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Page 10 of 33 Berardi et al. J Cancer Metastasis Treat 2019;5:79 I http://dx.doi.org/10.20517/2394-4722.2019.008

In collaborating and asymptomatic patients without gastrointestinal dysfunction, oral hydration is effective,
and should be preferred. In patients with severe hypernatremia or unable to intake fluid orally (due to
vomiting or neurological changes), intravenous hydration should be considered.

The infusion of free water (5% dextrose solution) should be considered in the case of loss of free water
alone. Loop diuretics should be considered in the case of pure sodium gain natriuresis.

In patients with acute hypernatremia (within 24 h) or severe symptoms, treatment with isotonic or
hypotonic solutions should be started immediately, since it was demonstrated that a prompt correction (up
to 8-12 mmol/L per day) improves patients’ prognosis without risk of convulsions or cerebral edema. A
[59]
correction of 1 mEq/L/h should be considered safe .

In patients with chronic hypernatremia or when time of onset is unknown, the correction should be
obtained within 48 h, with a reduction of serum osmolality of no more than 0.5 mOsm/L/h to avoid
cerebral edema onset. A reduction of serum sodium concentration of 8-10 mmol/L per day should be
considered safe. Monitoring serum sodium levels at regular intervals of 4 h is highly recommended to
[59]
control the correction speed .
Patients experiencing central insipidus diabetes should receive nasal or oral desmopressin. Nephrogenic
insipidus diabetes should be treated with a combination of thiazide diuretics and low sodium-low protein,
[60]
removing potential precipitation factors .

CALCIUM
Calcium is an extracellular cation and the normal serum calcium concentration range is 2.1-2.5 mmol/L
[61]
(8.5-10.5 mg/dL) or ionized calcium of 1.1-1.4 mmol/L (4.5-5.6 mg/dL) . Most of the calcium content
is deposited in the organic matrix by hydroxyapatite crystals of bones. Calcium appears in three different
forms: free ion (50%), bound to plasma proteins, and in diffusible complexes. Acid-base status influences
the binding between calcium and serum proteins. In particular, alkalosis favors the binding while acidosis
induces the ionized calcium form. Calcium derives from diet and it is excreted by kidney.

Calcium reabsorption in kidney occurs mainly in the proximal tubules, and a small share in the ascending
loop of Henle, thus loop diuretics decrease tubular calcium resorption, whereas thiazide diuretics
[62]
improve its resorption . Calcium metabolism requires a steady interaction between bone and ECF.
Several hormones are involved in calcium homeostasis. Parathyroid hormone (PTH), whose secretion is
mediated by reduced serum calcium levels, acts on bone, favoring osteoclastic-mediated bone resorption
and promoting calcium leakage and it induces the synthesis of active vitamin D and calcium intestinal
absorption. Calcitonin instead, whose secretion is mediated by increased serum calcium levels, reduces
the transfer of calcium from bone calcium pool to the ECF, and it decreases bone resorption inhibiting
[63]
osteoclasts’ activity and increases calcium renal excretion .
Vitamin D also plays a crucial role in serum calcium homeostasis, favoring increased intestinal calcium
absorption and bone calcium storage .
[64]
Several studies demonstrated a crucial role of calcium-mediated signaling pathways in carcinogenesis,
dedifferentiated into cancer stem cells, cellular motility favoring tumor invasion and metastasis, and the
regulation of apoptosis .
[65]
2+
Several calcium channels are involved and expressed in cancer cells. Ca ATPase I isoforms (SPCA1 and
ATP2C1) are described in basal-like breast cancer, favoring cell proliferation, while calcium efflux pump