings. Blood and fluid accumulation underneath the craniotomy flap leads to a nonlinear deformation of the brain surface and of the SDE array on postoperative CT scans and adversely impacts the accurate localization of electrodes located underneath the craniotomy. Older methods that localize electrodes based on their identification on a postimplantation CT scan with coregistration to a preimplantation MR image can result in significant problems with accuracy of the electrode localization. The authors report 3 novel methods that rely on the creation of a set of 3D mesh models to depict the pial surface and a smoothed pial envelope. Two of these new methods are designed to localize electrodes, and they are compared with 6 methods currently in use to determine their relative accuracy and reliability. Methods The first method involves manually localizing each electr...

Design of a prospective, dose-escalation study evaluating the Safety of Pioglitazone for Hematoma Resolution in Intracerebral Hemorrhage (SHRINC).

Abstract: Rationale Preclinical work demonstrates that the transcription factor peroxisome proliferator-activated receptor gamma plays an important role in augmenting phagocytosis while modulating oxidative stress and inflammation. We propose that targeted stimulation of phagocytosis to promote efficient removal of the hematoma without harming surrounding brain cells may be a therapeutic option for intracerebral hemorrhage. Aims The primary objective is to assess the safety of the peroxisome proliferator-activated receptor gamma agonist, pioglitazone, in increasing doses for three-days followed by a maintenance dose, when administered to patients with spontaneous intracerebral hemorrhage within 24 h of symptom onset compared with standard care. We will determine the maximum tolerated dose of pioglitazone. Study design This is a prospective, randomized, blinded, placebo-controlled, dose-escalation safety trial in which patients with spontaneous intracerebral hemorrhage are randomly allocated to placebo or treatment. The Continual Reassessment Method for dose finding is used to determine the maximum tolerated dose of pioglitazone. Hematoma and edema resolution is evaluated with serial magnetic resonance imaging (MRI) at specified time points. Functional outcome will be evaluated at three- and six-months. Outcomes The primary safety outcome is mortality at discharge. Secondary safety outcomes include mortality at three-months and six-months, symptomatic cerebral edema, clinically significant congestive heart failure, edema, hypoglycemia, anemia, and hepatotoxicity. Radiographic outcomes will explore the time frame for resolution of 25%, 50%, and 75% of the hematoma. Clinical outcomes are measured by the National Institutes of Health Stroke Scale (NIHSS), the Barthel Index, modified Rankin Scale, Stroke Impact Scale-16, and EuroQol at three- and six-months.

Intracranial Electroencephalography Reveals Different Temporal Profiles for Dorsal- and Ventro-lateral Prefrontal Cortex in Preparing to Stop Action

Abstract: Preparing to stop an inappropriate action requires keeping in mind the task goal and using this to influence the action control system. We tested the hypothesis that different subregions of prefrontal cortex show different temporal profiles consistent with dissociable contributions to preparing-to-stop, with dorsolateral prefrontal cortex (DLPFC) representing the task goal and ventrolateral prefrontal cortex (VLPFC) implementing action control. Five human subjects were studied using electrocorticography recorded from subdural grids over right lateral frontal cortex. On each trial, a task cue instructed the subject whether stopping might be needed or not (Maybe Stop [MS] or No Stop [NS]), followed by a go cue, and on some MS trials, a subsequent stop signal. We focused on go trials, comparing MS with NS. In the DLPFC, most subjects had an increase in high gamma activity following the task cue and the go cue. In contrast, in the VLPFC, all subjects had activity after the go cue near the time of the motor response on MS trials, related to behavioral slowing, and significantly later than the DLPFC activity. These different temporal profiles suggest that DLPFC and VLPFC could have dissociable roles, with DLPFC representing task goals and VLPFC implementing action control.

Photodynamic therapy vs radiofrequency ablation for Barrett's dysplasia: efficacy, safety and cost-comparison.

Abstract: AIM: To compare effectiveness, safety, and cost of photodynamic therapy (PDT) and radiofrequency ablation (RFA) in treatment of Barrett’s dysplasia (BD). METHODS: Consecutive case series of patients undergoing either PDT or RFA treatment at single center by a single investigator were compared. Thirty-three patients with high-grade dysplasia (HGD) had treatment with porfimer sodium photosensitzer and 630 nm laser (130 J/cm), with maximum of 3 treatment sessions. Fifty-three patients with BD (47 with low-grade dysplasia -LGD, 6 with HGD) had step-wise circumferential and focal ablation using the HALO system with maximum of 4 treatment sessions. Both groups received proton pump inhibitors twice daily. Endoscopic biopsies were acquired at 2 and 12 mo after enrollment, with 4-quadrant biopsies every 1 cm of the original BE extent. A complete histological resolution response of BD (CR-D) was defined as all biopsies at the last endoscopy session negative for BD. Fisher’s exact test was used to assess differences between the two study groups for primary outcomes. For all outcomes, a two-sided P value of less than 0.05 was considered to indicate statistical significance. RESULTS: Thirty (91%) PDT patients and 39 (74%) RFA were men (P = 0.05). The mean age was 70.7 ± 12.2 and 65.4 ± 12.7 (P = 0.10) year and mean length of BE was 5.4 ± 3.2 cm and 5.7 ± 3.2 cm (P = 0.53) for PDT and RFA patients, respectively. The CR-D was (18/33) 54.5% with PDT vs (47/53) 88.7% with RFA (P = 0.001). One patient with PDT had an esophageal perforation and was managed with non-surgical measures and no perforation was seen with RFA. PDT was five times more costly than RFA at our institution. The two groups were not randomized and had different BD grading are the limitations of the study. CONCLUSION: In our experience, RFA had higher rate of CR-D without any serious adverse events and was less costly than PDT for endoscopic treatment of BD.

Spirituality and confidence to resist substance use among celebrate recovery participants.

Abstract: Since self-efficacy is a positive predictor of substance use treatment outcome, we investigated whether it is associated with spirituality within a religious 12-step program. This was a cross-sectional survey (N = 91) of 10 different Celebrate Recovery sites held at community churches. The mean spirituality score for those with high confidence was significantly greater than those with low confidence. Spirituality associated with greater confidence to resist substance use (OR = 1.09, 95% CI 1.02–1.17, P < 0.05). So every unit increase of measured spirituality increased the odds of being above the median in self-efficacy by 9%. We conclude that spirituality may be an important explanatory variable in outcomes of a faith-based 12-step recovery program.

Memory T cells in transplantation - progress and challenges.

Abstract: PURPOSE OF REVIEW Memory T cells present a different set of challenges to transplant patients; they are needed for protection against invading pathogens, especially under conditions of immunosuppression. But their presence also threatens transplant survival, as some of them are alloreactive. Efforts to resolve this paradox will be critical in the induction of transplant tolerance. RECENT FINDINGS There has been significant progress made in the past few years in the areas of population diversity of memory T cells, metabolic control of their induction, and mechanisms and pathways involved in memory cell exhaustion. Multiple targets on memory T cells have been identified, some of which are under vigorous testing in various transplant models. SUMMARY Memory T cells are both friends and foes to transplant patients, and tolerance strategies should selectively target alloreactive memory T cells and leave other memory cells unaltered. This situation remains a major challenge in the clinic.

Enhanced cardiac function in Gravin mutant mice involves alterations in the β-adrenergic receptor signaling cascade.

Abstract: Gravin, an A-kinase anchoring protein, targets protein kinase A (PKA), protein kinase C (PKC), calcineurin and other signaling molecules to the beta2-adrenergic receptor (β2-AR). Gravin mediates desensitization/resensitization of the receptor by facilitating its phosphorylation by PKA and PKC. The role of gravin in β-AR mediated regulation of cardiac function is unclear. The purpose of this study was to determine the effect of acute β-AR stimulation on cardiac contractility in mice lacking functional gravin. Using echocardiographic analysis, we observed that contractility parameters such as left ventricular fractional shortening and ejection fraction were increased in gravin mutant (gravin-t/t) animals lacking functional protein compared to wild-type (WT) animals both at baseline and following acute isoproterenol (ISO) administration. In isolated gravin-t/t cardiomyocytes, we observed increased cell shortening fraction and decreased intracellular Ca2+ in response to 1 µmol/L ISO stimulation. These physiological responses occurred in the presence of decreased β2-AR phosphorylation in gravin-t/t hearts, where PKA-dependent β2-AR phosphorylation has been shown to lead to receptor desensitization. cAMP production, PKA activity and phosphorylation of phospholamban and troponin I was comparable in WT and gravin-t/t hearts both with and without ISO stimulation. However, cardiac myosin binding protein C (cMyBPC) phosphorylation site at position 273 was significantly increased in gravin-t/t versus WT hearts, in the absence of ISO. Additionally, the cardioprotective heat shock protein 20 (Hsp20) was significantly more phosphorylated in gravin-t/t versus WT hearts, in response to ISO. Our results suggest that disruption of gravin’s scaffold mediated signaling is able to increase baseline cardiac function as well as to augment contractility in response to acute β-AR stimulation by decreasing β2-AR phosphorylation and thus attenuating receptor desensitization and perhaps by altering PKA localization to increase the phosphorylation of cMyBPC and the nonclassical PKA substrate Hsp20.

Personalized Medicine for Glioblastoma: Current Challenges and Future Opportunities

Abstract: The failure to control glioblastoma progression is a major challenge for neuro-oncologists. Emerging data indicate that genetic and epigenetic heterogeneities within tumor cells play a dominant role in the development of resistant disease. These heterogeneities develop because driver mutations enable the proliferation of certain clones of transformed cells within the tumor microenvironment while pre-existing passenger or secondary mutations emerge from the clonal selection process during treatment. In addition, epigenetic changes provide another means of modifying the existing heterogeneous genetic background of tumor cells. These cumulative changes create challenges for the detection, characterization and treatment of glioblastomas, but new opportunities allow the development of advanced diagnostic modalities and individualized therapies. Furthermore, mutations in the epidermal growth factor receptor (EGFR) alter binding capability to targeted agents like erlotinib, rendering it inactive to block EGFR signaling. Receptor class switching and tyrosine kinase decoupling from cell cycle machineries are also mechanisms that can render tumor cells resistant to EGFR blockade. Therefore, effective therapy most likely requires the combination of personalized medicine treatment offered by targeted drugs and less specific therapies that aim at other processes within the tumor microenvironment. The goal is to take advantage of the specificity offered by targeted drugs to block proliferation of tumor cells harboring driver mutations while less specific treatments can be used against cells with passenger mutations.

Aerosolized amphotericin B lipid complex as adjunctive treatment for fungal lung infection in patients with cancer-related immunosuppression and recipients of hematopoietic stem cell transplantation.

Abstract: Aerosolized amphotericin B lipid complex (aeABLC) has been successfully used to prevent fungal disease. Experience with aeABLC as treatment of fungal lung disease is limited. We evaluated the safety and efficacy of aeABLC adjunct therapy for fungal lung disease in a retrospective study of 32 immunosuppressed adults. Acute leukemia (69%) and severe neutropenia (63%) were common. The median duration of aeABLC was 185 ± 424 days in patients who underwent allogeneic stem cell transplantation (56%). High-dose corticosteroids were administered during aeABLC in 28% of patients. Fungal lung disease was proven or probable in 41% of patients. Most patients (78%) received systemic antifungal therapy for a median of 14 ± 18 days before aeABLC. The median cumulative aeABLC dose was 1,050 ± 2,368 mg, and the median duration of aeABLC therapy was 28 ± 130 days. Most patients (78%) received 50 mg aeABLC twice daily. Partial or complete resolution of fungal lung disease was noted in 50% of patients. In 3 patients (9%) modest cough, mild bronchospasm, and transient chest pain with accompanying nausea and vomiting resolved completely after discontinuation of aeABLC. No patient required hospitalization for drug toxicity or had a serious (grade III or IV) drug toxicity. Treatment with aeABLC was tolerated without serious toxicity and may be considered in the setting of severe immunosuppression, cancer, and/or stem cell transplantation in patients with difficult-to-treat fungal lung disease.

Management of predictable pain using fentanyl pectin nasal spray in patients undergoing radiotherapy.

Abstract: Background Studies report the need for improved pain management in the radiation oncology setting. Many patients with well controlled background pain experience breakthrough pain in cancer (BTPc) that can interrupt their treatment schedule with a potentially negative impact on outcomes. BTPc can be unpredictable and predictable; both types of pain can be managed with fast-acting analgesics, but predictable pain lends itself to anticipatory management. Methods Five consecutive cases are described in which fentanyl pectin nasal spray (FPNS) was used to manage BTPc, with an emphasis on the anticipatory management of predictable pain in cancer patients receiving radiotherapy. Results Patients (four men, one woman), age range 32-84 years, were diagnosed with various cancers. All patients were receiving opioid treatment for chronic pain, and experienced predictable pain with radiotherapy which included pain associated with lying on a treatment table for a sustained time during an average of 29 radiotherapy treatments; pain associated with radiation simulation and radiotherapy; pain associated with odynophagia related to increasing mucositis during treatment, resulting in decreased nutritional intake; pain associated with the customized immobilization mask for head and neck cancer patients; and pain associated with defecation. Some patients also reported pain awakening them randomly at night (eg, sleep interruption). All patients attained lower pain intensity scores (2/10 to 3/10), reduced from approximately 7/10, when they were treated with FPNS 20 minutes before a predictable pain event. No patient experienced any pain-related interruptions to their course of radiotherapy. The average number of radiotherapy sessions was 29 per patient, excluding one short-course treatment for one patient. Conclusion FPNS offers a good solution to the management of BTPc because its fast onset of action makes it very suitable for the anticipatory treatment of predictable pain, which is likely to minimize interruptions to the radiotherapy schedule.

Communication between B-Cells and Microbiota for the Maintenance of Intestinal Homeostasis

Abstract: The human intestine is populated with an extremely dense and diverse bacterial community. Commensal bacteria act as an important antigenic stimulus producing the maturation of gut-associated lymphoid tissue (GALT). The production of immunoglobulin (Ig) A by B-cells in the GALT is one of the immune responses following intestinal colonization of bacteria. The switch of B-cells from IgM to IgA-producing cells in the Peyer’s patches and neighboring lamina propria proceeds by T-cell-dependent and T-cell-independent mechanisms. Several grams of secretory IgA (SIgA) are released into the intestine each day. SIgA serves as a first-line of defense in protecting the intestinal epithelium from enteric toxins and pathogenic microorganisms. SIgA has a capacity to directly quench bacterial virulence factors, influence the composition of the intestinal microbiota, and promote the transportation of antigens across the intestinal epithelium to GALT and down-regulate proinflammatory responses associated with the uptake of highly pathogenic bacteria and potentially allergenic antigens. This review summarizes the reciprocal interactions between intestinal B cells and bacteria, specifically, the formation of IgA in the gut, the role of intestinal IgA in the regulation of bacterial communities and the maintenance of intestinal homeostasis, and the effects of probiotics on IgA levels in the gastrointestinal tract.

Modeling Covariates of Self-Perceived and Epidemiologic Notions of Risk for Acquiring STIs/HIV among Military Personnel: A Comparative Analysis

Abstract: This study examined the socio-demographic and selected behavioral characteristics associated with self-perceived and epidemiologic notions of risk for acquiring STIs/HIV infection using data from a cross-sectional survey involving 346 consenting female military personnel from two cantonments in Southwestern Nigeria. Findings revealed significant discordance in participants’ risk status based on the two assessment methods, with Kappa coefficients ranging from −0.021 to 0.115. Using epidemiologic assessment as the “gold standard”, 45.4% of the study population were able to accurately assess their risk levels through self-perception with significant (P < 0.01) socio-demographic variations. Multivariate logistic regression analyses indicate that STIs/HIV risk models using both self-perceived and epidemiologic notions of risk were significantly determined by different set of covariates. It is recommended that STIs/HIV prevention intervention should integrate the identified covariates and be targeted at changing individual risk behaviors and perceptions, as well as the social contexts in which risky behaviors occur in the military population.

Sinonasal Undifferentiated Carcinoma (SNUC): Morphoproteomic-Guided Treatment Paradigm with Clinical Efficacy

Abstract: Sinonasal undifferentiated carcinoma (SNUC) is a rare and highly malignant tumor that occurs in the nasal cavity and/or paranasal sinuses. Prognosis is poor despite multimodality treatment. Currently, there is no optimal standard of treatment, partially due to a lack of research defining the biology of such tumors. This report discusses two SNUC cases where patients received a novel chemotherapeutic approach using cisplatin, etoposide, Adriamycin (doxorubicin), metformin, and adjuvant melatonin therapies based on morphoproteomic-guidance, followed by consolidation with chemoradiation therapy. This resulted in excellent and objective tomographic and magnetic resonance imaging and clinical responses including complete responses in the induction phase utilizing morphoproteomic-guided therapies. Later, endoscopic excision of the tumor bed failed to reveal any residual tumor. Morphoproteomics helped to define the biology of these SNUC tumors and provided targets for the agents employed, creating a new treatment paradigm for such tumors. This treatment regimen poses a new effective regimen to treat SNUC.

Pediatric Cardiac Emergencies

Abstract: With the advent of and advancesin diagnostic methods and transcatheter and surgical treatment modes, patients with Congenital Heart Defects (CHD) are surviving longer. Cardiac defects that were once fatal in infancy are now treatable and patients are surviving into adulthood. However, these patients are at increased risk of acute events and therefore, likely to frequent emergency rooms. These patients should now be added to the group of CHD patients that would ordinarily come thru’ the emergency rooms. Presented in this review is a selection of the more common lifethreatening pediatric cardiac emergencies likely to be encountered in the emergency department. The identification and management of Supraventricular tachycardia, hyper cyanotic spells, congestive heart failure, emergencies in the palliated patients with a functional single ventricle and neurologic events related to congenital heart disease are discussed.

Trastuzumab-Doxorubicin Conjugate Provides Enhanced Anti-Cancer Potency and Reduced Cardiotoxicity

Abstract: Since trastuzumab monotherapy for treatment of breast cancer with HER2/ErbB2 over-expression has been shown to have limited efficacy, combined treatment of trastuzumab with chemotherapy is widely practiced in clinic. However, certain combination treatments of trastuzumab and chemotherapy (i.e. doxorubicin) are not recommended due to high risk of cardiotoxicity. Antibody-drug conjugates (ADCs) offer selective delivery of cytotoxic agents into targeted cancer cells, thereby allowing for reduced general cellular cytotoxicity caused by chemotherapeutic agents through antibody mediated specific recognition of tumor antigens. In this study, we constructed a trastuzumab-doxorubicin conjugate (T-Dox) using a thioether linkage and characterized both biophysical stability and anti-cancer potency of the T-Dox using a panel of HER2 expressing cancer cell lines. The T-Dox conjugate showed significantly improved anti-cancer potency in comparison with trastuzumab. The results demonstrated for the first time that there were significant differences in the uptake of T-Dox among high HER2 expression cancer cells and higher T-Dox uptake also showed stronger anti-cancer potency. Similar to trastuzumab, T-Dox selectively bound to HER2 overexpressing cancer cells and low HER2 expression cells had no detectable uptake of T-Dox. Consistent to the uptake data, human cardiomyocyte cells had no detectable HER2 expression and T-Dox showed minimal cytotoxic effects. On the contrary, a treatment with combination of trastuzumab and doxorubicin showed severe cytotoxicity to human cardiomyocytes (>90% cell death after 3 day exposure). This study demonstrated that trastuzumab conjugated with doxorubicin (T-Dox) can provide valuable alternative to the combination treatment with doxorubicin and trastuzumab for high HER2 expressing cancer patients.

Phase II randomized trial of weekly and every-3-week ixabepilone in metastatic breast cancer patients

Abstract: This multicenter, open-label, randomized phase II trial compared the efficacy and tolerability of weekly ixabepilone versus the standard 3 weekly dosing regimen. Patients with human epidermal growth factor receptor 2-negative, metastatic breast cancer (MBC) were randomly assigned to receive either ixabepilone 16 mg/m2 as a 1-h intravenous (IV) infusion weekly on days 1, 8, and 15 of a 28-day cycle (1 week off therapy; n = 85), or 40 mg/m2 as a 3-h IV infusion on day 1 of a 21-day cycle (n = 91), until disease progression or unacceptable toxicity. Randomization was stratified by (i) measurable versus nonmeasurable (evaluable) disease, (ii) ≤two versus >two prior chemotherapy regimens for MBC, and (iii) hormone receptor (HR)-positive versus HR-negative breast cancer. The primary endpoint was rate of progression-free survival (PFS) at 6 months. Of 176 randomized patients, 171 were treated. The 6-month PFS rate was significantly higher in patients treated with ixabepilone every 3 weeks (42.7, 95 % confidence interval [CI] 31.5–53.5) compared with those who received ixabepilone weekly (28.6, 95 % CI 18.9–38.9; log-rank P = 0.03). Every-3-week dosing significantly prolonged median PFS versus weekly dosing (5.3 vs. 2.9 months; log-rank P = 0.05). The every-3-week regimen was associated with higher rates of grade 3/4 toxicities, particularly neutropenia (38.2 vs. 6.1 %) and a higher rate of patient withdrawal due to adverse events. These results suggest that every-3-week ixabepilone is more effective than weekly treatment in MBC, albeit with more toxicity.

The impact of medically indicated and spontaneous preterm birth among hypertensive women.

Abstract: Objective To (1) describe the frequency of spontaneous preterm birth (SPTB) and medically indicated preterm birth (PTB) among women with chronic hypertension (CHTN) and (2) to evaluate differences in neonatal outcomes according to SPTB or medically indicated PTB. Study Design Retrospective analysis of a previously conducted multicenter randomized trial. Deliveries were categorized as SPTB or medically indicated and stratified by gestational ages ( Results Of 765 women, 32.2% (n = 246) delivered at 0.05). Conclusion Nearly one-third of women with CHTN delivered preterm. The majority of PTBs were medically indicated and late preterm, but approximately one-third were due to SPTB.