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C. Raid, M.A.S., M.D.

Clinical Director, Rutgers Robert Wood Johnson Medical School

Severe infection is treated with a 10- to 14-day course of oral vancomycin due to possible higher efficacy in severe cases. Further recurrences are often treated with progressively long courses and tapers of oral vancomycin, although there are no randomized trials to support the practice. Quinupristin/dalfopristin is a 30:70 mixture of these two semisynthetic streptogramin antibiotics. It has been shown to be safe and effective in serious t h a 9 r9 i - n U V d the i Practice of oncology G R 1956 Practice of oncology / Management of Adverse Effects of Treatment infection, and may achieve a more enduring cure than vancomycin. About 20% to 30% of patients experience relapse,289 usually within 2 weeks and at approximately equivalent rates among those treated with metronidazole or vancomycin. Advanced age and continued antibiotic therapy are risk factors for severe, recurrent, and refractory infection. Many gram-negative bacteria are resistant to fluoroquinolones, particularly in patients who have received fluoroquinolone prophylaxis. For extended-spectrum beta lactamase­producing enteric bacteria, carbapenems are the treatment of choice, but a post hoc study suggests that piperacillintazobactam may be used successfully. A rapidly expanding subset of carbapenem-resistant bacteria carry a plasmid-mediated carbapenemase enzyme that hydrolyzes the antibiotic. The dearth of additional effective antibiotics leads to frequent treatment failure even when patients are treated with antibiotic combinations. These pathogens are readily transmitted in hospital wards, and bloodstream infections carry a mortality rate of >50% in hematology-oncology patient populations. Frequently, a carbapenem like doripenem is administered together with colistin and tigecycline. Prolonged infusion of meropenem may result in systemic levels above the minimum inhibitory concentration of some bacteria314,315; alternatively, it is possible the presence of carbapenem results in synergy. No single antimicrobial is effective against 100% of Pseudomonas isolates, which is the reason most authorities recommend combining an antipseudomonal -lactam antibiotic and an aminoglycoside until results of susceptibility testing become available. Colistin administered parenterally322 or aerosolized (in infections limited to the lung)323­325 may be considered as salvage therapy. The continuous infusion of ceftazidime or other -lactam antibiotics has also been used in attempts to prevent or overcome the emergence of resistance during therapy. These bacteria can cause bloodstream infections and device-related infections, and can colonize the gastrointestinal tract, skin, and respiratory tract of immunocompromised or critically ill patients. Acinetobacter is a pathogen that has become endemic in many health-care facilities. Stenotrophomonas isolates are intrinsically resistant to carbapenems and cephalosporins, and may be selected out by prior use of broad-spectrum antibiotics, particularly carbapenems. Surveillance efforts should be targeted identifying patient colonization with the most highly prevalent. Once identified, colonized patients are isolated in order to prevent transmission. Meticulous adherence to isolation precautions, rigorous hand hygiene, and effective environmental disinfection are essential to prevent transmission from colonized patients who are isolated and those whose colonization has not yet been discovered. Important drawbacks of surveillance and isolation are the adverse social and patient safety consequences of isolation. Improved antimicrobial stewardship both in health-care facilities and the community have been shown to reduce rates of colonization with resistant bacteria. Chlorhexidine gluconate 2% daily baths have been demonstrated repeatedly to reduce the risk of acquisition of multidrug-resistant bacteria, in addition to reducing rates of central line­associated bloodstream infections. Measures to prevent acquisition of these bacteria are essential given the increasing complexity and declining success of managing infections with the most highly resistant pathogens. Risks and outcomes of invasive fungal infections in recipients of allogeneic hematopoietic stem cell transplants after nonmyeloablative conditioning. Infectious complications associated with monoclonal antibodies and related small molecules. Infectious complications associated with alemtuzumab use for lymphoproliferative disorders. Risk of gastrointestinal perforation in patients with cancer treated with bevacizumab: a meta-analysis.

This nuance of cancer biology makes liver-directed therapy an attractive approach in the management of metastatic colorectal adenocarcinoma. Another impetus for aggressive liver-directed therapy is the broad availability of effective systemic chemotherapy. It is evident that a subset of patients who undergo resection of their hepatic colorectal metastases will be cured. Longitudinal analyses indicate that the cure rate is approximately 20% of all patients; these studies also demonstrate that recurrences can occur late, such that the declaration of cure cannot be made until 10 years after surgical resection. Indeed, tumor characteristics that were once considered contraindications to surgical intervention. As the indications for operative therapy broaden, and as surgical resection is offered to more and more patients with highly aggressive manifestations of metastatic disease, it is unlikely that the chance of actual cure will rise. However, in light of the ever-improving capacity of systemic chemotherapy to prolong survival for patients with advanced disease, it is also likely that aggressive hepatic metastasectomy, when used rationally and in the context of multimodality, multidisciplinary care, may prolong survival. Ablation can be performed intraoperatively during open or laparoscopic procedures, or percutaneously in a nonoperative setting. The less invasive nature of ablation can be attractive for patients who are suboptimal candidates for major operative intervention. Ablation is particularly appealing for cases of colorectal adenocarcinoma metastases that have recurred following previous resection, as it avoids the heightened risks of repeat hepatic resection. A review of single and multi-institutional experiences with thermal ablation for hepatic colorectal adenocarcinoma metastases indicates a risk of local recurrence. The overall survival estimates observed in these series is significantly lower than those associated with hepatic resection; however, this is likely reflective of the significant selection bias that is inherent in any decision to undertake ablation over operative resection. However, there is now accumulating experience with combined hepatic and extrahepatic metastasectomy. For these reasons, operative resection and systemic chemotherapy are typically used in close conjunction with one another, even for patients with readily resectable hepatic metastases. A fair amount of effort has been expended in an effort to measure the benefit of this multimodal approach to patients with resectable hepatic colorectal adenocarcinoma metastases. The largest multicenter prospective randomized trials evaluating the influence of adjuvant systemic chemotherapy are summarized in Table 125. Interestingly, comparatively worse survival outcomes have been described for patients presenting with hepatic pedicle or retroperitoneal lymph node metastases. Thus, it is quite possible that the reason these trials did not show differences in overall survival was because systemic chemotherapy was able to "salvage" patients who developed disease recurrence. Indeed, for patients with radiographic evidence of resectable disease (and whose underlying medical condition permits operative therapy), the decision is generally not whether to give chemotherapy, but when. It is likely that optimal therapy of hepatic colorectal adenocarcinoma metastases involves the multimodal use of systemic chemotherapy and operative tumor resection (or ablation). However, controversy persists regarding the ideal sequencing of treatment for patients with resectable tumors. The routine use of neoadjuvant chemotherapy (administered prior to operative therapy) offers several theoretical advantages: (1) it allows one to measure the chemosensitivity of tumors by observing radiographic evidence of tumoral regression; (2) in circumstances of rapid disease progression, as is the case with synchronous metastases, it allows for a period of safe observation in which other occult foci of metastases may become evident; and (3) it helps to ensure that patients will receive a vital component of multimodality therapy (chemotherapy), even if they develop major postoperative complications that prevent them from completing additional therapy. As the response rate of hepatic colorectal metastases to contemporary chemotherapy has improved to well over 50%, the rationale for using neoadjuvant therapy for drug selection or as a means of monitoring for prognostically adverse disease progression has diminished. Biologic agents such as bevacizumab, which targets the angiogenic vascular endothelial growth factor,59­61 and cetuximab, which targets the mitogenic epithelial growth factor,62,63 have been shown to improve response rates and progression-free survival when used in conjunction with traditional chemotherapy. One concern related to the use of bevacizumab is its potential negative influence on wound healing and bleeding. Although the extent to which preoperative administration of bevacizumab affects perioperative complication rates remains uncertain, a preferred approach has been to delay operative intervention until 4 to 8 weeks after the last administration of bevacizumab; when used in this manner, no significant changes in wound-related complications have been observed. As the efficacy of chemotherapeutic agents against colorectal adenocarcinoma has increased, so too has their side effect profile of hepatotoxicity. Livers afflicted by steatosis appear rounded and pink, and those with steatohepatitis demonstrate fibrotic changes that, over time, can progress to frank cirrhosis; both are associated with higher risks of intraoperative hemorrhage and impaired hepatic regeneration. Oxaliplatin is primarily toxic to endothelial or vascular tissues in the liver, and has been associated with sinusoidal vasodilation and obstruction that appears as a patchy bluish discoloration of the liver; heavy oxaliplatin use has been associated with higher risks of intraoperative hemorrhage.

Diagnostic Modalities Radiographic and Echocardiographic Studies Pericardial effusion should be suspected in the asymptomatic patient with cancer when an enlarged globular water-bottle pericardial silhouette is found on plain posteroanterior and lateral chest Pericardiocentesis Pericardiocentesis is the intervention of choice for patients with hemodynamic instability due to pericardial effusion as removal of as little as 50 ml of pericardial fluid can significantly improve signs and symptoms of acute cardiac tamponade. Echocardiography-guided percardiocentesis is the preferred technique as it minimizes complications and improves the success of the pericardiocentesis by delineating the size and location of the effusion relative to cardiac structures. This procedure can be performed under local anesthesia with intravenous sedation or general anesthesia. A comprehensive review of >800 patients with effusions of different etiologies who underwent subxiphoid pericardiostomy indicated an overall mortality rate of 0. Tetracycline and doxycycline have been most extensively evaluated as pericardial sclerosing agents. Successful placement of the pericardiostomy tube was achieved in 85 patients (92%). Pericardial effusion was controlled in 75 patients (88%); 10 patients (12%) did not respond to sclerosis, 8 of whom subsequently underwent surgical pericardiostomy. Successful sclerotherapy often requires multiple instillations of tetracycline or doxycycline (range, 1 to 8; median, 3); 50 patients required three or more instillations to control their effusions. Treatment-related complications (in decreasing order of frequency) included pain, catheter occlusion, fever, and atrial arrhythmias. The favorable results of this minimally invasive treatment strategy are offset by the need for repeated instillations of the sclerosing agent in order to achieve pericardial symphysis. Partial Pericardiectomy or Pericardial Window via Thoracotomy Pericardial window or pericardiectomy via thoracotomy is performed uncommonly today. However, comparative analysis indicated no difference in recurrence rates of patients treated by subxiphoid pericardiostomy compared with those undergoing transthoracic drainage. The highest success rates were noted in patients with leukemia/lymphoma and patients with breast cancer (93% and 71%, respectively). Forty-five percent of patients with other solid tumors had adequate control of their effusions as well. These authors also reported another Percutaneous Balloon-Tube Pericardiostomy Percutaneous balloon-tube pericardiostomy is an extension of the more commonly performed percutaneous tube pericardiostomy. In balloon-tube pericardiostomy, pericardiocentesis is performed as previously described but 150 to 200 ml of fluid is intentionally left in the pericardial space. Subsequently, dilatation of the needle tract is performed under fluoroscopy using a balloon catheter creating a larger pericardial opening to the subcutaneous space and mimicking surgical pericardiostomy to reduce recurrence. Ziskind and colleagues41 reported that this technique was effective in relieving pericardial effusions in 46 of 50 patients (92%). Procedurerelated complications included fever (six patients), pleural effusion requiring chest tube placement or thoracentesis (eight patients), small pneumothorax (two patients), and right ventricular injury requiring surgery (one patient) for an overall clinically significant complication rate of 18%. Of this group, 36 patients (78%) underwent initial therapeutic pericardiocentesis. Systemic chemotherapy prevented recurrence of effusion in 31 patients (67%); successful control of effusion was achieved in over two-thirds of these select individuals irrespective of whether pericardiocentesis preceded systemic therapy. Hence, the goals of intervention include relief of symptoms and prevention of recurrence if possible. Surgical (subxiphoid pericardiostomy) or medical (ultrasound-guided percutaneous tube pericardiostomy and sclerotherapy) interventions have acceptable risks and provide excellent results. Management of a malignant pleural effusion: British Thoracic Society Pleural Disease Guideline 2010. The safety and versatility of video-thoracoscopy: a prospective analysis of 895 consecutive cases. Intrapleural streptokinase in the management of malignant multiloculated pleural effusions. Intracavitary bleomycin and tetracycline in the management of malignant pleural effusions: a randomized study. Distribution of talc suspension during treatment of malignant pleural effusion with talc pleurodesis. Sclerotherapy for malignant pleural effusions: a prospective randomized trial of bleomycin vs doxycycline with small-bore catheter drainage. Pleurodesis practice for malignant pleural effusions in five English-speaking countries: survey of pulmonologists.

Syndromes

• Fainting or feeling light-headed
• If you are going to drink, have a designated driver, or plan an alternative way home, such as a taxi or bus.
• A single trial of antibiotics (if not given earlier)
• Difficulty with walking and balance
• Hunger
• Redness changing to blueness later
• Joint pain
• Spread of infection to the bloodstream (bacteremia)
• Try over-the-counter pain medications, such as acetaminophen.

Insulin also increases the activity of pyruvate dehydrogenase, acetyl-CoA carboxylase, and glycerol phosphate acyltransferase, reinforcing the effects of increased glucose uptake on the enhancement of fatty acid and acylglycerol synthesis. These three enzymes are regulated in a coordinate manner by phosphorylation-dephosphorylation mechanisms. A principal action of insulin in adipose tissue is to inhibit the activity of hormone-sensitive lipase, reducing the release not only of free fatty acids but of glycerol as well. Adipose tissue is much more sensitive to insulin than are many other tissues, which points to adipose tissue as a major site of insulin action in vivo. Positive and negative regulatory effects are represented by broken lines and substrate flow by solid lines. For an optimal effect, most of these lipolytic processes require the presence of glucocorticoids and thyroid hormones. These hormones act in a facilitatory or permissive capacity with respect to other lipolytic endocrine factors. The mechanism is analogous to that responsible for hormonal stimulation of glycogenolysis (Chapter 19). Lipolysis appears to be more sensitive to changes in concentration of insulin than are glucose utilization and esterification. Insulin also stimulates phosphodiesterase and the lipase phosphatase that inactivates hormone-sensitive lipase. These findings help to explain the role of the pituitary gland and the adrenal cortex in enhancing fat mobilization. Adipose tissue secretes hormones such as adiponectin, which modulates glucose and lipid metabolism in muscle and liver, and leptin, which regulates energy homeostasis. Although leptin protects against obesity in rodents, current evidence suggests that its main role in humans is to act as a signal of energy sufficiency rather than energy excess. The sympathetic nervous system, through liberation of norepinephrine in adipose tissue, plays a central role in the mobilization of free fatty acids. Thus, the increased lipolysis caused by many of the factors described above can be reduced or abolished by denervation of adipose tissue or by ganglionic blockade. Perilipin, therefore, enables the storage and breakdown of triacylglycerol to be coordinated according to the metabolic needs of the body. Activity of the respiratory chain produces heat in addition to translocating protons (Chapter 13). The passage of H+ via thermogenin is inhibited by purine nucleotides when brown adipose tissue is unstimulated. Note the dual role of acyl-CoA in both facilitating the action of thermogenin and supplying reducing equivalents for the respiratory chain. Indeed, it has been suggested that in humans there is a "carbohydrate excess syndrome" due to a unique limitation in ability to dispose of excess carbohydrate by lipogenesis. In birds, lipogenesis is confined to the liver, where it is particularly important in providing lipids for egg formation, stimulated by estrogens. Thus, the tissue is extremely active in some species in arousal from hibernation, in animals exposed to cold (nonshivering thermogenesis), and in heat production in the newborn animal. Though not a prominent tissue in humans, it is present in normal individuals, where it could be responsible for "diet-induced thermogenesis. Norepinephrine liberated from sympathetic nerve endings is important in increasing lipolysis in the tissue and increasing synthesis of lipoprotein lipase to enhance utilization of triacylglycerol-rich lipoproteins from the circulation. Oxidation and phosphorylation are not coupled in mitochondria of this tissue, and the phosphorylation that does occur is at the substrate level, eg, at the succinate thiokinase step and in glycolysis. A thermogenic uncoupling protein, thermogenin, acts as a proton conductance pathway dissipating the electrochemical potential across the mitochondrial membrane (Figure 25­9). Thermogenesis results from the presence of an uncoupling protein, thermogenin, in the inner mitochondrial membrane. The perilipin family of structural lipid droplet proteins: stabilization of lipid droplets and control of lipolysis.