Spinal cord compression (scc) and intracranial hypertension (Table 1).

Spinal cord compression represents an emergency diagnosed in 5–10% of cancer patients, especially in the presence of neoplasms with a marked tendency to bone metastasis (lung, breast and prostate). Only rarely is it related to the presence of a primary tumor affecting the central nervous system.

Spinal cord compression is attributed to three mechanisms:

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Most commonly, due to the invasion of the epidural space by an extradural extramedullary tumor (usually a vertebral body metastasis) or by an intradural extramedullary tumor (due to the presence of a primary central nervous system tumor). This mechanism causes permanent damage to the spinal cord (resulting in paraplegia or tetraplegia) due to the ischemia generated by compression of the venous plexus, leading to intramedullary edema and reduced capillary blood flow due to increased pressure on small arterioles.

-

Intramedullary metastases.

-

Invasion of the vertebral foramina by paraspinal masses.

Back pain, with characteristic pain and variable localization depending on the level of compression, often resistant to opioids, represents the main onset symptom (in 90–95% of cases). Pain can be associated with sensory neurological deficits (paresthesia, hypoesthesia and anesthesia), motor deficits (weakness up to paralysis) and autonomic nervous system deficits (urinary retention, constipation, incontinence) ^[1][2][35,36].

Regarding the diagnosis, MRI represents the diagnostic gold standard; however, it is not always executable in an emergency regimen. Alternatively, a CT scan of the spine, which provides an adequate representation of bony structures, may be considered ^[3][4][37,38]. From a treatment point of view, corticosteroids should be administered as early as possible to reduce edema. The treatment of choice is frequently radiotherapy (30 Gy in 10 fractions). On the other hand, in selected patients and those with good performance status, surgical treatment (laminectomy or resection and replacement of the vertebral body) is possible.

The main goals of treatment are the preservation of neurological function and the improvement in the quality of life ^[1][2][5][35,36,39].

The other major neurological oncological emergency is represented by intracranial hypertension, with subsequent edema and cerebral malfunction, up to herniation in the most serious cases. The main cause of intracranial hypertension is the presence and rapid expansion of primary or metastatic intracranial tumors. The main symptoms include headache, nausea, vomiting, visual disturbances, papillary edema, confused states, alterations in the state of consciousness and progressive neurological deficits (gait alterations, paralysis) ^[4][6][38,40].

Imaging techniques represent the diagnostic gold standard (CT, MRI). Treatment should take into account the patient’s clinical condition and the prognosis of the underlying disease. Medical therapy is based on the use of glucocorticoids and osmotic diuretics. Specific medical antineoplastic treatments (chemotherapy, targeted therapy) and radiotherapy can effectively contribute to symptom control and disease management. In some cases, neurosurgical treatment may be considered. However, the presence of intracranial hypertension markedly worsens the prognosis, with a median survival of 3 months and a one-year survival of 10% ^[1][3][7][8][35,37,41,42].

Tumor lysis syndrome (TLS) represents an oncological emergency that, if not recognized and treated promptly, is associated with a high risk of mortality (from 29% to 79%). This syndrome is due to the massive destruction of tumor cells, resulting in the release of their contents into the bloodstream ^[9][10][11][43,44,45].

The consequent release of cellular metabolites, including potassium, phosphates and uric acid, saturates the renal excretion mechanisms, leading to hyperkalemia, hyperphosphatemia, hyperuricemia and secondary hypocalcemia, which can be fatal. These substances can also precipitate directly inside the renal tubules, resulting in acute renal failure ^[12][13][46,47].

The risk is higher in the presence of aggressive tumors with high chemosensitivity, including both hematological malignancies (acute leukemias and high-grade non-Hodgkin’s lymphomas) and solid malignancies (SCLC and testicular tumors) ^[14][15][48,49].

Patients who develop this clinical condition must be promptly treated by correcting the metabolic alterations that have arisen. Additionally, careful monitoring of cardiac activity, diuresis, plasma concentration of electrolytes and uric acid, LDH, and creatinine is required. Despite prophylactic measures and treatments to reduce acute kidney injury, a small proportion of patients (approximately 5%) may require hemodialysis ^[16][17][50,51].

Hyponatremia and SIAD. Hyponatremia is defined as a serum sodium concentration below 135 mmol/L ^[18][52].

Hyponatremia is classified, according to the speed of onset, as acute or chronic (when onset is less or more than 48 h, respectively). The symptomatology is predominantly neurological, and the clinical manifestations depend on the severity and speed of onset. In the presence of mild or chronic hyponatremia, patients are often asymptomatic or have nonspecific symptoms (asthenia, nausea, headache). Symptoms such as headache, lethargy, convulsions, and coma may occur in severe or acute hyponatremia. Additionally, hyponatremia can be classified according to plasma osmolarity (hyposmolar or hyperosmolar) and volume (euvolemic, hypervolemic, hypovolemic) ^[19][20][21][53,54,55].

Decreased plasma sodium concentration is the most frequent electrolyte disturbance in cancer patients, especially in patients with lung, prostate, pancreatic and renal cancer. Furthermore, hyponatremia represents a negative prognostic factor for patients affected by cancer and, therefore, must be corrected.

However, in most cancer patients, hyponatremia is a consequence of the syndrome of inappropriate antidiuresis (SIADH), which should be suspected in the presence of hyposmolar and euvolemic hyponatremia. SIADH represents, in most cases, a paraneoplastic syndrome due to an ectopic secretion of vasopressin by the tumor, which leads to excessive water retention and a reduction in plasma sodium concentration. SIADH has an incidence of 1–2% in the oncological population, reaching 15% in patients with SCLC. Although it may also be associated with breast cancer, lymphoma and neck tumors ^{[22][23][24][25][26][27][28]}[56,57,58,59,60,61,62].

It should be noted that some chemotherapy drugs or pain relievers, including opioids, can also cause SIADH ^[29][30][31][63,64,65].

The treatment is based on the antineoplastic therapy of the underlying disease, and other measures must be taken in relation to the clinical condition. In patients with few symptoms, the use of AVP-receptor antagonists can be considered, while in patients with severe symptoms, a hypertonic solution remains the treatment of choice ^[32][33][34][66,67,68].

Hypercalcemia. Hypercalcemia is the most common metabolic cancer emergency, with a frequency of 10–30% among the cancer population. Hypercalcemia is defined as a corrected serum calcium concentration > 10 mg/dL and/or an ionized calcium concentration > 5.6 mg/dL.

This electrolyte disorder is most frequently associated with breast, lung, kidney, thyroid and head and neck cancer. Regarding hematological cancers, it is more frequent in lymphomas. It is also more common in the advanced disease setting and is associated with a poor prognosis ^{[35][36][37][38]}[33,69,70,71].

Four mechanisms underlying neoplastic hypercalcemia have been recognized:

-

Production of a PTH-like protein (PTHrp: parathyroid hormone-related protein);

-

Ectopic production of PTH;

-

Osteolytic metastases;

-

Release of 1,25-dihydroxycholecalciferol (especially in lymphomas) ^[39][40][41][72,73,74].

The symptomatology varies based on the speed of onset and the severity of the alteration, similar to what happens in hyponatremia. Symptoms can be non-specific, affecting various organs and systems, with neurological disorders (fatigue, muscle weakness, reduced reflexes, apathy, lethargy, behavioral changes up to coma), gastrointestinal disorders (loss of appetite, nausea, vomiting, constipation, paralytic ileus), cardiovascular issues (bradyarrhythmias, ECG changes) and urinary disorders (polyuria, polydipsia, acute kidney injury, nephrolithiasis) ^[39][42][72,75].

Similar to the clinic, the therapy for hypercalcemia also depends on the serum calcium concentration and the severity of the symptoms. The first step to take is the administration of intravenous fluids, often having to resort to hemodialysis in patients with acute kidney injury. In the presence of severe hypercalcemia unresponsive to hydration, the use of bisphosphonates should be considered. In fact, bisphosphonates cause a reduction in serum calcium starting from 12 to 48 h after administration, with a persistent effect for 2–4 weeks. Instead, treatment with glucocorticoids appears more effective in patients with calcitriol-producing tumors and lymphomas, both Hodgkin’s and non-Hodgkin’s ^{[38][43][44][45][46]}[71,76,77,78,79].

Hypomagnesaemia. Hypomagnesemia is defined as a serum magnesium concentration < 1.8 mg/dL ^[47][80].

Different categories of patients are at risk of developing hypomagnesemia, which can occur in up to 50–60% of cases in hospitalized or critically ill cancer patients ^[48][81].

There are several causes that can lead to hypomagnesemia in oncological patients, such as: hypoalbuminemia, chemotherapy based on platinum derivatives; therapy with anti-EGFR drugs (Cetuximab, Panitumumab), which inhibit the magnesium channel regulating renal and gastrointestinal transport; hypercalcemia (due to competition of calcium on the same transporter as magnesium in the loop of Henle); prolonged diarrhea; blood transfusions; drugs that interfere with renal tubular magnesium transport (loop diuretics); bisphosphonates; corticosteroids; proton pump inhibitors; antibiotics; antiviral drugs; short bowel syndrome; and pancreatic insufficiency (post-surgery) ^{[49][50][51][52][53][54][55][56][57][58][59][60][61]}[82,83,84,85,86,87,88,89,90,91,92,93,94].

Symptoms of hypomagnesemia include inappetence, nausea, vomiting and asthenia. An emergency condition can be indicated by the onset of behavioral alterations (confusion, agitation, depression), neuromuscular hyperexcitability (cramps, hyperreflexia of deep tendon reflexes, muscle contractions), and arrhythmias or ECG-graphic alterations (lengthening of the QT interval, ventricular tachycardia, torsade de pointes, ventricular fibrillation) ^[48][49][57][81,82,90].

However, the measurement of magnesemia is not a routine examination in cancer patients and is reserved only for patients receiving Cetuximab and Panitumumab therapy. Therefore, this condition must be detected based on clinical symptoms. In particular, hypomagnesemia should be suspected in the presence of hypocalcemia and hypokalemia, especially in patients taking the previously mentioned drugs.

The treatment is based on magnesium supplementation, depending on the dosage of magnesemia. The treatment for grade 2 hypomagnesemia (<1.2 mg/dL) involves using oral magnesium oxide, magnesium gluconate, or sulfate. For grade 3–4 hypomagnesemia (<0.9 mg/dL), the use of intravenous magnesium sulfate is necessary and cancer treatment should be suspended.

Significant magnesium supplementation is also required in patients with diarrhea, vomiting, or flu syndrome with an initial state of dehydration or major surgery ^{[62][63][64][65]}[95,96,97,98].

Adrenal insufficiency. Adrenal insufficiency is a life-threatening disorder caused by deficient glucocorticoid production, with or without mineralocorticoid underproduction, by the adrenal gland. In cancer patients, this condition often results from inadequate interruption or suspension of ongoing steroid therapy, leading to altered adrenal gland function or, rarely, from the use of immunotherapy drugs (anti-CTLA4 and anti-PD1). Less frequently, adrenal insufficiency arises from an alteration of the hypothalamic-pituitary axis, due to the altered production of corticotropin and, therefore, cortisol ^[66][67][99,100].

Adrenal insufficiency can occur acutely or chronically. Autoimmune-based hypophysitis can occur in patients treated with anti-CTLA4 drugs alone (mean incidence 13%) or in combination with anti-PD1 drugs and, less frequently, with anti-PD1 or anti-PDL1 drugs alone. Male gender and advanced age are risk factors for the onset of immunotherapy-related hypophysitis.

From a neuroradiological point of view, upon MRI of the brain, the pituitary is often enlarged. This sign, although not always present, is a specific and sensitive indicator of hypophysitis that precedes clinical symptoms and laboratory alterations ^{[68][69][70][71]}[101,102,103,104].

The timely diagnosis of iatrogenic hypophysitis is based on clinical suspicion and laboratory tests (hormonal dosage of ACTH and cortisolemia), performed at baseline and then at regular intervals. The diagnostic difficulty is often also linked to the presence of non-specific symptoms, often not unequivocally attributable to endocrinopathy. Symptoms of adrenal insufficiency include general malaise, asthenia, nausea, confusion, headache, hypovisus, orthostatic hypotension, abdominal pain, fever and, finally, coma ^[72][73][74][105,106,107].

Secondary autoimmune adrenal insufficiency from antineoplastic drugs is usually permanent and requires chronic supplemental treatment. In emergency or urgency settings, high-dose hydrocortisone treatment and hydration with physiological solution are necessary. Hydrocortisone is the preferred steroid for subsequent chronic therapy, with 2–3 administrations per day, simulating the circulating levels of glucocorticoids based on the circadian rhythm of secretion ^[75][76][108,109].

Superior Vena Cava Syndrome (also known as mediastinal syndrome) occurs as a result of an obstruction to blood flow in the superior vena cava. The thrombotic phenomenon in oncological patients can be due to various causes, including direct invasion of the superior vena cava by the neoplasm, extrinsic compression, or the presence of a central venous catheter.

This syndrome is determined by the presence of malignant tumor pathology in 80% of cases. The tumors most frequently associated with superior vena cava syndrome include lung cancer, Hodgkin’s lymphoma and metastases. The cardinal symptoms, which can manifest acutely, constituting an emergency situation, are dyspnea, cough, swelling of the neck, confusion and headache. Other typical signs include cyanosis, plethora, edema and distended veins on the face, neck and chest ^{[77][78][79][80]}[110,111,112,113].

Diagnosis is based on radiological imaging (chest CT), which identifies not only the cause but also the degree of superior vena cava obstruction and collateral venous supply. Radiotherapy is an emergency treatment. A targeted therapy based on the etiology is then necessary: chemotherapy, radiotherapy and possible placement of a stent in the case of tumor pathology; removal of the central venous catheter or fibrinolysis in the case of non-tumor disease ^[81][82][83][114,115,116].

Venous Thromboembolism.

Cancer-associated thrombosis includes both venous thromboembolism (VTE) and arterial events. Despite improvements in cancer treatment, the incidence of this event has increased in recent years and is associated with decreased survival and worsening quality of life, including increased mortality. This event would be related mainly to the type of tumor (pancreatic, stomach and nervous system tumors have the highest risk), risk factors related to the patient and the specific oncological treatment. Several mechanisms correlated with the onset of thrombosis have been highlighted: the most important would be determined by the release of procoagulant substances by the tumor itself, with consequent activation of the coagulation cascade and platelets (such as, for example, tissue factor and podoplanin) ^{[84][85][86][87]}[117,118,119,120].

The suspected diagnosis is mainly based on the clinic, as signs and symptoms may be nonspecific. Pretest probability assessments, laboratory tests and specific diagnostic tests (color Doppler ultrasound, ultrasonography, CT) are used for diagnosis. The therapy is based on the use of anticoagulant drugs (low molecular weight heparin or direct oral anticoagulants), also taking into account the risk of bleeding and any patient co-pathologies. Therefore, individualized treatment should also be considered in the presence of VTE ^[84][88][89][117,121,122].