Multidrug resistance genes (MRP) and MDR1 expression in small cell lung cancer xenografts: relationship with response to chemotherapy

Intrinsic or acquired drug resistance is a major limiting factor of the effectiveness of chemotherapy. Increased expression of either the MRP gene or the MDR1 gene has been demonstrated to confer drug resistance in vitro. In this study, we examined MRP and MDR1 gene expression in a panel of 17 small cell lung cancers (SCLC) xenografted into nude mice from treated and untreated patients using an RT-PCR technique. For some of them, the outcome of the corresponding patients was known and we related MDR1/MRP expression with the xenograft response to C′CAV (cyclophosphamide, cisplatin, adriamycin and etoposide) combined chemotherapy. Fifteen (88%) of the 17 cases of SCLC were found to be positive for either MDR1 or MRP. MRP gene expression was present in 12 (71%) of 17 cases, whereas MDR1 gene expression was detected in eight (50%) of 16 cases. For six SCLC, the survival duration of patients differed, with three patients surviving for more than 30 months after therapy. Among these six tumours, five expressed MRP and/or MDR1. These six xenografts responded to the C′CAV treatment but a significant rate of cure was obtained in only three cases. No obvious relationship was observed between the response to this treatment and MRP or MDR1 expression. However, the remarkably high levels and frequency of MRP expression in some SCLC samples indicate that future developments in chemotherapy of this tumour type should anticipate that drugs which are substrates of MRP may be of limited effectiveness.     

Decrease in plasma levels of 3,4-dihydroxyphenylethyleneglycol in major depression

Plasma levels of free and sulfoconjugated 3,4-dihydroxyphenylethyleneglycol (DOPEG), the main deaminated metabolite of norepinephrine, were measured in a group of 45 hospitalized patients presenting a major depression and a group of 45 healthy subjects, matched for sex and age. Compared to healthy subjects, depressed patients had significantly lower plasma levels of free and sulfoconjugated DOPEG. The ratio of free over conjugated DOPEG was not statistically different in the two groups. The reduction of plasma DOPEG levels in the depressed patients did not appear to be related to the duration of drug-free period and was similar in males and females. There was no statistically significant correlation between plasma DOPEG levels and total score on the Hamilton Rating Scale for Depression. Finally, plasma DOPEG levels did not differ in unior bipolar patients. The present data provides further evidence for a reduced CNS noradrenergic transmission in major depression.     

Phase III randomized study comparing 5 or 10 microg per kg per day of filgrastim for mobilization of peripheral blood progenitor cells with chemotherapy,followed by intensification and autologous transplantation in patients with nonmyeloid malignancies

BACKGROUND: It is not known whether increasing the dose of filgrastim after mobilizing chemotherapy improves collection of peripheral blood progenitor cells (PBPC) and leads to faster hematopoietic engraftment after autologous transplantation. STUDY DESIGN AND METHODS: A randomized, open-label, multicenter trial was carried out in patients with breast cancer, multiple myeloma, and lymphoma, in which patients were randomized to receive 5 or 10 microg per kg per day of filgrastim after standard chemotherapy to mobilize PBPCs. After high-dose chemotherapy, the components from the first two leukapheresis procedures were returned, and all patients received 5 microg per kg day of filgrastim after transplantation. RESULTS: A total of 131 patients were randomized, of whom 128 were mobilized (Group A, 5 microg/kg, n = 66; Group B, 10 microg/kg, n = 62) and 112 were transplanted. Only six patients were not transplanted because of insufficient CD34+ cell numbers. The median number of CD34+ cells collected in the first two leukapheresis procedures tended to be higher in Group B than in Group A (12.0 vs. 7.2 x 10(6)/kg, NS), but after transplantation there was no significant difference in median times to platelet (9 days in both groups) or neutrophil (8 days in both groups) engraftment or the number of platelet transfusions (three in both groups). A subsequent subgroup analysis separating patients transplanted after first- or second-line chemotherapy also showed no measurable impact of filgrastim dose on the median CD34+ cell yield or on platelet engraftment in either subgroup. CONCLUSION: PBPC mobilization with chemotherapy and 5 microg per kg of filgrastim is very efficient, and 10 microg per kg of filgrastim does not provide additional clinical benefit.     

End-of-life situations in cardiology: a qualitative study of physicians' and nurses’ experience in a large university hospital

Background

Professional societies call for integration of end-of-life discussions early in the trajectory of heart failure, yet it remains unclear where current practices stand in relation to these recommendations. We sought to describe the perceptions and attitudes of caregivers in cardiology regarding end-of-life situations.

Methods

We performed a qualitative study using semi-directive interviews in the cardiology department of a university teaching hospital in France. Physicians, nurses and nurses’ aides working full-time in the department at the time of the study were eligible. Participants were asked to describe how they experienced end-of-life situations. Interviews were recorded, transcribed and coded using thematic analysis to identify major and secondary themes.

Results

All physicians (N?=?16)(average age 43.5?±?13 years), 16 nurses (average age 38.5?±?7.6 years) and 5 nurses’ aides (average age 49?±?7.8 years) participated. Interviews were held between 30 March and 17 July 2017. The main themes to emerge from the physicians’ discourse were the concept of cardiology being a very active discipline, and a very curative frame of mind was prevalent. Communication (with paramedical staff, patients and families) was deemed to be important. Advance directives were thought to be rare, and not especially useful. Nurses also reported communication as a major issue, but their form of communication is bounded by several factors (physicians’ prior discourse, legislation). They commonly engage in reconciling: between the approach (curative or palliative) and the reality of the treatment prescribed; performing curative interventions in patients they deem to be dying cases causes them distress. The emergency context prevents nurses from taking the time necessary to engage in end-of-life discussions. They engage in comfort-giving behaviors to maximize patient comfort.

Conclusion

Current perceptions and practices vis-à-vis end-of-life situations in our department are individual, heterogeneous and not yet aligned with recommendations of professional societies.

     

Exploiting the tumor microenvironment for theranostic imaging

The integration of chemistry and molecular biology with imaging is providing some of the most exciting opportunities in the treatment of cancer. The field of theranostic imaging, where diagnosis is combined with therapy, is particularly suitable for a disease as complex as cancer, especially now that genomic and proteomic profiling can provide an extensive 'fingerprint' of each tumor. Using this information, theranostic agents can be shaped for personalized treatment to target specific compartments, such as the tumor microenvironment (TME), whilst minimizing damage to normal tissue. These theranostic agents can also be used to target multiple pathways or networks by incorporating multiple small interfering RNAs (siRNAs) within a single agent. A decade ago genetic alterations were the primary focus in cancer research. Now it is apparent that the tumor physiological microenvironment, interactions between cancer cells and stromal cells, such as endothelial cells, fibroblasts and macrophages, the extracellular matrix (ECM), and a host of secreted factors and cytokines, influence progression to metastatic disease, aggressiveness and the response of the disease to treatment. In this review, we outline some of the characteristics of the TME, describe the theranostic agents currently available to target the TME and discuss the unique opportunities the TME provides for the design of novel theranostic agents for cancer therapy.     

Role of MDCT in identification of the bleeding site and the vessels causing hemoptysis

OBJECTIVE: MDCT has improved the management of hemoptysis by providing more precise depiction of bronchial and nonbronchial systemic arteries than conventional CT. The purpose of this article is to review the role of MDCT in the identification of the bleeding site and the vessels causing hemoptysis. CONCLUSION: Identification of the origin of the involved systemic arteries (bronchial and nonbronchial) or involved pulmonary artery on MDCT enables the interventional radiologist to treat them, especially in elderly patients with a tortuous aorta and atheroma.     

Optimization of spatial resolution for peripheral magnetic resonance angiography

RATIONALE AND OBJECTIVES: To determine optimum spatial resolution when imaging peripheral arteries with magnetic resonance angiography (MRA). MATERIALS AND METHODS: Eight vessel diameters ranging from 1.0 to 8.0 mm were simulated in a vascular phantom. A total of 40 three-dimensional flash MRA sequences were acquired with incremental variations of fields of view, matrix size, and slice thickness. The accurately known eight diameters were combined pairwise to generate 22 "exact" degrees of stenosis ranging from 42% to 87%. Then, the diameters were measured in the MRA images by three independent observers and with quantitative angiography (QA) software and used to compute the degrees of stenosis corresponding to the 22 "exact" ones. The accuracy and reproducibility of vessel diameter measurements and stenosis calculations were assessed for vessel size ranging from 6 to 8 mm (iliac artery), 4 to 5 mm (femoro-popliteal arteries), and 1 to 3 mm (infrapopliteal arteries). Maximum pixel dimension and slice thickness to obtain a mean error in stenosis evaluation of less than 10% were determined by linear regression analysis. RESULTS: Mean errors on stenosis quantification were 8.8% +/- 6.3% for 6- to 8-mm vessels, 15.5% +/- 8.2% for 4- to 5-mm vessels, and 18.9% +/- 7.5% for 1- to 3-mm vessels. Mean errors on stenosis calculation were 12.3% +/- 8.2% for observers and 11.4% +/- 15.1% for QA software (P = .0342). To evaluate stenosis with a mean error of less than 10%, maximum pixel surface, the pixel size in the phase direction, and the slice thickness should be less than 1.56 mm2, 1.34 mm, 1.70 mm, respectively (voxel size 2.65 mm3) for 6- to 8-mm vessels; 1.31 mm2, 1.10 mm, 1.34 mm (voxel size 1.76 mm3), for 4- to 5-mm vessels; and 1.17 mm2, 0.90 mm, 0.9 mm (voxel size 1.05 mm3) for 1- to 3-mm vessels. CONCLUSION: Higher spatial resolution than currently used should be selected for imaging peripheral vessels.     

First Report of Widespread Wild Populations of Triatoma infestans (Reduviidae, Triatominae) in the Valleys of La Paz, Bolivia

Wild populations of Triatoma infestans, the main vector of Chagas disease in the Southern Cone countries, may be involved in reinfestation of human dwellings, limiting the success of vector-control campaigns in Bolivia. Knowledge of the distribution of these populations remains incomplete. We report here the detection of T. infestans wild populations in large areas in the department of La Paz, Bolivia. Among 18 sylvatic areas investigated, 17 were positive with T. infestans specimens. The infection rate of captured T. infestans with Trypanosoma cruzi was 85.7% in adult specimens. These results expand the geographical distribution of wild populations of T. infestans; it may be distributed throughout the Inter-Andean Dry Forest eco-region of Bolivia. The current information allows us to propose the hypothesis that a sylvatic origin of the reinfestation is located in the valleys of La Paz.