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Humoral hypercalcemia is predominant in squamous cell, renal cell and ovarian cancers, and lymphomas are associated with 1,25-dihydroxyvitamin D mediated hypercalcemia

20% of cases of hypercalcemia of malignancy and is frequently encountered in multiple myeloma, metastatic breast cancer, and to a lesser extent in leukemia and lymphoma

Physiologic bone turnover requires the complementary activity of osteoblasts – mesenchymal stem cell-derived bone-forming cells – and bone-resorbing cells of monocyte and macrophage lineage known as osteoclasts

In local osteolytic hypercalcemia, the RANKL/RANK interaction results in excessive osteoclast activation leading to enhanced bone resorption and thus hypercalcemia

In addition, osteoclast activation is also mediated by malignancy secreted cytokines, including interleukin-1, initially termed “osteoclast stimulating factor”

Macrophage inflammation protein 1-alpha (MIP 1-alpha)

hypercalcemia is through extra-renal 1,25-dihydroxyvitamin D (calcitriol) production

1% of cases

increased production of 1,25-dihydroxyvitamin D occurs nearly exclusively in Hodgkin and non-Hodgkin lymphoma with case reports of the same in ovarian dysgerminoma

1-α-hydroxylase in the kidney, a process regulated by PTH

in 1,25-dihydroxyvitamin D induced hypercalcemia, malignant cells likely recruit and induce adjacent macrophages to express 1-α-hydroxylase, converting endogenous calcidiol into calcitriol.31 Calcitriol then binds to receptors in the intestine leading to heightened enteric calcium reabsorption with resultant hypercalcemia

this mechanism of disease is best conceptualized as an absorptive form of hypercalcemia

Ectopic production of PTH by malignant cells has been described in a handful of cases involving cancer of the ovary and lung, as well as neuroendocrine tumors and sarcoma

primary hyperparathyroidism and malignancy comprising nearly 90% of cases of hypercalcemia

an initial panel consisting of PTH, PTHrP, phosphorus, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D should be obtained

Lymphoma, a hypercalcemia due to 1,25-dihydroxyvitamin D mediated pathways, is implied by elevations in 1,25-dihydroxyvitamin D without concomitant elevations in 25-hydroxyvitamin D. In such cases, PTH is low and PTHrP undetectable

Treatment of hypercalcemia of malignancy is aimed at lowering the serum calcium concentration by targeting the underlying disease, specifically by inhibiting bone resorption, increasing urinary calcium excretion, and to a lesser extent by decreasing intestinal calcium absorption

mildly symptomatic disease

marked symptoms

hydration with isotonic fluid (if admitted), avoidance of thiazide diuretics, and a low-calcium diet

denosumab

Denosumab is an RANKL antibody that inhibits osteoclast maturation, activation, and function

Hyperthermia differs fundamentally from fever in that it elevates the core body temperature without changing the physiological set point

hyperthermia is induced by increasing the heat load and/or inactivating heat dissipation

mor cells [2]. Although significant cell killing could be achieved by heating cells or tissues to temperatures > 42°C for 1 or more hours, the application, measurement and consistency of this temperature range within the setting of cancer clinical trials

mild temperature hyperthermia (ie, within the fever-range, 39–41°C)

moderate hyperthermia (41°C)

Hsps are a family of stress-induced proteins

they are key regulators of cellular protein activity, turnover and trafficking

Hsps ensure appropriate post-translational protein folding, and are able to refold denatured proteins, or mark irreversibly damaged proteins for destruction

the ability of fever-range hyperthermia to induce reactive immunity against tumor antigens through DCs and NK-cells is likely mediated by Hsps

thermotolerance

Hsps support the malignant phenotype of cancer cells by not only affecting the cells’ survival, but also participating in angiogenesis, invasion, metastasis and immortalization mechanisms

Hsps released from stressed or dying cells activate dendritic cells (DCs), transforming them into mature APCs

In theory, fever-range hyperthermia may take advantage of tumor cell Hsps by inducing their release from tumor cells and augmenting DC priming against tumor antigens

In several models of hyperthermia, heat-treated tumors exhibited improved DC priming and generation of systemic immunity to tumor cell

hyperthermia alone can enhance antigen display by tumor cells, thus rendering them even more susceptible to programmed immune clearance

Fever-range hyperthermia may also induce Hsps

Hsps may exert an adjuvant effect by bolstering MHC class II and co-stimulatory molecule expression by DCs

thermal ablation of liver tumors in particular has demonstrated an ability to potentiate immune responses [57, 58] and elicit robust T-cell infiltrates at ablation sites

specific Hsp, Hsp70, directly inhibits apoptosis pathways in cancer cells, as demonstrated in human pancreatic, prostate and gastric cancer cells

Cross-priming is the ability of extracellular Hsps complexed to tumor peptides to be internalized and presented in the context of MHC class I molecules on APCs, thus allowing potent priming of CTLs against tumor antigens

It has been reported that Hsps are generated from necrotic tumor cell lysates, but not from tumor cells undergoing apoptosis

tumor cells exposed to hyperthermia in the heat shock range (42°C for 4h) prior to lysing, DC activation and cross-priming were significantly enhanced with the application of heat

Due to the ability of Hsps to activate DCs directly by chaperoning tumor antigens upon their release [28], it is possible that both local and regional immune stimulation can be achieved with hyperthermia.

support the use of hyperthermia as an inducer of Hsps to serve as ‘danger signals’, activating antitumor immune responses

whole-body hyperthermia not only augments immune responses, but also stimulates the migration of skin-derived DCs to draining lymph nodes

suggest a valuable role of hyperthermia in DC cancer vaccine strategies

In mice treated with fever-range whole-body hyperthermia, tumor growth was significantly inhibited and NK-cell infiltration increased

exposure to fever-range hyperthermia resulted in improved endogenous NK-cell cytotoxicity to several cancer types

improved activation and function of DCs and NK cells following hyperthermia

Hyperthermia increases the expression ICAM-1 a key adhesion molecule,

The combined effects of hyperthermia on lymphoid tissue endothelium and lymphocytes can promote immune surveillance and increase the probability of naive lymphocytes leaving the circulation and encountering their cognate antigen displayed by DCs in lymphoid organs.

In independent clinical studies, whole-body hyperthermia resulted in a transient decrease in circulating lymphocytes in patients with advanced cancer [12, 94, 99, 100], a finding which mirrored observations in animal models in which lymphocyte entry into lymph noeds was increased following hyperthermia treatment [93]. Enhanced recruitment of lymphocytes to lymphoid tissues may be exploited in the treatment of malignancies.

The initial tumor antigen presentation and initiation of clonal expansion of CTLs transpires in the lymph nodes and cannot take place outside this specialized compartment

the ability of DCs present in the lymph nodes to stimulate an anti-tumor immune response is critical

hyperthermia has been shown to improve immune surveillance by T-cell

and to increase DC trafficking to lymph nodes

NK cells are large granular lymphocytes that comprise approximately 10 % of circulating lymphocytes

all human NK cells express the CD56 antigen

treatment with various concentrations of IL‐2 in vivo may induce distinct functions within the NK cell compartment and, therefore, may have profound effects on NK cell‐mediated cytotoxicity

CD56bright

CD56dim

We show here that ADCC conducted by NK cells in vitro is enhanced by IL‐2 activation and is critically dependent on interactions between FcγRIII on NK cells and Herceptin‐coated tumor targets

administration of low‐dose IL‐2 to patients results in the marked expansion of a CD56+ population of immune effectors with the ability to lyse antibody‐coated cancer targets

NK cells represented only 7 % of lymphocytes prior to therapy but comprised over 50 % of the population after 10 weeks of low‐dose IL‐2

These data suggest that the enhanced ADCC seen following the expansion of NK cells with low‐dose IL‐2 is likely due to an increase in the overall number of NK cells

co‐administration of IL‐2 with rhu4D5 mAb will enhance activation of NK cell effector functions

Stimulation of NK cells with IL‐2 resulted in a significant increase in the lysis of rhu4D5‐coated targets

We have shown that costimulation with IL‐2 plus rhu4D5 results in significant production of IFN‐γ by NK cells with concomitant up‐regulation of cell‐surface activation and adhesion molecules

It has been previously demonstrated that continuous low‐dose IL‐2 can expand a CD56+ lymphocyte population, and we have now shown that this cell population is a potent mediator of ADCC against rhu4D5 mAb‐coated Her2 / neu+ targets

These results suggest that administration of low‐dose IL‐2 can be used to expand NK cell numbers, while higher doses may be used to enhance their cytolytic capacity in the setting of mAb therapy

we have demonstrated that NK cell lysis of Her2 / neu+ breast cancer cell lines in the presence of rhu4D5 mAb is markedly enhanced following stimulation with IL‐2

we have presented evidence that administration of low‐dose IL‐2 in vivo results in the expansion of a potent NK cell effector population

Our experiments suggest that NK cells costimulated with IL‐2 and immobilized IgG can secrete potent immunomodulatory cytokines which may serve to potentiate the anti‐tumor immune response.

Essential hypertension, associated with endothelial dysfunction because of an impaired nitric oxide/l-arginine pathway and impaired vasodilation can be restored by vitamin C

marked increase in BP response when IVB12 is administered

The mean BP increased significantly up to 12–16 mmHg systolic and diastolic independent of the dosage of vitamin B12

The production of norepinephrine, which can stimulate angiotensin-II production, which in turn influences BP, has been suggested as a possible mechanism for the increase in BP with IVB12

excess norephinephrine levels stimulate the sympathetic nervous system, leading to increased cortisol production, which has also been linked to increases in BP

Animal studies have found higher serum levels of norepinephrine (noradrenaline) in the adrenal medulla of rats receiving methylcobalamin (methyl-vitamin B12)