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He has no other past history of significance and takes medications only for hyperten- sion kamagra chewable 100mg. Case 2 A previously healthy 27-year-old woman is the restrained driver in a head-on collision 100mg kamagra chewable. Nutrition Support in the Surgery Patient 43 received 4000mL of crystalloid solutions intraoperatively kamagra chewable 100 mg. Implications of Nutritional Support for Clinical Outcomes Many of the illnesses and injuries subject to surgical intervention and care promote alterations of metabolism that place patients at some risk of malnutrition-specific morbidities 100 mg kamagra chewable. It widely is assumed that mal- nutrition , especially within the context of hypermetabolism , increases the risk of infection , leads to wound-healing failure , prolongs rehabil- itation , and diminishes responses to adjunctive therapies . These consider- ations are undertaken repeatedly during the course of surgical care and may be modulated by changes in patient status and prognosis. It is axiomatic that it is always preferable to provide nutrients via the intestinal tract, but the capacity to effectively and efficiently do so may be altered by changes in clinical condition. The most pressing issue is whether the patient already has manifestations of “malnutrition. Unfortunately, the consensus regarding the most appropriate manner used to assess protein status is lacking, and the clinician often faces the dilemma of a continuum of nutritional situations ranging from seemingly normal to that of severe cachexia and wasting. Readily obtainable parameters, such as weight loss (especially in relation to normal or ideal body weight), circulating protein levels (such as albumin), surrogate markers of immune func- tion (such as lymphocyte count), as well as physical examination for evidence of muscle wasting (loss of temporal or other skeletal muscle mass), should be sought in all patients was done in Case 1. How such parameters translate into nutritional risk is a matter of some conjecture. There is clearly no “gold standard” for determining nutritional status because the influence of disease and injury independently may 44 S. Malnutri- tion appears to be a continuum that is influenced by altered intake and the degree of antecedent/concurrent metabolic stress. At a minimum, accurate documentation of weight loss over prior weeks and months is an indicator of the potential degree of malnutrition. They include (1) patients who are overtly malnourished and require restoration of protein and energy stores in preparation for or in conjunction with other therapies; 3. It is prudent, however, to be attentive to preoperative nutrient intake and urge sup- plemental oral feedings, where possible. The clinician is required to consider the complexity of the surgical/injury process, the magnitude and duration of hypermetab- olism, and the prospects for early return to oral feeding. Despite a general lack of class I evidence to support this decision, few would argue with such a decision. Perioperative and early feeding studies with substantial number of well- nourished or moderately malnourished patients. Fanb 1994 I A randomized prospective study of 124 patients undergoing resection of hepatocellular carcinoma randomized to perioperative intravenous nutrition with 35% branched-chain amino acids, dextrose, and lipid (50% medium-chain triglycerides) for 14 days in addition to oral diet or control group (oral diet alone). There were no significant differences in deaths although most of the benefit occurred in cirrhotic patients undergoing major hepatectomy. Brennanc 1994 I A prospective, randomized trial of 117 moderately malnourished patients randomized to postoperative parenteral nutrition (n = 60, albumin = 3. Heslind 1997 I Of 195 well-nourished patients undergoing esophageal, gastric, pancreatic, or gastric resection randomized to jejunal feedings (n = 97; albumin 4. Dogliettoe 1996 I Their 678 patients with normal or mild malnutrition undergoing major elective abdominal surgery randomized to protein-sparing therapy or no specialized nutrition had similar operative mortality rates and postoperative complication rate. Wattersf 1997 I Patients undergoing esophagectomy or pancreatoduodenectomy were randomized to postoperative early jejunal feedings (n = 13; albumin = 4. Postoperative vital capacity and fractional expired volume were lower in the fed group and postoperative mobility was lower in the fed group in this well-nourished group of patients at low risk of nutrition-related complications. This study was confounded by increased epidural anesthesia in the enterally fed group. Continued Class of Author Year evidence Conclusions Dalyg 1992 I Studied 85 patients randomized to standard (n = 44; albumin = 3. Dalyh 1995 I Studied 60 patients with upper gastrointestinal lesions requiring resection randomized to standard enteral diet (n = 30) or diet supplemented with arginine, omega-3 fatty acids, and nucleotides (n = 30). Patients also randomized to jejunal feedings during radiation chemotherapy tolerated chemotherapy significantly better. Perioperative nutritional support in patients undergoing hepatectomy for hepato- cellular carcinoma. A prospective, randomized trial of total parenteral nutrition after major pancreatic resection for malignancy. A prospective, randomized trial of early enteral feeding after resection of upper gastrointestinal malignancy. Immediate postoperative enteral feeding results in impaired respi- ratory mechanics and decreased mobility. Enteral nutrition during multimodality therapy in upper gastrointestinal cancer patients. Defining the Route of Nutritional Support Specialized nutritional support may be provided intravenously, enterally, or by some combination of both. Although parenteral and enteral nutrition likely promote similar metabolic efficacy, current class I data strongly suggest that enteral feeding is associated with a lower overall rate of complications. No data exist currently to suggest that mortality is influenced adversely by the choice of feeding route. The clinician always should consider feeding options during the decision-making process. While it is clearly preferable to establish an enteral feeding conduit, some conditions may preclude full use of this route for a variable period of time. Once established and maintained by the above criteria, these portals need not be changed routinely unless there is clinical or laboratory evi- dence of dysfunction or infection. Barring a sub- clavian insertion site, other options include jugular vein as well as peripheral catheter insertion sites. Such sites are more prone to complications of infection, dislodgment, and venous thrombosis and should be replaced with a more secure or permanent catheter at the earliest opportunity. Access for Enteral Nutrition Although some patients tolerate direct intragastric tube feedings, this practice is discouraged in patients who are prone to aspiration (criti- cally ill, unconscious, etc. Most patients with severe injury or after laparotomy have gastroparesis, and hence cannot tolerate gastric feed- ings. Some can be placed at the bedside using flexible small-bore tubes, while others require intra- operative, radiographically guided, or endoscopically assisted place- ment. Nutrition Support in the Surgery Patient 49 sis if the dextrose concentration exceeds 10%, and thus this route is more limiting in duration and patient comfort. Defining the Nutritional Prescription The initial approach to defining nutritional requirements in surgical patients assumes no difference either between the routes of feeding or among patients on the basis of antecedent nutritional status. For these initial calculations, it is important to have a measure or a reasonable estimate of preinjury body weight. For subsequent refinements in the prescription, knowl- edge of current fluid and electrolyte status and of organ function is necessary. These equations account for gender, age, height, and weight and provide a rough esti- mate of the basal (nonstressed) energy expenditure. This calculation therefore can be used once these simple parameters are ascertained. In the absence of these parameters, one may utilize the estimates provided in Table 3. While there are other, and perhaps more precise, methods of energy needs assessment, all involve obtaining more detailed biochemical or calorimetric data. Once this calculation has been performed, one next needs to estimate the degree of hypermetabolism arising from the underlying condition. Hence, the prescription for energy needs should encompass this stress factor and be targeted at 1. Consequently, there is an upper limit of the amount of parenteral or enteral glucose that should be administered. Therefore, patients should not receive more than 500 to 600g of glucose/day in an effort to keep their respiratory quotient near 1. Providing a majority of nonprotein calories as glucose, however, promotes reten- tion of nitrogen. Excess levels of glucose promote fat deposition and may be associated with impairment of respiratory function and hyperglycemia. While enteral formulas contain various medium- and long-chain lipid moieties, those available for parenteral administration are primarily omega-6-polyunsaturated long-chain fatty acids derived from vegetable oils. While such formulations are tolerated well by most patients, attention to lipid clearance and lipid sensitive diseases requires vigilance. At a minimum, lipids must be provided at >5% of total calories to prevent essential fatty acid deficiency. Protein While the normal intake of protein in healthy, well-nourished adults is approximately 0. In the absence of measured nitrogen (protein) losses, it is recommended that such patients receive 1. Although there is much discussion about the appropriate composi- tion of protein or parenteral amino acid formulas, little data currently exist to suggest that these more expensive mixtures significantly 3. To date, “designer formulas” for enhancing immune function have been documented to benefit only trauma patients. Documenting fluid status (as discussed in Chapter 4) also requires careful physical examination and a review of intake/output records and changes in body weight to assess this condition. It is essential to evaluate recent laboratory determinations for the presence of preexisting micronutrient imbalances. Dramatic and life-threatening changes in electrolyte concentration as well as other serious metabolic abnormalities may evolve rapidly in patients with serious illness. Patients with heart failure may require limitations of both fluid (reduced volume) and electrolyte (sodium) administration. Similarly, patients with renal insufficiency require attention to both volume and several electrolyte levels. Lowry should continue to receive adequate calories, with adjustments in the glucose load depending on the level of tolerance. Specialized amino acid formulas for hepatic failure may be used judiciously in selected patients. Basic Formulations for Nutritional Support Although there are numerous options for providing both enteral and parenteral formulations, the basic requirements are outlined below and in the referenced tables. The reader is referred to more detailed descrip- tions of these prescriptions elsewhere. In addition, the provider must be aware of the varying content of electrolytes in these formulations as well as of other micronutrients and vitamins (such as vitamin K). The latter, for instance, may not be appropriate for patients requiring anticoagulation therapy. An extensive listing of currently available enteral and parenteral nutrition formulations is provided in Tables 3. This is intended as a template for the initial prescription and should be modified according to clinical conditions. Enteral Formulas There are several basic categories of enteral formulas: Standard, isotonic formulas contain an appropriate balance of carbo- hydrate, protein, and fat and usually are tolerated well because of low osmolarity (approximately 300mOsm/L) and caloric density (1. These are considered low-residue diets in that they do not contain fiber and are used in stable patients with significant hypermetabolism. Standard, fiber-containing formulas are similar to the isotonic prod- ucts and usually contain both a higher protein content as well as soluble and insoluble fiber. These often are fed to critically ill patients via jejunostomy tubes and appear to reduce the incidence of diarrhea. Osmolarity is higher than standard formulas and the propensity for diarrhea is increased. Elemental/peptide-based formulas contain predigested proteins that may promote absorption in patients with malabsorption. Their higher osmolarity and lower fat content require a slower infusion rate initially. Special formulas for organ dysfunction have been designed specifi- cally for patients with established or evolving organ failure. Novamine Travasol TrophAmine 15% 10% 6% Protein equivalent (g/100mL) 15 10 6 Total nitrogen (g/100mL) 2. Order laboratory tests to monitor complications and efficacy of nutritional therapy. Hold feedings for 4 hours if the residual is greater than the hourly rate, and notify physician if two consecutive measurements are excessive. Irrigate feeding tubes with 20mL of tap water after each intermittent feeding or t. Nutrition Support in the Surgery Patient 57 las for renal and hepatic failure as well as newly promoted “immune enhancing” products are available. These formulas may prove useful in managing the complications associated with specific conditions, although evidence that they prolong life is limited. Complications of Enteral Feeding: The most common complications of enteral feeding include diarrhea, aspiration, vomiting, distention, metabolic abnormalities, and tube dislodgment. Aspiration is reduced by avoiding intragastric feeding in patients with reflux or in those who must be recumbent. Gastric residual volumes should be checked regu- larly, and prokinetic agents may benefit some patients. Diarrhea may represent a more complex diagnostic dilemma, and patients should be evaluated for Clostridium difficile infection and other medications as an etiology.

Modern molecular biotechnology permits the production of large amounts of tailor-made material 100 mg kamagra chewable. The antigen binding site of IgG molecules represents the homing part 100mg kamagra chewable, which specifically interacts with the target (cells kamagra chewable 100mg, pathogens kamagra chewable 100 mg, tissue) . The sites that are responsible for the pharmacological effects of IgG , such as complement activation and macrophage interaction , are located at the stem part of the Y . The rest of the molecule forms the connection between the homing device and the pharmacologically active sites and also contributes to the long blood circulation characteristics of the IgG molecule , which has an elimination half-life much greater than 24 h . Often, the full antibody molecule (Mw 150 kD) is not utilized for targeting, but the antigen binding domain carrying the Fab (Mw 50 kD) fragment, or even smaller fragments (single chain antibodies, Mw 25 kD) can be used. The present generation of murine monoclonal antibodies is now being replaced by humanized or human antibodies. Antibodies have received most attention as potential homing devices, but other potential candidates are emerging, in the cytokine and the growth hormone family and, finally, among the adhesion molecules that play a role in the homing of inflammatory cells to inflammation sites. Active targeting strategies for soluble carriers include attaching rather simple homing devices such as galactose, for targeting to liver parenchymal cells (see Table 5. However, a number of disadvantages are also associated with the use of soluble carriers: • Limited drug loading capacity: poor stoichiometry of drug to carrier limits the mass transport mediated by the drug carrier. Examples of toxins are ricin, diphtheria toxin and abrin, which are all glycoproteins. Their toxicity is based on their ability to block protein synthesis at the ribosomal protein assembly site. They are normally extremely toxic and not suitable for therapeutic purposes because they induce liver and vascular toxicity, even at low dose levels. Chain A (Mw 32 kD) blocks the ribosomal activity, and chain B (Mw 34 kD) is responsible for cell entry of the A chain. Unfortunately, studies completed so far show that the present generation of immunotoxins lack specificity and are also immunogenic; a major fraction still ends up in the liver and causes toxicity, and severe side- 116 Figure 5. Attempts are being made to reduce liver uptake, by blocking or removing certain ligands on the ricin molecule which recognize receptors on liver parenchymal cells. Here again, the emphasis is on the improvement in drug disposition conferred by the carrier and homing device, as well as the protection offered by the system against premature inactivation. The drug moiety can be bound via either a direct linkage, or via a short chain “spacer”. The spacer overcomes problems associated with the shielding of the drug moiety by the polymer backbone. The spacer allows greater exposure of the drug to the biological milieu thereby facilitating drug release. A targeting moiety, which can be either an integral part of the polymer backbone or covalently bound, may also be incorporated into the system. A crucial feature of such carrier systems is their solubility, which enables them to be taken up into target cells by the process of pinocytosis (which has been described in Section 1. Through an endosomal sorting step, the carrier reaches the lysosomes where it is exposed to the actions of a battery of degradative enzymes. The drug-carrier linkage is designed to be cleaved by these enzymes, liberating free, active drug that can leave the lysosome by passage through its membrane, reaching the cytoplasm and other parts of the cell. Intra-lysosomal release of the drug from the carrier can also be achieved by making the drug-carrier linkage acid-labile, as the lysosomal interior has a pH of approximately 4. Enzymatic cleavage breaks the peptide bond between the terminal glycogen and the daunosamine ring, liberating free doxorubicin, which can diffuse to the cytoplasm and nucleus where it (presumably) exerts its action. Targeting systems that have been investigated include: • galactose: for targeting to parenchymal liver cells; • melanocyte-stimulating growth factor: for targeting to melanocytes; • monoclonal antibodies: for targeting to tumors. Interestingly, the doxorubicin-polymer conjugate alone, without a homing device, showed an enhanced therapeutic index in animal models and considerable accumulation of the drug in tumor tissue. After optimizing conjugate performance in terms of doxorubicin “pay load” and desired molecular weight range of the polymer backbone, clinical grade material is now available and clinical trials are in progress to evaluate the potential of this concept. However, a major limitation of these systems is their inability to cross intact endothelial barriers and leave the general circulation. However, sterically stabilized particulate carriers have extended circulation times and can remain in the blood, either acting as circulating drug reservoirs, or they may slowly escape from the blood pool at pathological sites with increased vascular permeability. Intra-arterially administered particles with dimensions exceeding 7 µm will be trapped in the closest organ located upstream; for example, administration into the mesenteric artery leads to entrapment in the gut, into the renal artery leads to entrapment in the kidney etc. This approach is under investigation to improve the treatment of diseases in the liver. Active targeting strategies for particulate systems are similar to those discussed for soluble macromolecular systems (see Table 5. The lipid molecules are usually phospholipids, amphipathic moieties with a hydrophilic head group and two hydrophobic chains (“tails”). Such moieties spontaneously orientate in water to give the most thermodynamically stable conformation, in which the hydrophilic head-group faces out into the aqueous environment and the lipidic chains orientate inwards avoiding the water phase; this gives rise to bilayer structures. In order to reduce exposure at the edges, the bilayers self-close into one or more concentric compartments around a central discrete aqueous phase. Dependent on the preparation protocol used, liposome diameters can vary between 0. Depending on the physico-chemical nature of the drug, it can either: • be captured in the encapsulated aqueous phase (i. Thus liposomes can serve as carriers for both water-soluble and lipid-soluble drugs. The liposomal encapsulation of a wide variety of drugs, including antitumor and antimicrobial agents, chelating agents, peptides, proteins and genetic material have all been described. Bilayer composition can be almost infinitely varied by choice of the constituent lipids. Liposomal bilayers may also accommodate sterols, glycolipids, organic acids and bases, hydrophilic polymers, antibodies and other agents, depending on the type of vesicle required. The rigidity and permeability of the bilayer strongly depend on the type and quality of lipids used. The alkyl-chain length and degree of unsaturation play a major role For example, a C18 saturated alkyl chain produces rigid bilayers with low permeability at room temperature. Such systems are more stable and can retain the entrapped drug for relatively longer periods, whereas more “fluid” bilayer systems can be prepared if a more rapid release is required. As phospholipid bilayers form spontaneously when water is added, the important challenge in liposome preparation is not the assembly of simple bilayers (which happens automatically), but in causing the bilayers to form stable vesicles of the desired size, structure and physicochemical properties, with a high drug encapsulation efficiency. There are many different approaches to the preparation of liposomes; however, they all have in common that they are based on the hydration of lipids: Liposomes represent highly versatile drug carriers, offering almost infinite possibilities to alter structural and physicochemical characteristics. This feature of versatility enables the formulation scientist to modify liposomal behaviour in vivo and to tailor liposomal formulations to specific therapeutic needs. It has taken two decades to develop the liposome carrier concept to a pharmaceutical product level, but commercial preparations are now available in important disease areas and many more formulations are currently undergoing clinical trials. Examples of the different applications and commercial products of various types of liposomal systems are given below. Most of the early work on liposomes as a drug-carrier system employed this liposomal type. Conventional liposomes have also been used for antigen delivery and a liposomal hepatitis-A vaccine has received marketing approval in Switzerland. A commercial product based on conventional liposomes has been introduced for the parenteral delivery of the anti-fungal drug, amphotericin B, which is poorly tolerated in conventional formulations. Two other lipid-based formulations of amphotericin B have also recently been commercially introduced: • Abelcet consists of ribbon-like structures having a diameter in the 2–5 µm range. In spite of the large differences in structural features (a further example of “liposomal” versatility), all formulations have been shown to greatly reduce the toxicity of amphotericin B, allowing higher doses to be given and thereby improving clinical efficacy. DaunoXome liposomes are also long circulating liposomes, in this case encapsulating the cytostatic daunorubicin. Although a non-stealth system, long circulation times are attained by using a particularly rigid bilayer composition, in combination with a relatively small liposome size. The encapsulation of these anthracycline cytostatics in liposomes effects a modified biodistribution of the drug; the drug is distributed away from the heart, where it can exert considerable toxic effects, and is preferentially taken up by solid tumor tissue. The primary focus of their use has been in the targeted delivery of anticancer agents. The stability of these micelles depends on the nature of the hydrophilic and hydrophobic effects. Micellar systems based on amphipathic block-copolymers have gained most attention as intravenously administered drug carrier systems over the years. These block-copolymers form micelles in aqueous solution with spherical core/shell structures and diameters around 20–40 nm (Figure 5. The hydrophobic core of these micelles can be loaded with a hydrophobic drug such as doxorubicin. After intravenous administration the micelles tend to accumulate at tumor sites and release the entrapped drug there. Polymeric micelles loaded with doxorubicin have shown strongly increased antitumor activity in animal models. Work in progress to optimize the performance of polymeric micelles includes varying the copolymer characteristics, drug pay load, covalent binding strategies and using other types of drugs. Drug loading efficiency varies widely between different drugs, monomers and reaction conditions. Poor drug loading is therefore generally achieved for alkaline drugs because the polymerization reaction takes place under acidic conditions. Poly(butyl cyanoacrylate) nanoparticles are degraded fairly rapidly (1 day), whereas poly(hexyl cyanoacrylate) nanoparticles take a number of days to degrade. Poly(alkyl cyanoacrylate) nanoparticles accumulate in the liver (60–90% of the injected dose) and the spleen upon iv injection, with the macrophages in the liver being their major target. Nanoparticles loaded with doxorubicin have shown a markedly enhanced therapeutic index in a number of animal tumor models. Release of drug from the Kupffer cells upon breakdown of the nanoparticles in the lysosomal system (see Figure 5. Another application where these nanoparticles have been shown to have large therapeutic promise is the killing of pathogens that are specifically located in the Kupffer cells in the liver. The lipid core material consists of cholesterol and other lipids (cholesterol esters, triacylglycerols and phospholipids) which are transported in plasma and other body fluids in the form of lipoproteins. These endogenous lipid carriers have been studied for the site-specific delivery of lipophilic drugs. This system is being investigated for the targeting of hydrophobic antiviral prodrugs to parenchymal liver cells in viral hepatitis. This can be chemically cross-linked by the addition of a cross-linking agent such as glutaraldehyde or butadione, or thermally cross-linked by applying heat. The size of the particles is based on the droplet size of the initial emulsion, and can range from 15 nm–150 µm. The preparation, properties and degradation of these polymers have been discussed extensively in Chapter 4 (see Section 4. They are based on several different families of synthetic, non-ionic amphipatic molecules. At present, there is rather limited experience with niosomes as a parenteral delivery system and no clear advantages over liposomal systems have been established yet. The typical pharmaceutical considerations described above were not dealt with seriously in the early days of drug carrier research, thus early drug-carrier systems were associated with long gestation periods from product development to product marketing. The time-frame associated with the development of a drug targeting concept to a targeted drug product can be illustrated by the “liposome story”. Liposomes were originally used as biochemical tools for the study of cell membrane behaviour in the 1960s; the idea to use them as drug carriers was subsequently developed in the early 1970s. It took more than twenty years to develop the system from a concept to the first commercial parenteral liposome preparation carrying a drug (amphotericin B). Although this may seem 127 like quite a long gestational period, it must be remembered that liposomes were one of the first colloidal carrier systems designed for targeted drug delivery. Comparatively little was known about such systems and many technological and biopharmaceutical hurdles had to be overcome before marketing authorization for the first product could be obtained. Some of these hurdles encountered and solved over the years while developing liposomes as drug carriers include: • Poor quality of the raw material: In the early 1980s, the quality of lipids of several suppliers could vary considerably, both in quantitative and qualitative terms. Interestingly, over the years, the price per unit has dropped considerably while the quality has improved. Therefore a full physicochemical characterization of pharmaceutical liposomes is required in early stages of a development program (Table 5. In later development stages, these quality control assays can be used to obtain regulatory approval and to ensure batch-to-batch consistency. Biochemists, who worked with drug-loaded liposomes in the early days, had a completely different perception of “stability”, reproducibility, upscaling and toxicity than pharmaceutical scientists, who are familiar with the development of pharmaceutical formulations. For example, for a biochemist, a shelf life of a week at −70 °C may be acceptable, whereas a pharmaceutical product would be expected to have a minimum shelf-life of two years, preferably without refrigerator cooling. It took several years and considerable “mental adaptation” to bridge this cultural gap. Currently, quality is ensured by improved purification schemes, the introduction of validated analytical techniques and a better insight into lipid degradation mechanisms leading to better shelf-life conditions (Table 5. In addition, liposomal development has provided fundamental knowledge on the fate of particulate systems in vivo and how this fate can be manipulated for therapeutic gain. It should not exert side-effects, neither on its way to the therapeutic target, nor at the target site, nor during the clearance process. These systems have in common that they are indicated for the treatment of life-threatening diseases like cancer, and severe infectious diseases and, therefore, contribute considerably to our therapeutic armamentarium. It has become apparent that multidisciplinary approaches, employing the combined forces of such disciplines as molecular biology, biotechnology, pathology, pharmacology, immunology, pharmaceutical sciences, engineering, clinical sciences etc. In particular, insights into the anatomical, physiological and pathological constraints to the targeting concept have been growing fast over the past two decades.

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The surgeon closed the neck 100 mg kamagra chewable, and the patient went home 6 hours later; he was able to swallow and felt only some mild discomfort 100mg kamagra chewable. Salivary Glands Parotid tumors are much more frequent than tumors in the other salivary glands kamagra chewable 100mg, and most are benign kamagra chewable 100 mg. All tumors are removed under general anesthesia , dissecting the gland containing the tumor off the facial nerve . The tumor is never just lifted out of the glandular tissue because doing so leads to a high rate of recurrence , with difficulty of cure thereafter . Pleomorphic adenoma , the most common benign parotid tumor , can become very large, and removal should be under- taken early when cure and safe removal are much easier. Tumors of submandibular, sublingual, and minor salivary glands are more likely malignant, and all are treated by complete removal of the gland. Be warned—the submandibular gland can be enlarged because of blockage of the orifice of Stensen’s duct by a “stone” or by cancer of the floor of the mouth. Sites of Head and Neck Cancer Skin Premalignant and low-grade skin cancers are common, but melanoma is the more feared lesion, and we constantly must be on the lookout for it. Therefore, plan biopsy for any pigmented lesion that has changed, is asymmetric, has irregular borders, has variegated color pattern, or is ulcerated. Seborrheic keratoses are the “age spots” seen on the skin; some of these are difficult to differentiate from melanoma. The scalp may be hiding a malignancy, a wen, a buried tick, or the site of a Lyme disease–carrying tick bite. Oral Cavity includes lips, floor of mouth, anterior two thirds of tongue, buccal mucosa, hard palate, upper and lower alveolar ridge, and retro- molar trigone. They often are painful, generally raised or ulcerated, and firmer to the touch than surrounding tissue. The pain from superficial infection often can be relieved through antibi- otic treatment. A patient with a suspected lesion is referred immedi- ately for early biopsy, and, if necessary, a multidisciplinary treatment plan for cancer cure can be instituted. A new onset of hoarseness or painful or difficult swallowing, especially when coupled with a history of tobacco or alcohol use, should prompt a thorough evaluation to iden- tify a primary cancer. The therapy for oral cavity cancers is dependent on the site and cancer stage at presentation. Squamous cell carcinoma of the lip, almost always the lower lip, is the most common oral cavity malignancy. Neck dissection is indicated when neck metastases are present or when the primary cancer is large. Additional treatment is given in cases in which a margin is involved, if there is perineural, vascular, or lymphatic invasion, and for large primary tumors (>3cm). Early-stage lesions not involving bony structures are well treated with radiation therapy. Head and Neck Lesions 191 Cancers of the oral tongue often are associated with occult cervical lymph node metastases. Selective neck dissection is combined with primary resection (usually hemiglossectomy) in all but the most super- ficial lesions. Forty percent to 70% of patients with cancers of the floor of the mouth larger than 2cm have occult lymph node metastases. Because of this, surgical resection includes selective neck dissection or cervical lymph node irradiation. Early cancers of the retromolar trigone or alveolar ridge are treated effectively by transoral resection. More advanced lesions may require mandibulectomy and neck dissection, followed by postoperative radiation. Pharynx The pharynx is a muscular tube that extends from the base of the skull to the cervical esophagus. It consists of three subdivisions—the nasopharynx, the oropharynx, and the hypopharynx (Fig. The nasopharynx extends from the nose openings to the soft palate, and about 2% of the squamous cell cancers of the head and neck begin in this part of the pharynx. These may present with nose bleed, nasal obstruction, headache, or unilateral hearing loss. The majority of these cancers are associated with enlarged cervical lymph nodes at the time of presentation. Sagittal view of the face and neck depicting the subdivisions of the pharynx as described in the text. The oropharynx includes the tonsillar fossa and anterior and poste- rior tonsillar pillars, tongue base, uvula, and lateral and posterior pharyngeal walls. Cancers of the oropharynx commonly present with chronic sore throat and ear pain, and later-stage patients may notice voice change, difficulty swallowing, or pain upon opening the mouth. Small cancers without cervical lymph node involvement can be treated equally well with surgical excision or primary radiation therapy. These often are diagnosed late, metastases are more common, and there is significant morbidity asso- ciated with treatment. The hypopharynx extends from the hyoid bone to the level of the cricoid cartilage. Cancers in this zone are very aggressive and gener- ally have poor outcome irrespective of the therapy chosen. Larynx The larynx is composed of three parts—the supraglottis, the glottis, and the subglottis (Figs. The supraglottic larynx con- sists of the epiglottis, the aryepiglottic folds, the arytenoids, and the false vocal cords. The glottis includes the true vocal cords and the ante- rior and posterior commissures. The subglottic larynx extends from the lower portion of the glottic larynx to the hyoid bone. The primary symptom associated with laryngeal cancer is hoarseness, but airway obstruction, painful swallowing, neck mass, and weight loss may occur. In general, early-stage disease can be managed with radiation therapy or conservation surgery. More advanced cancers require laryn- gectomy, with or without neck dissection, and postoperative radiation therapy or induction (“neoadjuvant”) chemotherapy plus radiation therapy. Sinuses and Nasal Cavity These cancers are rare, and most are squamous cell cancers. Salivary Glands Cancers of the salivary glands can arise in major glands (including the parotid, submandibular, and sublingual) and minor glands. Malignant tumors of the parotid gland are treated with total parotidectomy with preservation of the facial nerve, unless the nerve is involved directly. If the cancer is “high grade,” selective or modified radical neck dissection is added, then usually followed by postoperative radiation therapy. The preepiglottic space is that area anterior to the epiglottis bordered by the hyoid bone superiorly and the thyrohyoid membrane and superior rim of the thyroid cartilage anteriorly. Whether to remove all or most of the thyroid gland has been controversial (Tables 11. Weigel’s chapter on thyroid surgery in Surgery: Basic Science and Clin- ical Evidence, edited by J. T4 Consider whole body scan in 1–2 years Papillary cancer, thyroglobulin less than 5, scan probably Surgical follow-up unnecesary Endocrine follow-up Algorithm 11. The majority of thyroid cancers are the papillary type, Even those lesions classified as “follicular” will behave similar to “papillary” lesions if papillary elements are identified. The final pathology report for our patient was available in the after- noon of the first postoperative day. The surgeon discussed the case with you and advised returning the patient to the operating room for completion total thyroidectomy. The patient had been forewarned about this pos- sibility and reentered the hospital for the procedure, which was carried out without complication 72 hours after the first operation. Papillary thyroid carcinomas are highly curable, spreading locally and into nearby lymph nodes before becoming blood-borne and metastatic to lung, bone, or other sites. Residual disease or metastases usually can be controlled using radioactive iodine (131I); chemotherapy is not effective. Most often, the surgeon does a total thyroidectomy, per- forming a lymph node dissection only when metastases are identified; modified radical neck dissection preserves the sternocleidomastoid muscle, spinal accessory nerve, and jugular vein while cleaning out the lymph nodes lateral to the thyroid and along the trachea. For follicular cancers, the surgical approach is similar; however, these lesions are more likely to spread via the bloodstream and are not as easily controlled with 131I when metastatic. Anaplastic carcinomas are rare thyroid neoplasms that are highly aggressive, extensive (almost impossible to remove), and resistant to therapy. The surgical approach is to try to clear the anterior wall of the trachea and remove all cancer locally, if possible; tracheostomy may be necessary. More recently, the ret proto-oncogene has been used to determine the presence of this cancer prior to changes in the calcitonin levels, allowing even earlier surgical intervention. The surgical approach is aggressive, consisting of total thyroidectomy with meticulous “central compartment” dissection and ipsilateral modified radical neck dissection. In determining the management of papillary and follicular thyroid cancer, the relative risk of recurrence and death is evaluated so as to plan the most effective treatment. In patients with thyroid cancer, a man over 40, a woman over 50, and anyone with distant metastases or cancer involving both lobes or invading adjacent tissues is classified as “high risk. Involvement of one or two nearby lymph nodes may increase the risk slightly but does not have the same significance 198 J. These patients should be fol- lowed with periodic neck examinations and determination of the serum thyroglobulin levels. A very low thyroglobulin level is evidence against papillary cancer (or “Hürthle cell cancer”) recurrence. These patients present with high serum calcium levels and usually a hard mass in the neck. Perils and Pitfalls In any surgery of or near the thyroid, there is a risk of temporary or permanent injury to the recurrent laryngeal nerve and to the exter- nal branch of the superior laryngeal nerve. Removing or destroying too much parathyroid tissue carries the risk of producing severe hypoparathyroidism, which is difficult to manage and very unpleas- ant for the patient. An extremely important complication, because it is life threatening, is an unrecognized postoperative compression of the trachea from an expanding hematoma after thyroid surgery. When called to see a postop- erative thyroid patient who has difficulty breathing, the responding physician must not hesitate to open the incision and spread the closed muscles to relieve the pressure on the trachea by releasing the trapped blood. Summary An overview of this complex topic has stressed diagnostic techniques, lesions, and cancers most frequently encountered in the head and neck. Appropriate referral, careful evaluation, and biopsy of suspicious lesions has been encouraged. We have stressed the need for careful, logical progression from detailed history-taking to choice of appropriate diagnostic testing, only after careful physical examination. Oropharyngeal and neck lesions, in smokers, are especially worrisome because of the greatly increased risk of cancer in these individuals. Abnormalities of the thyroid cause most lumps of the neck that trigger a visit to a physician’s office. Relative contribution of tech- netium-99m sestamibi scintigraphy, intraoperative gamma probe detection, and the rapid parathyroid hormone assay to the surgical management of hyperparathyroidism. Thyroid carcinoma: biological implications of age, method of detection, and site and extent of recurrence. To discuss the anatomy and physiology of the swallowing structures and mechanism, including the physiologic lower esophageal sphincter. To discuss pertinent clinical history and physical examination findings as they relate to structural and functional pathology. To describe various therapeutic options for patients with neurologic, neoplastic, reflex- mediated, and dysmotility-mediated disorders. Cases Case 1 A 58-year-old man presents to your office complaining of difficulty in swallowing. Case 2 A 39-year-old woman presents to your office with burning chest pain, rapidly worsening over 3 years. Case 3 A 72-year-old woman presents to your office with difficulty in swal- lowing for decades. Swallowing Difficulty and Pain 201 Introduction The swallowing mechanism is a complex interaction of pharyngeal and esophageal structures designed for the seemingly simple purpose of propelling food to the stomach and of allowing the expulsion of excess gas or potentially toxic food out of the stomach. Initial evaluation of a patient complaining of difficulty (dysphagia) or pain (odynophagia) with swallowing involves a thorough, focused history and a physical examination. The advent of esophageal motility and pH studies has permitted correla- tion of physiologic data to the anatomic information obtained through radiographic and endoscopic studies. Others may only confuse the diagnosis, having no relationship to the patient’s complaints. In evaluating swallowing difficulty and pain, it is extremely important to relate symptoms to diagnosis, as inappropri- ate therapy actually may worsen the patient’s symptoms or initiate new complications. Anatomic Considerations The esophagus is a muscular tube extending from the cricoid to the stomach. It is composed of a mucosal layer, a submucosa, and a double outer muscular layer (Fig. No serosa is present on the esopha- gus, resulting in a structure that has less resistance to perforation, infiltration of malignant cells, and anastomotic breakdown follow- Ganglia of myentetric plexus [Auerbach] Ganglia of submucosal plexus (Meissner) Epithelium Submucosa Muscularis mucosa Lamina propria Muscularis externa Esophageal gland Longitudinal muscle layer Figure 12. Three layers compose the esophageal mucosa: a stratified, nonkeratinizing squamous epithelial lining; the lamina propria (a matrix of collagen and elastic fibers); and the muscularis mucosae. The squamous epithelium of the esophagus meets the junctional columnar epithelium of the gastric cardia in a sharp transition called the Z-line, typically located at or near the lower esophageal sphincter (Fig. Although the upper third of esophageal muscle is skeletal and the distal portion is smooth, the entire esophagus functions as one coordi- nated structure. Contraction of the longitudinal muscle fibers of the esophageal body produces esophageal shortening. The inner circular muscle is arranged in incomplete rings, producing a helical pattern that, on contraction, produces a corkscrew-type propulsion.

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Patients less than or equal to 5 years comprised 48% (160/335) of patients in the ciprofloxacin group and 46% (159/349) of patients in the comparator group 100mg kamagra chewable. The following table was compiled by the applicant using information recorded in the pharmacy log at each investigator site kamagra chewable 100mg. Due to changes and clarifications of patient data kamagra chewable 100 mg, these patients were removed by the applicant 100 mg kamagra chewable. Clinical Reviewer’s Comment: The reviewer agrees with the applicant’s removal of these 4 patients from the arthropathy algorithm , as they do not appear to be true arthropathies , as defined by the protocol . An additional 21 patients were identified by the applicant that had not already been identified by the algorithm at the end of the study (i . A break down of cases by treatment received can be found in Tables 20 and 21 in Appendix 1 . There were 46 cases of arthropathy in the ciprofloxacin arm and 33 in the comparator arm by one year of follow-up . The p-value from the Breslow-Day test for treatment by treatment route interaction was marginally statistically significant at 0. Clinical Reviewer’s Comment: The one year arthropathy rates by treatment type/disease stratum do not show a statistically significant result (p-value 0. Therefore, the clinical significance of this statistical result is felt to be minimal by the reviewer. Tables 24 and 25 in Appendix 1 detail the ciprofloxacin and comparator cases of arthropathy, respectively, that occurred by Day +42 of follow-up. Clinical Reviewer’s Comment: Tables 24 and 25 in Appendix 1 were created by the reviewer. In the reviewer’s assessment, there were 30 patients who experienced adverse events by Day +42. The reviewer moved one ciprofloxacin patient from the Day +42 to one year grouping based on a reassessment of when the event occurred. In the comparator arm, 21 patients experienced events before Day +42 and 1 also experienced another event after Day +42. Table 26 summarizes arthropathy by Day +42 follow-up by selected baseline characteristics in patients valid for safety. There was a much bigger difference between treatment group arthropathy rates in the United States (21% ciprofloxacin versus 11% comparator) than in the overall rates. The arthropathy rate was higher than the overall rate in Caucasians (14% ciprofloxacin versus 10% comparator) and lower than the overall rate in Hispanics (8% ciprofloxacin versus 3% comparator) and the “uncodable” race group (5% ciprofloxacin versus 3% comparator). The arthropathy rates were quite similar between males and females and consistent between treatment groups. Differences between treatment groups in the arthropathy rate by Day +42 were fairly consistent with the overall rate in the different age groups, and the arthropathy rate in both treatment groups increased with age. The highest arthropathy rate was seen in the ≥12 year to <17 year age group, where the rate was 22% for ciprofloxacin patients and 14% for comparator patients. Theoretical reasons for this difference posed by the applicant for explaining the higher rate in the older patients are: greater physical activity, more accurate ability to report pain, and greater weight across weight-bearing joints of adolescents versus younger children. Theoretical reasons proposed by the applicant for these differences could be differences in concomitant medications, in age, in pre-existing joint problems, in infection-associated arthropathy and in duration of infection. All proposed reasons are potentially valid, but it is not possible to identify the true cause of the differences, due to the nature of the data collection and because many of the variables are correlated with each other. Of these, 5/21 ciprofloxacin patients and 1/13 comparator patients had an event(s) occurring by Day +42 as well as an event(s) occurring between Day +42 and one year. Patients treated with ciprofloxacin were found to have an increased rate of arthropathy compared to patients treated with the non-quinolone comparator. The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not exceed that of the comparator group by more than 6. Since the 95% confidence interval indicated that the arthropathy rate in the ciprofloxacin group could be up to 7. The high percentage of females in both groups is reflective of the fact that the approximately 85% of the entire study population in is female. Of the 46 patients with arthropathy in the ciprofloxacin arm, radiological testing of the affected joint was reported for 9 patients. X-ray results were negative in 6 patients and included: hip for abnormal gait (Patient 301213), lumbosacral area for lumbar pain (302026), hips and spinal cord for back pain and thoracic spine pain (307004), leg (i. One patient had an X-ray of both knees (307015) for pain and swelling and the findings were “bilateral genu valgum”, which was a pre-existing condition for that patient. Another patient (16001) had an ankle X-ray for pain which showed “lateral soft tissue swelling, no radiological evidence of definite osseous abnormality. Of the 33 comparator patients, one patient (37001) had an X-ray for ankle pain and the results were negative. Another patient (401047) had an X- ray of both knees performed for oligoarthralgia, which was also negative. In addition, for each arthropathy classification, it is noted the number of cases which were probably, possibly, or not related to study drug. The arthropathy cases in the ciprofloxacin group were nearly equally divided between definite and possible, with a minority of probable cases. In Table 33B the cases for ciprofloxacin and comparator are grouped by relationship to study drug (i. The majority of cases in each treatment group were possibly related to study drug. Since many patients had more than one event, they were classified by the reviewer based upon the most severe event. Patient 301089 had a right Achilles tendon ache, no history of trauma (possible arthropathy; possibly related to study drug). The relative start of an arthropathy event in relation to the last dose of medication was calculated for all events. As each patient may have had more than one event, the numbers reflect the total number of events, and not patients. In the ciprofloxacin group the mean relative start of an arthropathy event was 102 days (range -12 to 404) and 81 days (range ­ 11 to 363) for comparator. Table 36 shows the arthropathy events which developed while the patient was still receiving study medication. Of the patients with arthropathy, similar percentages (26% for ciprofloxacin and 30% for comparator) developed arthropathy before the end of treatment with study drug. Of the patients with arthropathy, twice as many ciprofloxacin patients as comparator patients (i. Under Body as a Whole, the Day +42 event rates were 14% (46/335) in the ciprofloxacin group versus 10% (36/349) in the comparator group. The largest difference between treatment groups (data not shown) in the Body as a Whole, Day +42 event rates, was for abdominal pain, which was seen in 3% of ciprofloxacin patients versus <1% of comparator patients. The rate of digestive system events by Day +42 was higher in the ciprofloxacin group than in the comparator group (15% [50/335] ciprofloxacin versus 9% [31/349] comparator). The events primarily responsible for this difference (data not shown) were nausea (3% ciprofloxacin versus <1% comparator) and vomiting (5% ciprofloxacin versus 1% comparator). Musculoskeletal events were also higher in the ciprofloxacin group than the comparator group (7% [20/335] vs. The drug-related musculoskeletal adverse events by Day +42 are listed in Table 41. Table 42 lists the patients with arthralgia events occurring by Day +42 for ciprofloxacin and comparator, respectively, Clinical Reviewer’s Comment: Table 42 was created by the reviewer. The number of patients is greater than what is shown in the applicant’s table above (Table 41). For ciprofloxacin there are 16 patients (as opposed to 5) and 8 patients (as opposed to 3) for comparator in the reviewer’s table. The average age for the patients experiencing arthralgia in the two groups was similar (9 years for the ciprofloxacin patients compared to 8 years for comparator patients). The mean duration of arthralgia was 13 days in both groups (in the ciprofloxacin group the range was1 to 49 days compared to 1 to 33 days in the comparator group). As with the overall Day +42 event rates, the drug-related digestive system rates by Day +42 were higher in the ciprofloxacin group (9% ciprofloxacin versus 5% comparator). The largest specific event rate difference between treatment groups in drug-related Day +42 digestive system events was vomiting (3% ciprofloxacin versus <1% comparator). In general, the between treatment group findings by 1 year were similar to those at Day +42, with ciprofloxacin showing higher event rates. The overall 1-year event rate in both treatment groups increased by approximately 5% when compared to the Day +42 event rate. The overall incidence rate of adverse events by 1 year was 45% (151/335) for ciprofloxacin and 36% (124/349) for comparator as shown in Table 44. Body as a Whole event rates in both treatment groups increased by 3% from those by Day +42. Both digestive system and drug-related digestive system events were the same by 1 year as they were by Day +42. Of the adverse events occurring by one year, 47% (71/151) of ciprofloxacin events versus 38% (47/124) of comparator events were considered unrelated to treatment. In the ciprofloxacin group, 13/25 (52%) of arthralgias were considered unrelated to treatment. Of patients treated with ciprofloxacin 34% (113/335) experienced adverse events that were mild in severity, 8% (26/335) had moderate events and 4% (12/335) had severe events. Twenty-three percent (82/349) of comparator patients had mild events, 9% (30/349) had moderate events and 3% (11/349) had severe events. Most musculoskeletal events in both treatment groups were of mild severity (31/36, 86% ciprofloxacin versus 21/25, 84% comparator). In the ciprofloxacin group, 131/151 (87%) events were resolved, compared to 105/124 (85%) in the comparator group. Twenty-two of the 25 (88%) arthralgias in the ciprofloxacin group resolved versus 12/16 (75%) in the comparator group. All other drug-related musculoskeletal adverse events occurred in <1% of either treatment group. Table 47 Drug-Related Musculoskeletal Adverse Events up to 1 Year Follow-Up Patients Valid for Safety Musculoskeletal Adverse Ciprofloxacin Comparator Events N=335 N=349 Any Event 9 (3%) 6 (2%) Arthralgia 5 (1%) 3 (<1%) Arthrosis 2 (<1%) 0 (0%) Bone Pain 1 (<1%) 0 (0%) Myalgia 1 (<1%) 3 (<1%) Joint Disorder 1 (<1%) 0 (0%) Tendon disorder 0 (0%) 1 (<1%) The majority of musculoskeletal adverse events at 1 year follow-up were mild or moderate. Only two ciprofloxacin patients (2015 with arthralgia, and 301100 with myopathy) had a severe musculoskeletal adverse event. Patient 2015 had severe knee pain (no relationship to study drug) and severe hip pain (unlikely related to study drug). One comparator patient (2012) had severe myalgia (fibromyalgia; not considered related to study drug). One ciprofloxacin patient (302026) with arthralgia and 2 ciprofloxacin patients (2015, 301100) with myalgia were “improved” at the end of the study. Patient 302026 had mild hip pain, patient 2015 had moderate fibromyalgia, and patient 301100 had myalgia thought to be related to underlying Duchenne’s disease. These events were not considered by the investigators to be related to study drug. The outcome of two ciprofloxacin patients (13047, 44036) with arthralgia was unknown due to insufficient follow-up. Patient 13047 had moderate bilateral knee pain due to a fall and patient 44036 had mild bilateral ankle pain. One comparator patient (306004) with arthralgia also had an unknown outcome due to insufficient follow-up. In the comparator group, 3 patients (12001, 32008, 307008) with arthralgia and one patient (2012) with myalgia had outcomes of “unchanged” at the end of the study. Table 48 lists the patients with arthralgia events occurring by one year for ciprofloxacin and comparator, respectively, Clinical Reviewer’s Comment: Table 48 was created by the reviewer. The number of patients differs from what is shown in the applicant’s table above (Table 46) because the applicant’s table is inclusive of all patients through one year of follow-up. As shown in Table 48, there 10 patients experiencing 12 events which occurred between Day +42 and one year of follow-up in the ciprofloxacin group and 5 patients with 6 events in the comparator group. The average age for the patients experiencing arthralgia in the two groups was the same (8 years). The duration of the event was not noted in this table (as in Table 42, which contains arthralgia events occurring by Day +42) because the evaluation visits did not occurring as frequently and the duration of the event may be distorted by the timing of the return visits. There were 9 instances where the mean change in the treatment groups differed by 1 degree or more. In 7 of these cases, the ciprofloxacin patients had experienced a mean increase from baseline that was more than that of the comparator patients. In the remaining two instances, ciprofloxacin patients experienced smaller mean increases than comparator patients. Of these, 10 ciprofloxacin and 7 comparator patients had these abnormalities at baseline. Of these, 28 ciprofloxacin patients and 12 comparator patients had the abnormalities at baseline. Most findings were post­ treatment and the majority of abnormal findings occurred less than 5 times per treatment group (data not shown). The most common locations for procedures were renal/kidneys and urinary tract, and the majority of these procedures yielded normal or abnormal, clinically insignificant findings as per the reviewing physician. Four abnormal, clinically significant findings were present post-therapy in the ciprofloxacin group versus none in the comparator group. The abnormal findings were for a muscle electromyogram, head electroencephalogram, brain electroencephalogram, and muscle biopsy.

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