Cancer stem cell niche: the place to be

Tumors are being increasingly perceived as abnormal organs that, in many respects, recapitulate the outgrowth and differentiation patterns of normal tissues. In line with this idea is the observation that only a small fraction of tumor cells is capable of initiating a new tumor. Because of the features that these cells share with somatic stem cells, they have been termed cancer stem cells (CSC). Normal stem cells reside in a "stem cell niche" that maintains them in a stem-like state. Recent data suggest that CSCs also rely on a similar niche, dubbed the "CSC niche," which controls their self-renewal and differentiation. Moreover, CSCs can be generated by the microenvironment through induction of CSC features in more differentiated tumor cells. In addition to a role in CSC maintenance, the microenvironment is hypothesized to be involved in metastasis by induction of the epithelial-mesenchymal transition, leading to dissemination and invasion of tumor cells. The localization of secondary tumors also seems to be orchestrated by the microenvironment, which is suggested to form a premetastatic niche. Thus, the microenvironment seems to be of crucial importance for primary tumor growth as well as metastasis formation. Combined with its role in the protection of CSCs against genotoxic insults, these data strongly put forward the niche as an important target for novel therapies.     

Hypothyroidism in patients with renal cell carcinoma

BACKGROUND:

Sunitinib and sorafenib are tyrosine kinase inhibitors that have important antitumor activity in metastatic renal cell carcinoma (mRCC). Hypothyroidism constitutes a commonly reported side effect of both drugs, and particularly of sunitinib. The objective of this analysis was to investigate whether the occurrence of hypothyroidism during treatment with sunitinib and sorafenib affects the outcome of patients with mRCC.

METHODS:

Eighty‐seven consecutive patients with mRCC who were to receive treatment with sunitinib or sorafenib were included in a prospective analysis. Thyroid function was assessed in each patient every 4 weeks during the first 2 months of treatment and every 2 to 4 months thereafter. Assessment included serum levels of thyroid‐stimulating hormone (TSH), tri‐iodthyronine (T3), and thyroxine (T4). Subclinical hypothyroidism was defined as an increase in TSH above the upper limit of normal (>3.77 μM/mL) with normal T3 and T4 levels.

RESULTS:

Subclinical hypothyroidism was evident in 5 patients at baseline and occurred in 30 patients (36.1%) within the first 2 months after treatment initiation. There was a statistically significant correlation between the occurrence of subclinical hypothyroidism during treatment and the rate of objective remission (hypothyroid patients vs euthyroid patients: 28.3% vs 3.3%, respectively; P < .001) and the median duration of survival (not reached vs 13.9 months, respectively; hazard ratio, 0.35; 95% confidence interval, 0.14‐0.85; P = .016). In multivariate analysis, the development of subclinical hypothyroidism was identified as an independent predictor of survival (hazard ratio, 0.31; P = .014).

CONCLUSIONS:

The current results indicated that hypothyroidism may serve as a predictive marker of treatment outcome in patients with mRCC. Thus, the interpretation of hypothyroidism during treatment with sunitinib and sorafenib as an unwanted side effect should be reconsidered. Cancer 2011. © 2010 American Cancer Society.     

Serbian medical students’ fertility awareness and attitudes towards future parenthood

Objectives: Medical students represent a group particularly at risk of involuntary childlessness due to their highly demanding careers and university curriculum. The aim of this study was to investigate Serbian medical students’ attitudes towards future parenthood and their awareness of fertility issues.

Methods: A cross-sectional study was conducted among fourth year students at the Faculty of Medicine, University of Belgrade, Serbia, between 12 and 16 December 2016. Data were collected through an anonymous 56-item validated questionnaire, translated into the Serbian language. The participation rate was 87.1%.

Results: More than 95% of students, regardless of gender, wanted to have children in the future; most indicated three as the desired number of children. Both genders equally rated the importance of having children. Women rated significantly higher the likelihood of IVF treatment or child adoption if faced with infertility (both p?=?.001). All students wanted to have their first child before the age of 35 years. Knowledge about the age-related decline in female fertility was not satisfactory. Women found it more important to have children when they felt sufficiently mature, were in a stable relationship, were financially secure, had completed their studies, were not too old to have children, and had access to childcare, although these prerequisites were rated highly by both genders.

Conclusion: Serbian medical students greatly value and have a positive perception of future parenthood. Appropriate education is needed, however, because of their inadequate knowledge of the age-related decline in female fertility.     

Thyroid peroxidase and galectin-3 immunostaining in differentiated thyroid carcinoma with clinicopathologic correlation

Thyroperoxidase and galectin-3 have been reported as useful immunohistochemical markers of thyroid malignancy. In this study, we evaluated the relationship between immunohistochemical staining results for these markers and clinicopathologic features of patients with differentiated thyroid cancer. A total of 193 archival thyroid samples including 28 follicular adenomas, 18 follicular carcinomas, and 147 papillary carcinomas with 114 adjacent thyroid tissues were analyzed by immunohistochemistry. Thyroperoxidase was underexpressed (<50% stained thyrocytes), and galectin-3 was expressed (>5% stained thyrocytes) in most carcinomas. The sensitivity for diagnosis of differentiated thyroid carcinoma was 86.1% for thyroperoxidase and 82.4% for galectin-3, whereas the combination of both markers increased the sensitivity up to 94.5%. Thus, the combination of thyroperoxidase and galectin-3 immunohistochemistry may help to ascertain the malignant nature of the lesion. Furthermore, tumor size, nodal involvement, extrathyroidal invasion, and high tumor-node-metastasis stage in patients with papillary carcinoma were related to thyroperoxidase absence and high galectin-3 expression in most cases (P < .05). In patients with follicular carcinoma, the extent of invasiveness was associated with galectin-3 positivity. Thus, expression of these markers is related to more or less aggressive biological behavior of differentiated thyroid carcinomas. Although thyroperoxidase presence may indicate favorable prognosis of papillary cancer, expression of galectin-3 illustrates the potential importance of this protein in the pathogenesis and/or progression of differentiated thyroid carcinomas.     

Mast cells: Versatile gatekeepers of pain

Mast cells are important first responders in protective pain responses that provoke withdrawal from intense, noxious environmental stimuli, in part because of their sentinel location in tissue–environment interfaces. In chronic pain disorders, the proximity of mast cells to nerves potentiates critical molecular cross-talk between these two cell types that results in their synergistic contribution to the initiation and propagation of long-term changes in pain responses via intricate signal networks of neurotransmitters, cytokines and adhesion molecules. Both in rodent models of inflammatory pain and chronic pain disorders, as well as in increasing evidence from the clinic, it is abundantly clear that understanding the mast cell-mediated mechanisms underlying protective and maladaptive pain cascades will lead to improved understanding of mast cell biology as well as the development of novel, targeted therapies for the treatment and management of debilitating pain conditions.     

Single-dose pharmacokinetics of cefodizime in critically ill elderly patients

Cefodizime is an extended-spectrum third-generation cephalosporin antibiotic that is widely used in the treatment of severe infections of the respiratory and urinary tracts. Pharmacokinetic characteristics of cefodizime were assessed in 13 critically ill elderly patients (median age 73+/-6 years). The mean cefodizime peak serum concentration following a single 2g cefodizime infusion was 219+/-58 mg/L and the mean trough level 12 h after infusion was 29+/-17 mg/L. The elimination half-life was 6.19+/-2.45 h. Total body clearance, area under the plasma concentration-time curve and volume of distribution were 35.8+/-13.2 mL/min, 1089.4+/-505.3 mg h/L and 17.4+/-6.3 L, respectively. Pharmacokinetics of cefodizime in critically ill elderly patients were comparable with those reported previously in healthy volunteers.     

Color Doppler Transesophageal Echocardiography in Detection of Massive Pulmonary Embolism: Is Pulmonary Angiography Always the Gold Standard?

In this article, the potential value of color Doppler in improving diagnostic accuracy of transesophageal echocardiography (TEE) in patients with incomplete obstruction of large pulmonary vessels is illustrated. We present an unusual case of massive pulmonary embolism that was unequivocally detected by color Doppler TEE both before and after pulmonary angiography, which failed to demonstrate filling defects in the pulmonary artery. (ECHOCARDIOGRAPHY, Volume 13, November 1996)     

The role of radiation therapy in the treatment of metastatic cancer

Radiation therapy continues to play an important role in the management of cancer. In this review, we discuss the use of radiation therapy to target and control micrometastatic disease (adjuvant use of radiation), or using stereotactic radiation therapy to address small volumes of gross disease, such as oligometastases, and finally the use of radiation therapy in the era of immunotherapy. Radiation therapy is commonly used to treat nodal basins suspected of harboring microscopic disease. More recently, computer and technical innovations have allowed radiation oncologists to treat small volumes of gross disease within the brain and also in the body with great success, adding to the cancer armamentarium. This modality of cancer treatment that began shortly after the discovery of X-rays by William Roentgen continues to evolve and finds new clinical applications which minimize toxicity while increasing effectiveness. The newly discovered interactions of high dose/fraction radiation (stereotactic radiosurgery) with immune check point inhibitors in melanoma is the latest example of how synergism can be achieved between two different modalities thus increasing the therapeutic ratio to control metastatic cancer.     

Prognostic significance of the dobutamine echocardiography test in idiopathic dilated cardiomyopathy

Dobutamine stress echo provides potentially useful information on idiopathic dilated cardiomyopathy (IDC). From February 1, 1997, to October 1, 1999, 186 patients (131 men and 55 women, mean age 56 ± 12 years) with IDC, ejection fraction <35%, and angiographically normal coronary arteries were studied by high-dose (up to 40 μ/kg/min) dobutamine echo in 6 centers, all quality controlled for stress echo reading. In all patients, wall motion score index (WMSI) (from 1 = normal to 4 = dyskinetic in a 16- segment model of the left ventricle) was evaluated by echo at baseline and peak dobutamine. One hundred eighty-four patients were followed up (mean 15 ± 13 months) and only cardiac death was considered as an end point. There were 29 cardiac deaths. Significant parameters for survival prediction at univariate analysis are: ΔWMSI (chi-square 20.1; p <0.0000), New York Heart Association (NYHA) class (chi-square 17.57; p <0.0000), rest ejection fraction (chi-square 10.41; P = 0.0013), angiotensin-converting enzyme inhibitors (chi-square 8.23; P = 0.0041), and hypertension (chi-square 8.08, P = 0.0045). In the multivariate stepwise analysis only ΔWMSI and NYHA were independent predictors of outcome (ΔWMSI = hazard ratio 0.02, p <0.0000; NYHA CLASS = hazard ratio 3.83, p <0.0000). Kaplan-Meier survival estimates showed a better outcome for patients with a large inotropic response (ΔWMSI ≥0.44, a cutoff identified by receiver-operating characteristic curves analysis) than for those with a small or no myocardial inotropic response to dobutamine (93.6% vs 69.4%, P = 0.00033). Thus, in patients with IDC, an extensive contractile reserve identified by high-dose dobutamine stress echocardiography is associated with a better survival.     

The interactions of vanadium with Phycomyces blakesleeanus mycelium: enzymatic reduction,transport and metabolic effects

The biological and chemical basis of vanadium action and transport in fungi is relatively poorly understood. In this study we investigated the interactions of vanadium in physiologically-relevant redox states: vanadate (+5) and vanadyl (+4), with mycelium of fungus Phycomyces blakesleeanus using EPR and ³¹P NMR spectroscopy and biochemical assays. We determined that P. blakesleeanus reduces V⁵⁺ to V⁴⁺ in the extracellular compartment by the means of cell surface enzyme with ferricyanide reductase activity, which contains molybdenum–molybdopterin as a cofactor. Both, V⁵⁺ and V⁴⁺ bind to cell wall. They enter the cytoplasm via phosphate transporter and cation channels, respectively, and exhibit different metabolic effects. Vanadate provokes increased biomass production, the effects being inverted to toxic at higher V⁵⁺ concentrations. In addition, V⁵⁺ activates the synthesis of sugar phosphates and oligophosphates. On the other hand, V⁴⁺ exhibits toxic effects even at low concentrations. The V⁴⁺ detoxification route involves binding to vacuolar polyphosphates. Altogether our results imply that the mechanism of interaction of vanadium with P. blakesleeanus involves three major steps: extracellular enzymatic V⁵⁺/V⁴⁺ reduction, V⁴⁺ influx, and vacuolar storage, with an additional step – V⁵⁺ import occurring at higher vanadate concentrations.