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Page 18 of 33 Berardi et al. J Cancer Metastasis Treat 2019;5:79 I http://dx.doi.org/10.20517/2394-4722.2019.008

the influence of KCNH2 in modulating VEGF-A secretion [112] . Overexpression of KCNH2 has been also
[113]
demonstrated to be associated with poorer prognosis in squamous-cell carcinoma of esophagus . Over-
expression of KCNH2 seems to also have a role in pancreatic cancer. In particular, it is involved in EGFR
pathway, conferring an aggressive behavior and poorer prognosis [114] . KCNH2 has also been investigated
in gastric cancer. In particular, it has been demonstrated to be negatively correlated with grading, stage of
[115]
disease, venous invasion, and shorter survival . Otherwise, it has been investigated in surgical samples of
patients undergoing radical tumor resection and it seem to correlate with Lauren’s intestinal type, fundus
localization, low grading, and early stages (TNM I and II) [116] . Furthermore, it has been demonstrated to
[117]
modulate VEGF-A secretion and cisplatin-induced apoptosis .

Hypokalemia
Definition and clinical implications
Hypokalemia is defined as a low serum potassium concentration (< 3.5 mEq/L). Severe hypokalemia is
defined as a potassium level lower than 2.5 mEq/L, representing a potential life-threatening disorder [118] .

Causes
Hypokalemia is a common electrolyte disorder in cancer patients. Several causes might induce hypokalemia
in cancer patients [108] :
(1) Cancer: several conditions related to cancer might induce a reduced potassium intake (malnutrition,
anorexia, and malabsorption due to cancer bowel infiltration or bowel obstruction). Some neuroendocrine
tumors might cause hypokalemia through secretive diarrhea, favoring potassium losses. Other tumors
induce renal potassium losses through the production of hormones such as adrenocorticotropic hormone
(ACTH), cortisol, and mineralocorticoids, or through kidney damage, such as multiple myeloma.

(2) Cancer treatment: chemotherapeutic agents, target therapies and immunotherapies might cause
hypokalemia secondary to diarrhea or vomiting.

(3) Concomitant drugs: thiazide diuretics, insulin, granulocyte growth factors, beta-2 agonists, and
glucocorticoids might cause hypokalemia.

(4) Concomitant diseases: endocrine dysfunctions causing excess glucocorticoids or mineralocorticoids,
toxic epidermal necrolysis, and inflammatory bowel diseases might cause hypokalemia.

Causes of hypokalemia might be resumed substantially in three mechanisms: an inadequate potassium
intake, redistribution of potassium among intra- and extracellular compartments, and potassium losses
[Table 5].

In cancer patients, inadequate intake is often related to malnutrition and anorexia due to drugs and/or
tumor condition.

The passage of potassium into the intracellular compartment might depend on many mechanisms:
uptake of potassium by tumor cells, alkalosis, hypothermia, and drugs. For example, granulocyte growth
factors, often employed in cancer patients, provoke an acute hematopoietic cell formation, favoring rapid
potassium intake by the new cells [119] . Hypokalemia is similarly induced by rapid cell proliferation in acute
leukemia [120] .

Potassium losses can be classified into renal and non-renal losses. The most common extra-renal losses are
gastrointestinal losses due to drugs or cancer-induced diarrhea and vomiting, infections, radiation enteritis,
and type of tumors (villous adenoma and neuroendocrine neoplasms) [121] . In particular, neuroendocrine
neoplasms, although rare, are represented with the carcinoid syndrome characterized by serotonin and