Targeting triple-negative breast cancer: A clinical perspective

Triple-negative breast cancer (TNBC) is a disease with often an aggressive course and a poor prognosis compared to other subtypes of breast cancer. TNBC accounts for approximately 10%–15% of all diagnosed breast cancer cases and represents a high unmet need in the field. Up to just a few years ago, chemotherapy was the only systemic treatment option for this subtype (1). To date, TNBC is considered a heterogeneous disease. One of the existing classifications is based on the analysis of mRNA expression in 587 TNBC cases, in which Lehman et al. proposed six subtypes of TNBC as follows: two basal-like (BL1 and BL2) subtypes, a mesenchymal (M) subtype, a mesenchymal stem-like (MSL) subtype, an immunomodulatory (IM) subtype, and a luminal androgen receptor (LAR) subtype (2). Later studies have demonstrated that the IM and MSL subtypes do not correlate with independent subtypes but reflect background expression by dense infiltration of tumor-infiltrating lymphocytes (TILs) or stromal cells. According to this finding, the classification of TNBC has been revised into the following four subtypes: basal 1, basal 2, LAR, and mesenchymal subtypes (3). Over the last years, several new strategies have been investigated for the treatment of patients with TNBC. Among them, immunotherapy, antibody drug conjugates, new chemotherapy agents, and targeted therapy have been and are currently being developed. The present article aims to provide an updated overview on the different treatment options that are now available or are still under investigation for patients with TNBC.     

In vivo anti-tumor activity of murine hematopoietic stem cells expressing a p185HER2-specific chimeric T-cell receptor gene

We have confirmed efficient anti-tumor activities of the peripheral lymphocytes transduced with a p185HER2-specific chimeric T-cell receptor gene both in murine and in human in our previous studies. To further test the feasibility of chimeric T-cell receptor in a bone marrow transplantation model, we first, made two murine tumor cell lines: MT901 and MCA-205, to express human p185HER2 by retroviral gene transduction. Murine bone marrow cells were retrovirally transduced to express the chimeric T-cell receptor and gene-modified bone marrow cells were transplanted into lethally irradiated mouse. Six months post transplantation, p185HER2-positive tumor cells:MT-901/HER2 or MCA-205/ HER2 was subcutaneously or intravenously injected to make mouse models simulating primary breast cancer or pulmonary metastasis. The in vivo anti-tumor effects were monitored by the size of the subcutaneous tumor or counting the tumor nodules in the lungs after India ink staining. The size of the subcutaneous tumor was significantly inhibited and the number of pulmonary nodules were significantly decreased in mouse recipients transplanted with chimeric T-cell receptor modified bone marrow cells compared with the control group. Our results suggest the efficient in vivo anti-tumor activities of chimeric T-cell receptor gene modified bone marrow cells.     

Alertness management: strategic naps in operational settings

SUMMARY  Managing fatigue in complex operational settings requires attention to multiple factors, including hours of service, scheduling, education and training, countermeasures, technology, and research. Alertness-management strategies can be used to promote safety, performance, and productivity in operational settings. These strategies can involve both preventive (used prior to duty/shift) and operational (used during duty/shift) approaches. Studies have demonstrated the effectiveness of naps to improve subsequent performance and alertness. Strategic naps can be used effectively to promote performance and alertness in operational settings. Two potential negative effects of naps, sleep inertia and effects on subsequent sleep periods, are discussed. Sleep inertia can involve sleepiness and decreased performance immediately upon awakening from a nap. It should be a consideration prior to implementing nap strategies in work environments. A study of planned rest periods in long-haul flight operations demonstrated the effectiveness of in-flight naps to promote performance and alertness during subsequent critical phases of flight (descent and landing). Empirical evaluation of alertness-management strategies during regular operations will be critical to their implementation. Combining strategies may be the most effective approach to managing fatigue engendered by 24-h operational demands. Other considerations prior to implementing alertness-management strategies in operational environments are discussed.     

Effect of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) on Influenza Virus Host Resistance in Mice

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) causes numerous immunotoxiceffects including thymic involution and an immunosuppressionof nonspecific as well as specific cell- and humoralmediatedimmunity. TCDD administration to laboratory animals also resultsin a decreased resistance to numerous bacteria, viruses, andparasites. Effects on virus host resistance appear to be amongthe most sensitive effects of TCDD immunotoxicity. However,previous studies have not achieved a no effect level. The presentstudies utilized an influenza virus host resistance model inmice to quantify the sensitivity of this model to TCDD and todetermine the NOAEL (no observed adverse effect level) of TCDDfor influenza virus. Results indicated that a single dose ofTCDD at 0.10, 0.05, or 0.01 µg/kg resulted in an increasedmortality to Hong Kong influenza virus when mice were challenged7 days after TCDD administration. Increased mortality was notcorrelated with increased virus titers in the lungs. TCDD at0.005 or 0.001 µg/kg had no effect on influenza-inducedmortality. TCDD alone did not affect thymus weight at any doseadministered in this study. TCDD also did not alter the virus-enhancedincrease in lung weight:body weight ratio nor the virus-induceddecrease in thymus weight. Thus, low levels of TCDD exposurelead to enhanced mortality to influenza virus; however, themechanism of this effect remains to be elucidated. Nonetheless,enhanced mortality to influenza virus in mice following a singledose of 10 ng TCDD/kg represents the most sensitive adverseeffect yet reported for TCDD.     

Characterization of Olfactory Deficits in the Rat Following Administration of 2,6-Dichlorobenzonitrile (Dichlobenil), 3,3'-Iminodipropionitrile, or Methimazole

The histopathology of the olfactory mucosal lesion associatedwith ip adminstration of 2,6-dichlorobenzonitrile (dichlobenil)and 3,3'-iminodipropionitrile (IDPN) has been well documented.Whether there is an olfactory deflicit associted with the partialloss of the olfactory mucosa (localized around the dorsal medialmeatus of the nasal cavity) has yet to be determined. Dichlobenil(100 mg/kg) or IDPN (200 mg/kg) was administered ip to adultmale Long-evans rats previously trained in an olfactory taskto find a food pellet buried in approximately 7.5 cm of bedingin a 0.61x1.2x0.61-m Plexiglass chamber. As a positive control,another group received 300 mg/kg ip of 1-methyl-2-mercaptoimidazole(methimazole), a dosing regimen which destroys nearly all ofthe olfactory mucosa. All three compounds caused a transientincrease in the mean latency to find the pellet, with the magnitudeof the effect positively correlated with the extent of the olfactorylesion. In order to determine whether theses deficits resultedfrom olfactory dysfunction or impaired cognitive function (adeficit previously attributed to IDPN exposure), another groupof rats was dosed as above and tested in another spatial memorytask, the Morris water maze (MWM), which is less dependent uponolfactory function. No performance deficit was detected in theMWM. These data suggest the transient olfactory deficit in thedichlobenil-, IDPN-, and methimazole-treated rats is attributableto defective olfactory function.     

Estimation of Temperature During Radiofrequency Catheter Ablation Using Impedance Measurements

Temperature monitoring during radiofrequency catheter ablation is useful but requires specialized equipment that is not generally available. Previous studies have shown that impedance characteristically decreases as the result of heating at the electrode-tissue interface. The purpose of the current study was to determine if impedance changes during radiofrequency current application could be used to estimate endocardial temperature in patients undergoing catheter ablation. Data from 43 patients treated with a thermistor ablation catheter were retrospectively analyzed. The slope of the initial 2 seconds of the impedance curve and subsequent changes in impedance were incorporated into an equation for estimation of temperature in real-time. The accuracy of this equation was assessed by prospectively comparing the calculated and measured temperatures in 19 patients. Of the 88% of energy applications that were suitable for analysis, the average difference between calculated and measured temperatures was 5.2 ± 5.6°C. The average error was ± 10° in 89% of applications. The results of this study suggest that impedance measurements can be used to quantify tissue temperature in real-time during radiofrequency catheter ablation. This method is sufficiently accurate to allow titration of power output to produce temperatures in the useful range (50–80°C) while avoiding excessive heating (± 90°C).     

Inadequacy of Qualitative Implantable Cardioverter Defibrillator Electrogram Analysis to Distinguish Supraventricular from Ventricular Tachycardia Due to Electrogram Changes During Normally Conducted Complexes

Stored electrograms (EGMs) recorded from ICD leads are used to evaluate the appropriateness of ICD therapies. Stored EGMs different from sinus have been interpreted as ventricular in origin. We present a patient with a n ICD for VT wh o received multiple shocks for a tachycardia with a stored EGM different than sinus, suggesting VT. An electrophysiological study demonstrated EGMs different than sinus during atrial pacing and induced supraventricular arrhythmias. This case points out the limitations of stored EGMs and suggests complete electrophysiological study with analysis of ECMs during induced arrhythmias should be performed prior to discharge.     

Sexual health seeking behaviours of young people in the Gambia

In the Gambia, sexually transmitted infections (STIs) and their complications are a major health problem and although the prevalence of HIV-1 in the Gambia is currently low, it is increasing. Relatively little is known about the sexual health treatment-seeking behaviours of young people in West Africa. This information is vital to target resources appropriately. To investigate this concept, twelve single-sex focus group discussions (FGDs), within three rural villages, elicited the views, opinions, attitudes and experiences of 49 young men (mean age 17.4 years; range 15-21) and 48 young women (mean age 18.2 years; range 15-25). The participants talked openly about sexual activity within their peer communities. Six major themes were identified from the FGDs: (1) groups perceived to be at risk of acquiring STIs; (2) STI transmission and classification; (3) treatment-seeking behaviours; (4) barriers to treatment; (5) consequences of non-treatment; and (6) problem resolution strategies. The study concludes that whilst there may be barriers to improving sexual and reproductive health, young people in rural West Africa have enthusiasm for and commitment to finding solutions to the problems that local communities face.     

Long-Term Performance of the Attain Model 4193 Left Ventricular Lead

Background: Cardiac resynchronization therapy (CRT) has proven to be a valuable therapy addition for patients with drug-refractory heart failure and a ventricular conduction delay. Delivery of CRT is dependent upon the successful implantation and chronic performance of a left ventricular (LV) pacing lead. This study assessed the long-term electrical performance and safety of a steroid-eluting, transvenous, over-the-wire, cardiac vein pacing lead.
Methods: The Attain Model 4193 LV lead (Medtronic, Inc, Minneapolis MN, USA) was successfully implanted in 1,070 patients with 286 patients completing 3 years of follow-up. Clinical data were collected at pre-implant, implant, and at 6-month intervals for 3 years.
Results: Over 3 years, the mean chronic pacing threshold ranged from 1.9 V to 2.1 V, the mean R-wave sensing amplitudes ranged between 13.6 mV and 15.0 mV, and the mean pacing impedance ranged between 562 ohms and 590 ohms. Additionally, the observed freedom from first post-implant LV-lead-related complications was 90.4%. Of 1,070 total patients, 82 experienced 89 LV-lead-related adverse events requiring invasive interventions or resulting in the termination of the CRT therapy. The LV lead was repositioned in 31 patients, replaced in 21 patients, and explanted/capped in four patients. There were no deaths related to the LV lead during implantation or during the follow-up period.
Conclusions: The data suggest that the 4193 LV lead is safe and effective over time. The LV lead electrical measurements remained stable through follow-up, demonstrating reliable long-term performance within the recommended value range at 36 months and had an acceptable complication rate.     

Prospective Comparison of Temperature Guided Microwave and Radiofrequency Catheter Ablation in the Swine Heart

Microwave energy has been proposed as an alternative to radiofrequency energy for use during catheter ablation procedures. The purpose of this study was to prospectively compare, in an animal model, the lesion size associated with temperature guided catheter ablation using either microwave or radiofrequency energy. Eleven swine underwent catheter ablation with either radiofrequency (N = 4) or microwave energy (N = 7). In each animal catheter ablation was performed at 7–15 sites. At each site energy was delivered for 60 seconds using closed loop feedback temperature control to achieve a target temperature of 70°C. Cardiac catheterization was performed before and after ablation. Animals were sacrificed approximately one month following the ablation procedure. Analysis of lesion size demonstrated that overall lesions created using radiofrequency energy were larger than those created using microwave energy. In the ventricle, lesions created using microwave energy were longer, but had a similar width and depth as those created using radiofrequency energy. An important relation was observed between tbe depth of lesions created using microwave energy and catheter stability, as evidenced by the temperature profile. Overall, lesions created using microwave energy are smaller than those created using radiofrequency energy. Catheter stability has an important impact on lesion size.