Contralateral lymph node metastasis in a woman with new primary breast cancer: Systemic desease or locoregional diffusion?

INTRODUCTION: Contralateral axillary lymph node metastases (CAMs) in patients with breast cancer are rare (Daoud et al., 1998); however, CAMs may be already detected at the time of primary breast cancer diagnosis (synchronous CAM) or after a previous treatment of breast cancer as a recurrence if not as an ipsilateral breast recurrence (IBR) (metasynchronous CAM) (Zhou and Richir, 2013). The involvement of the contralateral axilla could be caused by a systemic disease (stage IV), a regional metastasis from a new occult primary tumor (T0N1, stage II) or a breast cancer recurrence It may also arise from a locally advanced disease in a patient who has suffered from a primary breast cancer. PRESENTATION OF CASE: This report focuses on the case of a 50-year-old woman who has developed a new primary breast cancer, breast skin invasion and CAMs. DISCUSSION: We intend to show that an altered lymphatic drainage may result from CAMs; in fact, patients who have previously undergone axillary lymph node dissection (ALND) are more likely to develop contralateral lymph drainage (Maaskant-Braat et al., 2013). CONCLUSION: Along with that, we want to support the theory that CAMs should be treated with curative intent rather than as a stage IV disease, as we believe that CAMs are due to a locoregional extension of the disease.

Effect of Indolic-Amide Melatonin on Blood Cell Population: A Biophysical Gaussian Statistical Analysis.

The problem of the correlation of indolic molecules with special regard to melatonin and immune processes has been widely investigated. However, there are only few studies focusing on circadian variation of peripheral blood leukocytes. The purpose of this study is thus to understand the influence of MLT on leukocyte populations and its correlation with leukocyte distribution. This is accomplished by administrating placebo and melatonin to different groups of individuals and by performing a biophysical Gaussian analysis on the number of leukocytes by means of a comparison of their p.m. vs. a.m. variations under the effect of placebo and of melatonin and via a comparison in the morning between leukocytes population of untreated group and MLT group. It is shown that: (a) melatonin has the effect of narrowing the normal distribution concentrating most of the individuals towards the mean value of the observed variation of leukocytes population and (b) the individuals who have not received either placebo or supplement have a leukocyte population that follows a normal distribution. These results confirm the crucial role played by melatonin, as the most representative of indolic amide in biological systems, in the circadian peripheral variations of leukocyte numbers because counts of white blood cells are essential in medical urgency and differential diagnosis situations. Hence, further studies are suggested to account for these physiological variations and for the evaluation of the full involvement of the action of MLT on leukocytes distribution.

Entropy Density Acceleration and Minimum Dissipation Principle: Correlation with Heat and Matter Transfer in Glucose Catabolism.

The heat and matter transfer during glucose catabolism in living systems and their relation with entropy production are a challenging subject of the classical thermodynamics applied to biology. In this respect, an analogy between mechanics and thermodynamics has been performed via the definition of the entropy density acceleration expressed by the time derivative of the rate of entropy density and related to heat and matter transfer in minimum living systems. Cells are regarded as open thermodynamic systems that exchange heat and matter resulting from irreversible processes with the intercellular environment. Prigogine's minimum energy dissipation principle is reformulated using the notion of entropy density acceleration applied to glucose catabolism. It is shown that, for out-of-equilibrium states, the calculated entropy density acceleration for a single cell is finite and negative and approaches as a function of time a zero value at global thermodynamic equilibrium for heat and matter transfer independently of the cell type and the metabolic pathway. These results could be important for a deeper understanding of entropy generation and its correlation with heat transfer in cell biology with special regard to glucose catabolism representing the prototype of irreversible reactions and a crucial metabolic pathway in stem cells and cancer stem cells.

Oncostatic-Cytoprotective Effect of Melatonin and Other Bioactive Molecules: A Common Target in Mitochondrial Respiration.

For several years, oncostatic and antiproliferative properties, as well as thoses of cell death induction through 5-methoxy-N-acetiltryptamine or melatonin treatment, have been known. Paradoxically, its remarkable scavenger, cytoprotective and anti-apoptotic characteristics in neurodegeneration models, such as Alzheimer's disease and Parkinson's disease are known too. Analogous results have been confirmed by a large literature to be associated to the use of many other bioactive molecules such as resveratrol, tocopherol derivatives or vitamin E and others. It is interesting to note that the two opposite situations, namely the neoplastic pathology and the neurodegeneration, are characterized by deep alterations of the metabolome, of mitochondrial function and of oxygen consumption, so that the oncostatic and cytoprotective action can find a potential rationalization because of the different metabolic and mitochondrial situations, and in the effect that these molecules exercise on the mitochondrial function. In this review we discuss historical and general aspects of melatonin, relations between cancers and the metabolome and between neurodegeneration and the metabolome, and the possible effects of melatonin and of other bioactive molecules on metabolic and mitochondrial dynamics. Finally, we suggest a common general mechanism as responsible for the oncostatic/cytoprotective effect of melatonin and of other molecules examined.

Cancer stem cell theory and the warburg effect, two sides of the same coin?

Over the last 100 years, many studies have been performed to determine the biochemical and histopathological phenomena that mark the origin of neoplasms. At the end of the last century, the leading paradigm, which is currently well rooted, considered the origin of neoplasms to be a set of genetic and/or epigenetic mutations, stochastic and independent in a single cell, or rather, a stochastic monoclonal pattern. However, in the last 20 years, two important areas of research have underlined numerous limitations and incongruities of this pattern, the hypothesis of the so-called cancer stem cell theory and a revaluation of several alterations in metabolic networks that are typical of the neoplastic cell, the so-called Warburg effect. Even if this specific "metabolic sign" has been known for more than 85 years, only in the last few years has it been given more attention; therefore, the so-called Warburg hypothesis has been used in multiple and independent surveys. Based on an accurate analysis of a series of considerations and of biophysical thermodynamic events in the literature, we will demonstrate a homogeneous pattern of the cancer stem cell theory, of the Warburg hypothesis and of the stochastic monoclonal pattern; this pattern could contribute considerably as the first basis of the development of a new uniform theory on the origin of neoplasms. Thus, a new possible epistemological paradigm is represented; this paradigm considers the Warburg effect as a specific "metabolic sign" reflecting the stem origin of the neoplastic cell, where, in this specific metabolic order, an essential reason for the genetic instability that is intrinsic to the neoplastic cell is defined.

Combined effects of melatonin and all-trans retinoic acid and somatostatin on breast cancer cell proliferation and death: molecular basis for the anticancer effect of these molecules.

Melatonin has been shown to inhibit breast cancer cell growth in numerous studies. However, our understanding of the therapeutic effects of this hormone is still marginal and there is little information concerning its combination with other antitumor agents to achieve additional potential benefits. All-trans retinoic acids or somatostatin have been used in combination with melatonin in several pre-clinical and clinical trials, but they have never been combined altogether as an anti-breast cancer treatment. In the present study, we investigated whether the association of melatonin, all-trans retinoic acid and somatostatin leads to an enhanced anticancer activity in MCF-7 breast cancer cells. In such conditions, MCF-7 cells were investigated for cell growth/viability and proliferation, as well as for the expression of cyclin A, and components of the Notch and EGFR pathways, by Western blotting and confocal immunofluorescence. Electrophysiological, morphological, and biochemical analysis were also performed to reveal signs of cell damage and death. We found that melatonin in combination with all-trans retinoic acid and somatostatin potentiated the effects of melatonin alone on MCF-7 cell viability and growth inhibition; this phenomenon was associated with altered conductance through Ca²âº and voltage-activated K⁺ (BK) channels, and with substantial impairments of Notch-1 and epidermal growth factor (EGF)-mediated signaling. The combined treatment also caused a marked reduction in mitochondrial membrane potential and intracellular ATP production as well as induction of necrotic cell death. Taken together our results indicate that co-administration of melatonin with all-trans retinoic acid and somatostatin may be of significant therapeutic benefit in breast cancer.

Melatonin enhances the in vitro action of cytochalasin B on globular resistance and osmotic fragility of erythrocytes.

BACKGROUND: Some researches have shown that melatonin (MLT) has effects on the erythrocyte deformability and on the osmotic fragility which, currently, seem to be heterogeneous and fragmentary. OBJECTIVE: This work wished to evaluate in vitro the possible modifying action of MLT at pharmaceutical doses on the osmotic fragility of rat blood samples treated with cytochalasin B (CB). The variation of the lactate dehydrogenase (LDH) levels have been measured because LDH is an enzyme which is considered an important marker of hemolysis. Working in a strongly reducing environment has been necessary in order to avoid possible antioxidant actions of MLT, measuring the plasma levels of malondialdehyde and total phospholipids in order to highlight possible MLT actions which are not related to its recognized antioxidant properties. RESULTS: The data show a possible MLT action which strengthens the CB action on the osmotic fragility and on the membrane deformability of the erythrocytes. CONCLUSIONS: Under the adopted working conditions, a direct relation of MLT with the biochemical dynamics of the cytoskeleton-mediated processes can be suggested. Further studies will be needed to clarify the mechanisms and the extent of the observed phenomena.

Action of melatonin on bone marrow depression induced by cyclophosphamide in acute toxicity phase.

BACKGROUND: In the course of the last few years, various studies have researched the relations linking melatonin (MLT) with hematopoiesis and the immune-hematopoietic system. Nevertheless, to date there are numerous issues still opened and many questions are yet unanswered. Much emphasis has been recently placed on the reducing role of MLT, which has been demonstrated by many studies to mitigate the genotoxic damage inflicted by various alkylating agents. Although in vitro MLT has shown to be effective in limiting the cytological alterations provoked by chemotherapeutic drugs, some clinical studies seem to point to a somewhat lower effectiveness in countering chemotherapy-induced leukopenia and anemia. OBJECTIVE: The aim of this study was to evaluate the activity exerted by pharmacological doses of MLT in limiting leukopenia, anemia and other hemocytometric modifications in animals facing acute toxicity caused by the treatment with cyclophosphamide (CP). Moreover, we have compared the activity of MLT with well-known alpha-tocopherol/ascorbic acid antioxidant system. RESULTS: Our results indicate that overall MLT exerts a remarkable countering activity towards leukopenia and anemia in the early phase of administration of CP. CONCLUSIONS: Our findings suggest possible active involvement of MLT in hematopoiesis and erythrocyte- and leukocyte turnover. This paper summarizes the essential aspects of the available literature, researching the possible relations between MLT and immune-hematopoietic system.