The clinical relevance of serum vascular endothelial growth factor (VEGF) in correlation to circulating tumor cells and other serum biomarkers in patients with metastatic breast cancer

Background

Advanced therapeutic strategies are often accompanied by significant adverse effects, which warrant equally progressive countermeasures. Physical exercise has proven an effective intervention to improve physical function and reduce fatigue in patients undergoing chemotherapy. Effects of high-intensity interval training (HIIT) in this population are not well established although HIIT has proven effective in other clinical populations. The aim of the OptiTrain trial was to examine the effects of concurrent resistance and high-intensity interval training (RT-HIIT) or concurrent moderate-intensity aerobic and high-intensity interval training (AT-HIIT), to usual care (UC) on pain sensitivity and physiological outcomes in patients with breast cancer during chemotherapy.

Methods

Two hundred and forty women were randomized to 16 weeks of RT-HIIT, AT-HIIT, or UC. Outcomes: cardiorespiratory fitness, muscle strength, body mass, hemoglobin levels, and pressure-pain threshold.

Results

Pre- to post-intervention, RT-HIIT (ES = 0.41) and AT-HIIT (ES = 0.42) prevented the reduced cardiorespiratory fitness found with UC. Handgrip strength (surgery side: RT-HIIT vs. UC: ES = 0.41, RT-HIIT vs. AT-HIIT: ES = 0.28; non-surgery side: RT-HIIT vs. UC: ES = 0.35, RT-HIIT vs. AT-HIIT: ES = 0.22) and lower-limb muscle strength (RT-HIIT vs. UC: ES = 0.66, RT-HIIT vs. AT-HIIT: ES = 0.23) were significantly improved in the RT-HIIT. Increases in body mass were smaller in RT-HIIT (ES = ? 0.16) and AT-HIIT (ES = ? 0.16) versus UC. RT-HIIT reported higher pressure-pain thresholds than UC (trapezius: ES = 0.46, gluteus: ES = 0.53) and AT-HIIT (trapezius: ES = 0.30).

Conclusion

Sixteen weeks of RT-HIIT significantly improved muscle strength and reduced pain sensitivity. Both exercise programs were well tolerated and were equally efficient in preventing increases in body mass and in preventing declines in cardiorespiratory fitness. These results highlight the importance of implementing a combination of resistance and high-intensity interval training during chemotherapy for women with breast cancer.

     

Noncontact detection of experimental amelanotic ocular melanoma with l-3-123I-iodo-α-methyltyrosine

An application of l-3-¹²³I-iodo--methyltyrosine for the detection of ocular melanoma is presented. In rabbits with malignant Greene amelanotic melanoma transplanted to the anterior chamber of the eye, all tumors were detected in positive contrast using a gamma camera with a single pinhole collimator. The smallest tumor identified weighed 65 mg. Our data are compared with those obtained with ³²PO₄, ⁶⁷Ga, ²⁰³Pb or labelled iodochloroquine.

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Zusammenfassung Die Verwendung von L-3-¹²³Iod--methyltyrosin zum Nachweis des Augenmelanoms wird dargestellt. Bei Kaninchen mit einem malignen amelanotischen Melanom (Greene), das in die Vorderkammer des Auges transplantiert wurde, konnten alle Tumoren mit einer Gamma-Kamera, ausgerüstet mit einem Lochblendenkollimator, in positivem Kontrast nachgewiesen werden. Der kleinste nachgewiesene Tumor wog 65 mg. Unsere Daten werden mit denen verglichen, die bei Verwendung von ³²PO₄, ⁶⁷Ga, ²⁰³Pb oder markiertem Iodchloroquin erhalten wurden.

     

Expression of neuroendocrine markers: a signature of human undifferentiated carcinoma of the colon and rectum

The frequency and prognostic significance of neuroendocrine marker expression in undifferentiated colorectal cancers has not yet been studied in great detail. Therefore, the survival of 20 patients with small cell undifferentiated colorectal cancers, treated at our institution between 1982 and 1997 (0.8% of all operated colorectal carcinomas), was correlated with the extent of neuroendocrine differentiation. Chromogranin A, synaptophysin, syntaxin1, VAMP2, SNAP25 and alpha/beta-SNAP were used as neuroendocrine markers. Based on the degree of immunoreactivity for these marker proteins, tumors were separated into group 0 (<2% cells stained positive for neuroendocrine markers) and group 1 (>2% cells stained positive). Patients were followed up for at least 5 years or until death. Of 20 (45%) undifferentiated colorectal tumors, 9 expressed neuroendocrine markers (group 1). Only one patient of this group survived for 2 years (11%), whereas the 2-year-survival rate was 45.4% in group 0. Of the 11 patients in group 0, 9 were diagnosed with UICC stages I-III, whereas 8 of 9 tumors with expression of neuroendocrine markers were diagnosed with UICC stage IV ( P=0.002). Our results show that neuroendocrine differentiation is often seen in small cell undifferentiated colorectal cancer. It correlates with a more aggressive course of the disease.     

A Pilot Randomized Trial of a Companion Robot for People With Dementia Living in the Community

Objectives

To investigate the affective, social, behavioral, and physiological effects of the companion robot Paro for people with dementia in both a day care center and a home setting.

High frequency of TGF-beta-receptor-II mutations in microdissected tissue samples from laryngeal squamous cell carcinomas

In this study we analyze 105 paraformaldehyde-fixed and paraffin-embedded tumor samples from 12 patients with invasive squamous cell carcinoma of the larynx for the presence of gene mutations of the complete TGF-beta-receptor-II (TBR-II) gene. This study was conducted on tissue samples following separation of tumor cell groups from adjacent stroma cell compartments by laser microdissection, resulting in pure tumor cell complexes of approximately 50 to 500 cells. We detected 35 different mutations in 5 of the 12 patients analyzed but none in numerous samples of the normal peritumoral stroma or in normal epithelium. Twelve of the mutations were silent and nonfunctional, whereas the 23 relevant mutations were either bp replacements leading to amino acid exchanges or deletions leading to frame shifts and premature stop codons. Except for the so-called "big polyadenine tract" in exon 3 with several similar mutations, no further mutational hot spot was found. In addition we found a correlation between mutations and a loss of typical TGF-beta effects in tumor cells (high cell proliferation rate) but not in the stroma cells (low proliferative capacity, significant de novo deposition of matrix material). This study is the first to identify a high mutational rate of the TBR-II gene in laryngeal squamous cell carcinoma. We show that that only small tumor-cell groups are affected. The molecular abnormalities are variable, and only one hot spot of mutations can be identified (exon 3, big polyadenine tract). These defects and possibly comparable mutations in other proteins of the TGF-beta-signaling cascade seem to be associated with enhanced cell proliferation rates and alterations of the peritumoral matrix.     

Barium sulfate micro- and nanoparticles as bioinert reference material in particle toxicology

The inhalation of particles and their exposure to the bronchi and alveoli constitute a major public health risk. Chemical as well as particle-related properties are important factors for the biological response but are difficult to separate from each other. Barium sulfate is a completely inert chemical compound, therefore it is ideally suited to separate these two factors. The biological response of rat alveolar macrophages (NR8383) was analyzed after exposure to barium sulfate particles with three different diameters (40?nm, 270?nm, and 1.3?μm, respectively) for 24?h in vitro (particle concentrations from 12.5 to 200?μg mL^?1). The particles were colloidally stabilized as well as fluorescently-labeled by carboxymethylcellulose, conjugated with 6-aminofluorescein. All kinds of barium sulfate particles were efficiently taken up by NR8383 cells and found inside endo-lysosomes, but never in the cell nucleus. Neither an inflammatory nor a cytotoxic response was detected by the ability of dHL-60 and NR8383 cells to migrate towards a chemotactic gradient (conditioned media of NR8383 cells) and by the release of inflammatory mediators (CCL2, TNF-α, IL-6). The particles neither caused apoptosis (up to 200?μg?mL^?1) nor necrosis (up to 100?μg?mL^?1). As only adverse reaction, necrosis was found at a concentration of 200?μg?mL^?1 of the largest barium sulfate particles (1.3?μm). Barium sulfate particles are ideally suited as bioinert control to study size-dependent effects such as uptake mechanisms of intracellular distributions of pure particles, especially in nanotoxicology.     

Chlorella viruses evoke a rapid release of K+ from host cells during the early phase of infection

Infection of Chlorella NC64A cells by PBCV-1 produces a rapid depolarization of the host probably by incorporation of a viral-encoded K(+) channel (Kcv) into the host membrane. To examine the effect of an elevated conductance, we monitored the virus-stimulated efflux of K(+) from the chlorella cells. The results indicate that all 8 chlorella viruses tested evoked a host specific K(+) efflux with a concomitant decrease in the intracellular K(+). This K(+) efflux is partially reduced by blockers of the Kcv channel. Qualitatively these results support the hypothesis that depolarization and K(+) efflux are at least partially mediated by Kcv. The virus-triggered K(+) efflux occurs in the same time frame as host cell wall degradation and ejection of viral DNA. Therefore, it is reasonable to postulate that loss of K(+) and associated water fluxes from the host lower the pressure barrier to aid ejection of DNA from the virus particles into the host.     

Tissue-specific promoters active in CD44+CD24-/low breast cancer cells

It has been proposed that human tumors contain stem cells that have a central role in tumor initiation and posttreatment relapse. Putative breast cancer stem cells may reside in the CD44(+)CD24(-/low) population. Oncolytic adenoviruses are attractive for killing of these cells because they enter through infection and are therefore not susceptible to active and passive mechanisms that render stem cells resistant to many drugs. Although adenoviruses have been quite safe in cancer trials, preclinical work suggests that toxicity may eventually be possible with more active agents. Therefore, restriction of virus replication to target tissues with tissues-specific promoters is appealing for improving safety and can be achieved without loss of efficacy. We extracted CD44(+)CD24(-/low) cells from pleural effusions of breast cancer patients and found that modification of adenovirus type 5 tropism with the serotype 3 knob increased gene delivery to CD44(+)CD24(-/low) cells. alpha-Lactalbumin, cyclo-oxygenase 2, telomerase, and multidrug resistance protein promoters were studied for activity in CD44(+)CD24(-/low) cells, and a panel of oncolytic viruses was subsequently constructed. Each virus featured 5/3 chimerism of the fiber and a promoter controlling expression of E1A, which was also deleted in the Rb binding domain for additional tumor selectivity. Cell killing assays identified Ad5/3-cox2L-d24 and Ad5/3-mdr-d24 as the most active agents, and these viruses were able to completely eradicate CD44(+)CD24(-/low) cells in vitro. In vivo, these viruses had significant antitumor activity in CD44(+)CD24(-/low)-derived tumors. These findings may have relevance for elimination of cancer stem cells in humans.