|Year : 2015 | Volume
| Issue : 1 | Page : 1-10
Oncological emergencies for the internist
Umesh Das, KC Lakshmaiah, TM Suresh, K Govind Babu
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
|Date of Submission||06-May-2014|
|Date of Decision||09-Dec-2014|
|Date of Acceptance||24-Dec-2014|
|Date of Web Publication||12-Feb-2015|
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, No. 5, OPD Block, Bengaluru - 560 029, Karnataka
Source of Support: None, Conflict of Interest: None
An oncologic emergency is defined as any acute, potentially life-threatening event, either directly or indirectly related to a patient's cancer (ca) or its treatment. It requires rapid intervention to avoid death or severe permanent damage. Most oncologic emergencies can be classified as metabolic, hematologic, structural, or side effects from chemotherapy agents. Tumor lysis syndrome is a metabolic emergency that presents as severe electrolyte abnormalities. The condition is treated with aggressive hydration, allopurinol or urate oxidase to lower uric acid levels. Hypercalcemia of malignancy is treated with aggressive rehydration, furosemide, and intravenous (IV) bisphosphonates. Syndrome of inappropriate antidiuretic hormone should be suspected if a patient with ca presents with normovolemic hyponatremia. This metabolic condition usually is treated with fluid restriction and furosemide. Febrile neutropenia is a hematologic emergency that usually requires inpatient therapy with broad-spectrum antibiotics, although outpatient therapy may be appropriate for low-risk patients. Hyperviscosity syndrome usually is associated with Waldenstrφm's macroglobulinemia, which is treated with plasmapheresis and chemotherapy. Structural oncologic emergencies are caused by direct compression of surrounding structures or by metastatic disease. Superior vena cava syndrome is the most common structural oncological emergency. Treatment options include chemotherapy, radiation, and IV stenting. Epidural spinal cord compression can be treated with dexamethasone, radiation, or surgery. Malignant pericardial effusion, which often is undiagnosed in ca patients, can be treated with pericardiocentesis or a pericardial window procedure.
Keywords: Oncological emergency, tumor lysis syndrome, hypercalcemia, febrile neutropenia, hyperviscosity, superior vena cava syndrome
|How to cite this article:|
Das U, Lakshmaiah K C, Suresh T M, Babu K G. Oncological emergencies for the internist. J Med Sci 2015;35:1-10
| Introduction|| |
An oncologic emergency is defined as any acute, potentially life-threatening event, either directly or indirectly related to a patient's cancer (ca) or its treatment. Delay in diagnosis and treatment can result in unfavorable outcomes. Once an oncologic emergency has been recognized, the aggressiveness of management should be influenced by the reversibility of the immediate event, the probability of long-term survival and cure, or the ability to offer effective palliative treatment to the patient. The care of ca patients with emergency problems presents a challenge not only for medical oncologists, but also to clinicians involved in emergency medicine. There are many kinds of problems for which ca patients may require assistance in an emergency care facility. The ca patients may often have complex medical problems in addition to the diagnosis of ca, such as coronary artery disease, chronic obstructive pulmonary disease, diabetes mellitus, and hypertension. Most oncologic of emergencies can be categorized as metabolic, hematologic, structural, or adverse effects of chemotherapy agents.  Overall, most ca patients experience one of these complications at some point in the course of their disease.
| Metabolic Emergencies|| |
Metabolic emergencies include tumor lysis syndrome (TLS), hyperuricemia, hypercalcemia of malignancy, syndrome of inappropriate antidiuretic hormone (SIADH), lactic acidosis and hemolytic uremic syndrome.
Tumor lysis syndrome
Tumor lysis syndrome is characterized by a group of metabolic derangements caused by the massive and abrupt release of cellular components into the blood after the rapid lysis of malignant cells.  It is observed most frequently in patients with hematologic malignancies such as acute lymphoblastic leukemia (ALL) and Burkitt's lymphoma after the initiation of cytotoxic therapy, although it may also occur spontaneously and/or in other tumor types with a high proliferative rate, large tumor burden, or high sensitivity to cytotoxic therapy. TLS is diagnosed as per the Cairo Bishop classification system [Table 1].  The release of intracellular metabolites, including nucleic acids, proteins, phosphorus, and potassium, can overwhelm normal homeostatic mechanisms, potentially leading to hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and uremia [Table 2]. The risk factors of TLS are shown in [Table 3].
Prevention and management of tumor lysis syndrome
Since TLS can develop rapidly and is difficult to treat once established, prevention is of prime importance. The most important key for prevention and management of TLS include awareness of its causes, physiological consequences and predisposing risk factors and identification of high-risk patients. Close monitoring of at-risk patients and appropriate interventions are the key to preventing or managing TLS. Aggressive hydration with intravenous (IV) fluid 3 L/m  and diuresis are fundamental to the prevention and management of TLS. The combination of hydration and enhanced urine flow promotes the excretion of uric acid and phosphate by improving intravascular volume, renal blood flow, and glomerular filtration. ,, The use of diuretics may also be necessary to maintain adequate urine output, but use of diuretics is contraindicated in patients with hypovolemia or obstructive uropathy.
One approach to preventing or managing TLS associated hyperuricemia is to block the conversion of xanthine and hypoxanthine to uric acid. Allopurinol is a xanthine analog, which when converted in vivo to oxypurinol, acts as a competitive inhibitor of xanthine oxidase, thereby blocking the conversion of the purine metabolites to uric acid. , Use of allopurinol has been shown to decrease the formation of uric acid and to reduce the incidence of obstructive uropathy caused by uric acid precipitation in patients at-risk for developing TLS. Dose of allopurinol is 100 mg/m  /dose every 8 h (10 mg/kg/day divided every 8 h) PO (maximum, 800 mg/day) or 200-400 mg/m  /day in 1-3 divided doses; IV (maximum, 600 mg/day). Recombinant urate oxidase (rasburicase) is a newer agent use for the prevention and treatment of TLS. It catalyzes the conversion of uric acid to allantoin. Allantoin is an inactive metabolite of purine metabolism and is 5-10 times more soluble than uric acid, so renal excretion is more effective. Recommend dose is 0.15-0.2 mg/kg once daily. Urine alkalinization is controversial. Management of other metabolic abnormalities is summarized in [Table 2].
Hypercalcemia of malignancies
Hypercalcemia of malignancy occurs in 20-30% of patients with ca.  This condition most commonly is associated with multiple myeloma and carcinoma lung, breast, and kidney. Mechanisms of hypercalcemia of malignancy include bone-resorbing cytokines; parathyroid hormone-related peptide secreted by the tumor that binds to parathyroid hormone receptors; tumor-mediated calcitriol production; and ectopic parathyroid hormone secretion. ,
Symptoms of this condition include nausea, vomiting, constipation, progressive decline in mental function, renal failure, and coma. , Hypercalcemia of malignancy is associated with a poor prognosis, with more than 50% of patients dying within 30 days of diagnosis.  Treatment of hypercalcemia of malignancy includes aggressive rehydration followed by diuresis with furosemide. Serum phosphorus should be monitored because hypophosphatemia is common and can worsen the condition.  IV bisphosphonate can effectively manage hypercalcemia of malignancy. Clinical trial showed that zolidronic acid is superior to pamidronate.  Bisphosphonates have been shown to improve quality of life in patients with metastatic bone disease by reducing skeletal-related events, bone pain, and the need for analgesic medications. , Adjunctive treatments include dialysis and glucocorticoid, calcitonin, plicamycin, and gallium nitrate therapies. 
Syndrome of inappropriate antidiuretic hormone
Whenever ca patients presented with normovolemic hyponatremia, SIADH should be suspected. Bronchogenic carcinoma is the most common cause of ectopic source of antidiuretic hormone production, although certain chemotherapy agents can also cause SIADH.  Patients may present with anorexia nervosa, nausea, myalgia, headaches, and severe neurologic symptoms (e.g., seizures, coma). Laboratory testing may reveal hyponatremia and decreased serum osmolarity (<280 mOsm/L) and concentrated urine (100 mOsm/L or more). Treatment of the underlying tumor is the cornerstone of therapy. Emergency care includes fluid restriction and furosemide therapy. Slow correction of serum sodium levels is necessary to avoid central pontine myelinolysis. Hypertonic saline should be considered for patients with severe neurologic symptoms.  Demeclocycline is recommended for persistent hyponatremia or for outpatient treatment of minor symptoms. 
| Hematological Emergencies|| |
Hematologic emergencies include febrile neutropenia, hyperviscosity syndrome (HVS), hyperleukocytosis and leukostasis and bleeding.
Febrile neutropenia is one of the most common complications related to ca treatment, particularly chemotherapy. The condition contributes to 50% of deaths if untreated associated with leukemia, lymphomas, and solid tumors.  Bacterial infections particularly Gram-negative in our setting (Gram-positive organisms are common in western countries) are common in patients with febrile neutropenia, but fungal sources are increasingly prevalent.  Febrile neutropenia is defined as fever of a single oral temperature measurement of >38.3°C (101°F) or a temperature of >38.0°C (100.4°F) sustained over a 1-h period in the setting of neutropenia. Neutropenia is defined as an absolute neutrophil counts (ANCs) of <500 cells/mm  or an ANC that is expected to decrease to <500 cells/mm  during the next 48 h. "Profound neutropenia" is defined as neutropenia in which the ANC is <100 cells/mm  . Febrile neutropenia is a medical emergency. These patients are divided into low-risk and high-risk group. High-risk patients to be those with anticipated prolonged (>7 days duration) and profound neutropenia following cytotoxic chemotherapy and/or significant medical co-morbid conditions, including hypotension, pneumonia, new-onset abdominal pain, or neurologic changes. Such patients should be initially admitted to the hospital for empirical therapy.  Low-risk patients, including those with anticipated brief (<7 days duration) neutropenic periods or no or few comorbidities, are candidates for oral empirical therapy.  Formal risk classification may be performed using the Multinational Association for Supportive Care in Cancer (MASCC) scoring system. MASCC score <21 (high-risk), all patients should be admitted at the hospital for empirical antibiotic therapy if they are not already inpatients. Patients having MASCC score ≥21 (low-risk), may be candidates for oral and/or outpatient empirical antibiotic therapy.  Before starting antibiotics at least two sets of blood cultures are recommended, with a set collected simultaneously from each lumen of an existing central venous catheter, if present, and from a peripheral vein site; two blood culture sets from separate venipunctures should be sent if no central catheter is present. Blood culture volumes should be limited to <1% of total blood volume. Culture specimens from other sites of suspected infection should be obtained as clinically indicated. A chest radiograph is indicated for patients with respiratory signs or symptoms.
High-risk patients require hospitalization for IV empirical antibiotic therapy; monotherapy with an antipseudomonal beta lactam agent, such as cefepime, a carbapenem, or piperacillin-tazobactam, is recommended. Other antimicrobials (aminoglycosides, fluoroquinolones, and/or vancomycin) may be added to the initial regimen for the management of complications (e.g., hypotension and pneumonia) or if antimicrobial resistance is suspected or proven. Vancomycin should not be used as a standard part of the initial antibiotic regimen for febrile neutropenia. These agents should be considered for specific clinical indications, like suspected catheter-related infection, skin or soft`tissue infection, pneumonia, or hemodynamic instability.
Afebrile neutropenic patients who develop new signs or symptoms suggestive of infection should be evaluated and treated as high-risk patients. Low-risk patients should receive initial oral or IV empirical antibiotic doses in a clinic or hospital setting. Ciprofloxacin plus amoxicillin-clavulanate in combination is recommended for oral empirical treatment in low-risk patient. Hospital re-admission or continued stay in the hospital is required for persistent fever or signs and symptoms of worsening infection. If vancomycin or another coverage for Gram-positive organisms was started initially, it might be stopped after 2 days if there is no evidence for a Gram-positive infection.
Empirical antifungal coverage should be considered in high-risk patients who have persistent fever after 4-7 days of a broad-spectrum antibacterial regimen and no identified fever source.
In patients with clinically or microbiologically documented infections, the duration of therapy is depend on the particular organism and site; appropriate antibiotics should continue for at least the duration of neutropenia (until ANC is >500 cells/mm  ) or longer if clinically necessary. In patients with unexplained fever, it is recommended that the initial regimen be continued until there are signs of marrow recovery (ANC >500 cells/mm  ). Alternatively, even if patients remain neutropenic after completion full course of antibiotics and no signs and symptoms of documented infection resume oral fluoroquinolone prophylaxis until marrow recovery. Prophylactic use of hematopoietic growth factors should be considered for patients in whom the anticipated risk of fever and neutropenia is >20%. Hematopoitic growth factors are not generally recommended for treatment of established febrile neutropenia. Flow chart showing the initial management of febrile neutropenia that is very important for internist [Figure 1].
One of the most striking complications in hematological neoplasms. Classically, hyperviscosity presents with the triad of bleeding, visual disturbances, and focal neurologic signs.  Hyperviscosity occurs from a pathologic elevation of either the cellular or acellular fractions of blood.  Viscosity is defined as the internal frictional resistance of the fluid to flow, or in simple terms, the "thickness" of the fluid. , Hyperviscous blood creates sludge and stasis in the capillary beds resulting in clinical manifestations at the tissue and circulatory level.  Waldenstrom macroglobulinemia is the most common cause of HVS followed by multiple myeloma.  IgA myelomas are more commonly (25%) associated with HVS than IgG (<5%).  Light chain diseases are also associated with HVS. 
The classical triad for HVS consists of bleeding, visual disturbances, and focal neurologic signs. However, a variety of end organ damage can also see.  The bleeding typically arises from oozing mucosal surfaces including epistaxis, bleeding gums and gastrointestinal hemorrhage due to impaired platelet function.  Retinopathy caused by thrombosis, microhemorrhage, exudates, and papilledema results in the common visual derangements.  Physicians should consider the diagnosis of HVS if a patient presents with unexplained neurologic symptoms such as visual change or headache in the setting of a concomitant immunoglobulin-producing hematologic condition. ,
Hyperviscosity syndrome is a clinical diagnosis made on a combination of the symptoms discussed above in conjunction with a viscosity of 4 cp or greater as measured by a viscosimeter (normal viscosity is 1.4-1.8 cp).The management of HVS divided into four phases: Supportive therapy, plasma exchange, plasmapheresis, and specific chemotherapy for the underlying hematologic condition. These patients may have high output cardiac failure and despite dehydration, so judicial use of fluid and diuretics is necessary. Antibiotics should be started if there in any sign of infection. Packed red blood cell transfusions cause increase in blood viscosity so it should be avoided until the viscocity is lowered appropriately in anemic patients. Plasmapheresis is the definitive treatment for HVS. After stabilization definitive treatment should be started.
Hyperleukocytosis and leukostasis
Hyperleukocytosis is an extreme elevation of the blast count or white blood cell (WBC) count >100,000/mm  . It occurs in malignant and nonmalignant disorders, especially acute leukemia.  Hyperleukocytosis occurs more frequently in acute leukemia than in chronic one, and its incidence ranges from 5% to 13% in adult acute myeloid leukemia (AML) and from 10% to 30% in adult ALL. ,, Risk factors for hyperleukocytosis include age <1-year, male gender, AML-M4, AML-M5, and select cytogenetic abnormalities (11q23 rearrangements and the Philadelphia chromosome).  Leukocytosis and leukostasis is a medical emergency and mortality rate may approach up to 40% if not treated urgently.  The management of acute hyperleukocytosis and leukostasis involves supportive measures and reducing the number of circulating leukemic blast cells. As chances of development of TLS are very high so prophylaxis of TLS is also the very important step of management. The morbidity of hyperleukocytosis results primarily from the leukostasis syndrome caused by the increased viscosity and sluggish flow of circulating leukemic blasts in tissue microvasculature resulting in organ damage. ,, More recent evidence suggests that interactions between leukemic blasts and the surface of endothelial cells might be responsible for the aggregation in the microcirculation. , Increased production of cytokines and expression of adhesion markers such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and selectin by endothelial cells enables myeloblasts to recruit additional myeloblasts.  This forms a vicious cycle in which increasingly more cells are trapped in the microcirculation [Table 4]. 
Rapid reduction in the number of circulating blast cells (leukocytoreduction) is fundamental to managing hyperleukocytosis and leukostasis syndrome.  Prompt introduction of chemotherapy remains the mainstay of treatment of acute hyperleukocytosis and leukostasis with leukapheresis as an important adjunct.  Hydroxyurea given at dosages of 50-100 mg/kg/day in 3-4 divided doses has been shown to reduce the leukocyte count by 50-60% within 24-48 h. Hydroxyurea should be started at the time of initial diagnosis and continued until the count has decreased to safer levels.  Specific chemotherapy modalities should be initiated after final diagnosis.
Leukapheresis rapidly yields leukoreduction and is the initial treatment of hyperleukocytosis with symptoms.  Leukapheresis involves the removal of circulating cells with re-infusion of leukocyte-poor plasma. Although there is no specific guide line on when to start leukapheresis but it is usually initiated in patients with symptoms of leukostasis or in patients with AML if the blast count is more than 100 × 10 9 /L.  Clinical leukostasis occurs in fewer than 10% of patients with ALL with WBC counts <400 × 10 9 /L and is rarely indicated.  However, children with ALL who have WBC counts more than 400 × 10 9 /L have more than a 50% chance of developing central nervous system, and pulmonary complications and leukapheresis should be strongly considered.  The goal with leukoreduction is to reduce the count to 50,000/mm  or less.  Leukapheresis is associated with an increase in short-term survival.  Direct treatment of the underlying cause is the ultimate therapy.
Bleeding is the most common presentation of ca patients at emergency department (ED) and.it may be due to related to the underlying malignancy, antineoplastic treatment, or nonmalignancy related factors. No matter how extreme the situation, the physician should try to obtain a complete history about the patient including therapies that they have recently received. In additional, the physical examination can provide valuable clues. For example, the presence of multiple sites of diffuse bleeding signals the presence of coagulopathy such as disseminated intravascular coagulation. It should be treated accordingly.
| Structural|| |
Structural emergencies include superior vena cava syndrome (SVCS), epidural spinal cord compression, and malignant pericardial effusion.
Superior vena cava syndrome
Superior vena cava syndrome is a common complication of malignancy, especially in ca lung and lymphoma. The frequency of SVCS varies depending on the specific malignancy. Approximately 2-4% of all patients with lung ca develop SVCS at some time during their disease course. ,,,,, The incidence is higher (10%) in small cell lung ca, due to rapid growth and higher predilection for mediastinal involvement.  SVCS develops in approximately 2-4% of non-Hodgkin's lymphoma but is relatively rare in Hodgkin's lymphoma despite the presence of mediastinal lymphadenopathy. ,, For primary mediastinal large B-cell lymphomas with sclerosis, the incidence has been reported as high as 57% in one series of 30 patients.  Together, lung ca and lymphoma are responsible for over 90% of malignant causes of SVCS.  In the modern era, 60-90% of cases of SVCS are caused by malignant tumors, with the remaining cases accounted for largely by fibrosing mediastinitis and thrombosis of indwelling central venous devices and/or pacemaker leads. 
The most common symptoms are facial or neck swelling (82%), arm swelling (68%), dyspnea (66%), cough (50%), and dilated chest veins (38%).  other symptoms include chest pain, dysphagia, hoarseness, headache, confusion, dizziness, and syncope. Life-threatening signs include stridor, as this is as this is usually indicative of laryngeal edema, as well as confusion and obtundation, since these may indicate cerebral edema.
Management of superior cava syndrome due to malignancy depends on the etiology of the ca, the extent of the disease, the severity of symptoms, and the prognosis of the patient.  Median life expectancy in patients with SVCS is approximately 6 months; and dependents on the underlying malignancy. Intervention needs to consider both treatments of the ca and relief of the symptoms of the obstruction. The treatment options include supportive measures, stent insertion, radiation therapy (RT) alone, chemotherapy alone and combine multimodality. In most cases, the initial supportive management includes elevation of the head, oxygen support, diuretics, and steroids, although none has been proven to be of benefit. This should be followed by confirmation of diagnosis by imaging and interventions to establish the etiology. A histological diagnosis confirming malignancy should be obtained before initiating therapy in a patient with no previous diagnosis of ca. Steroids are often used to decrease swelling but may obscure a histological diagnosis. In patients with life-threatening signs, such as worsening laryngeal edema and stridor, initial placement of an intravascular stent can provide rapid relief without compromising future treatments or diagnostic interventions. No randomized studies have shown the superiority of one approach over the other, and the choice should be tailored to the particular clinical scenario.
Malignant epidural spinal cord compression
Malignant epidural spinal cord compression (MESCC) is a medical emergency advanced neoplasm. It is due to metastasis to the spine or epidural space and compresses the spinal cord.  Patients usually present with acute deterioration of neurologic functions such as monoplegia, paraplegia or quadriplegia. It is of paramount importance that the ED physician appreciate that MESCC is considered a treatable medical emergency, and that prompt management requires swift decision making with the collaboration of specialists such as oncologists, imaging and pathology specialists, and spine surgeons to avoid further deterioration of the patient's neurologic functions. 
Almost all major types of systemic ca can metastasize to the spinal column. Evidence suggests that 2.5-5% of patients with terminal cas have spinal involvement within the last 2 years of illness. In adults, the most common primary tumor site leading to MESCC are the prostate, breast, and lung, each accounting for 15-20% of all cases. Non-Hodgkin lymphoma, renal cell carcinoma, and multiple myeloma account for 5-10%, and the remainder of cases is due to colorectal sarcomas and other unknown primary tumors.  In the pediatric population, neuroblastoma, Ewing sarcoma, Wilms tumor, lymphoma, and soft-tissue and bone sarcoma are the most common types that lead to spinal cord compression.  The most common level of MESCC involvement is the thoracic spine (60-78%), followed by the lumbar (16-33%) and cervical spine (4-15%); multiple levels are involved in up to 50% of patients. 
Patients with malignancy who present with new-onset of neurologic signs and symptoms should undergo emergent evaluation including magnetic resonance imaging of the entire spine. If MESCC is diagnosed, patients should receive an IV loading dose of 10 mg dexamethasone followed by a maintenance dose of 4-6 mg (IV or oral) every 6-8 h. Simultaneously, the spine surgery and oncology teams should be immediately consulted. If indicated, patients should undergo maximal tumor resection and stabilization, followed by postoperative radiotherapy administered in 10-15 fractions with a total radiation dose of 25-40 Gy. In patients for whom surgery is contraindicated, palliative radiotherapy remains the standard of care. Emerging treatment options such as stereotactic radiosurgery and vertebroplasty may be able to provide some symptomatic relief for patients who cannot undergo surgery.
Malignant pericardial effusions
Malignant pericardial effusions often are undiagnosed in patients with ca, although as many as 10-15% of patients with ca will have some degree of pericardial effusion at autopsy,  and some patients with otherwise treatable ca succumb to undiagnosed pericardial effusion. Most effusions develop from metastatic lung or breast ca. Other causes include malignant melanoma, leukemia, lymphoma, RT to the chest wall, and chemotherapy agents. , Echocardiography is the preferred diagnostic study. Acute symptoms are treated with pericardiocentesis or a pericardial window procedure.  Fluid samples should be analyzed with cytology. Chemotherapy, radiation, or sclerosis therapy can prevent fluid reaccumulation. 
| Intravenous side effects of chemotherapy agents|| |
There are a multitude of side effects and allergic reactions associated with the use of chemotherapy agents. Many of these adverse reactions initially are managed by family physicians.
Many chemotherapy agents (e.g., anthracyclines, vinca alkaloids) are irritants or vesicants.  Leakage of these agents onto the skin during infusion therapy can cause extravasation injuries such as severe scarring or contractures if the injury is near joints. Clinical signs of extravasation injuries include erythema, swelling, and necrosis at the infusion site, usually occurring within hours of chemotherapy. Prompt diagnosis is crucial to avoid extensive skin damage.
Treatment includes cessation of infusion treatments, application of heat or ice, avoidance of site compression, and initiation of antidotes.  Patients presenting with erythema should receive rapid referral to an oncologist or plastic surgeon, because extensive debridement occasionally is needed. 
| Gastrointestinal complaints|| |
Dehydration is a serious side effect of ca treatment that often is missed. Up to 30% of patients with ca who have delirium are dehydrated, and as many as 50% of patients treated for colon ca develop dehydration from vomiting, diarrhea, and mucositis.  Treatment includes fluid resuscitation and initiation of antiemetics and antidiarrheals. Obstipation, characterized by hard stools every 3-5 days and abdominal pain, also is commonly associated with narcotic medications and occasionally with neurotoxic chemotherapy agents. If severe, an oncologist should be consulted to consider a change of treatment [Table 5]. 
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]