Connie Watkins Bales, PhD

• Professor in Medicine
• Senior Fellow in the Center for the Study of Aging and Human Development

https://medicine.duke.edu/faculty/connie-watkins-bales-phd

The effects of age on survival and other parameters in squamous cell carcinoma of the oral cavity vindhya herbals himplasia 30 caps buy with amex, pharynx and larynx herbals india himplasia 30 caps on-line. Factors contributing to the poorer survival of black Americans diagnosed with oral cancer (United States) herbals amla shikakai reetha shampoo cheap 30 caps himplasia visa. Lifestyle habits as prognostic factors in survival of laryngeal and hypopharyngeal cancer: a multicentric European study herbals choice cheap himplasia 30 caps with amex. Comorbidity in head and neck cancer: a critical appraisal and recommendations for practice herbalsagecom buy genuine himplasia on line. Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: review and meta-analysis. Cervical lymph node metastases-diagnostic, therapeutic, and prognostic implications. Prognostic significance of epidermal growth factor receptor in laryngeal squamous cell carcinoma. Molecular markers in laryngeal squamous cell carcinoma: towards an integrated clinicobiological approach. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. Morphological and wavelet features towards sonographic thyroid nodules evaluation. Computer-aided diagnosis for the differentiation of malignant from benign thyroid nodules on ultrasonography. The use of artificial intelligence to identify people at risk of oral cancer and precancer. An artificial neural network improves prediction of observed survival in patients with laryngeal squamous carcinoma. Nomograms for preoperative prediction of prognosis in patients with oral cavity squamous cell carcinoma. Nomograms are superior to staging and risk grouping systems for identifying highrisk patients: preoperative application in prostate cancer. Nomogram for deciding adjuvant treatment after surgery for oral cavity squamous cell carcinoma. Nomogram for predicting malignancy in thyroid nodules using clinical, biochemical, ultrasonographic, and cytologic features. Nomogram to aid selection of patients for short-stay thyroidectomy based on risk of postoperative hypocalcemia. Pretreatment probability model for predicting outcome after intraarterial chemoradiation for advanced head and neck carcinoma. Development and validation of a nomogram for prediction of survival and local control in laryngeal carcinoma patients treated with radiotherapy alone: a cohort study based on 994 patients. Overall C as a measure of discrimination in survival analysis: model specific population value and confidence interval estimation. Assessing the performance of prediction models: a framework for traditional and novel measures. Regression Modeling Strategies: With Applications to Linear Models, Logistic Regression, and Survival Analysis. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. Everything you always wanted to know about evaluating prediction models (but were too afraid to ask). The goal of the multidisciplinary team is to maximize tumor control and minimize treatment-related sequelae, which impact upon the quality of life. Nowhere in the head and neck region is this more important than in the oral cavity and the oropharynx. The role of the dental surgeon and the prosthodontist is crucial from the day of initial diagnosis until after completion of treatment, rehabilitation and, thereafter, lifelong for management of the long-term sequela and complications of treatment. Intraoperative and perioperative dental management is crucial to the successful outcome of a surgical procedure. Similarly, preradiation assessment of dentition, fabrication of protective devices during radiation and post-radiation management of the radiated dentition are crucial to the successful outcome of treatment with radiation with none or minimal impact of radiation exposure on the teeth. Management of the dentition in patients receiving chemotherapy is equally important and complex. Avoidance of complications due to long-term bisphosphonate therapy is an integral part of the overall care of the patient. These personalized, individually fabricated devices significantly improve form and function and thus the quality of life after treatment of patients with head and neck cancers (1). This should be done prior to any invasive intervention, during the treatment planning phase, either preoperatively or preradiation. The initial examination by the dentist involves assessment of the teeth clinically and by at least a screening orthopantomogram. Septic teeth that are not salvageable are extracted, unless they are in a tumor-bearing area. If possible, restorative dentistry should be completed prior to radiation treatment. Ideally, a period of at least 2 weeks should be available to allow healing of soft tissue manipulations and dental extractions so that mucosal integrity is restored before treatment begins. It must be emphasized that dental extraction in the proximity of the tumor opens up a route for implantation of malignant cells through the alveolar process/dental socket and therefore it should be avoided. However, prolonged dental treatments should be delayed until after completion of cancer therapy because it is imperative that the cancer treatment takes priority over long-term elective dental treatment. The general practice dentist and hygienist can use the interval between initial screening appointment and commencement of external beam radiation therapy to complete all hygiene procedures such as scaling, polishing, soaking, root planning and curettage. Overhanging and faulty restoration can be removed and replaced appropriately and ill-fitting dentures should be corrected. Home care should include infective daily plaque removal and use of soft toothbrushes with application of high-potency fluoride. Fluoride trays are made for most patients and the need for daily topical fluoride is emphasized to reduce the risk of dental caries. Patients are instructed to floss daily and brush their teeth after every meal, which includes liquid supplements, because they contain cariogenic carbohydrates. A toothpaste or gel that contains neutral 1% sodium fluoride is preferred over stenosed fluoride, which has an unpleasant taste and adverse effects such as sensitivity of the teeth and gingiva. One may expectorate as much as desired, but patients should not rinse the mouth clean in the evening, leaving a thin film of fluoride on the teeth while sleeping (1). Dental extractions should be done as soon as possible in those patients that require them (Table 22. Teeth may be extracted if they are decayed and unrestorable, lack opposing teeth, prosthetically useless and are likely to be lost during the course of treatment or in patients who are unwilling to carry out the rigorous oral care and hygiene regimen required. In addition, partly erupted third molar teeth and those with severe periodontal disease should be removed to prevent pericoronitis or other infections. Teeth with periodontal inflammatory disease or non-vital teeth may be kept if the patient is willing to undergo root canal treatment. As previously mentioned, all extractions should be completed in time for mucosal healing to occur prior to starting cancer treatment. These should be smoothed out by filing and, if possible, the mucosa of the gingiva at the extraction site should be closed with sutures (2). Upon extraction, it is imperative to consider alveoloplasty and primary mucoperiosteal flap closure to expedite healing. This is especially true in areas where the alveolus has been expanded to permit delivery of divergent root tips. Areas of thin, friable mucosa overlying bony prominences such as tori or exostosis can also be excised and the bone smoothed out to avoid problems secondary to delay in wound healing. Evaluation of the patient and dental prophylaxis / Oral care during radiation therapy 481 or chemotherapy. The indirect effect on these structures can also result from exposure of the parotid and submandibular glands to radiation with consequent alteration of the composition and quantity of saliva production. Patients who have extensive metallic restorations require custom mouth guards to reduce scatter that causes increased mucositis. These guards should be fabricated in time for them to be delivered before the simulation appointment (1). Patients should be seen by the dentist as necessary, but at least once during the course of their radiation treatment. During this visit, patients should be assessed for the presence of radiation-related side effects. Mucositis generally occurs 5­7 days after initiation of external bean radiation therapy. The extent and intensity of mucosal changes depend on the fractionation, energy source, total dose of radiation and oral and dental status (4). The mucosal reactions on the side of the entering beam may consist of patchy or confluent exudate, whereas the contralateral side may show only erythema. During the course of radiation therapy, the mucosa becomes thin as a result of direct cell death and the sloughing of radically replicating epithelial cells (5). Hot foods, smoking, alcohol or phenol-containing mouth rinses and sodium should be avoided (6). Good oral hygiene is essential to improving oral comfort and reducing the risk of oral contamination. This is easily maintained with frequent rinses and gargles with a solution of one quart of warm water with a teaspoonful of table salt and a teaspoonful of baking soda. Bacterial fungal and viral infections can occur as superinfections with mucositis, but are less likely to induce septicemia in patients undergoing radiation therapy than in patients receiving chemotherapy (7). Candidiasis occurs in most patients receiving radiation therapy to the oral cavity, sometimes during the course of their treatment. It can manifest as pseudomembranous, hyperplastic or atrophic (erythematous or white) patchy lesions (8). The sites most frequently affected are the tongue, buccal mucosa, hard or soft palate or commissure labiorum oris. Clinically, it can manifest as a whitish patch of the oral mucosa that may be removed with gentle pressure on wet gauze. Treatment consists of such topical antifungal agents as nystatin oral suspension or clotrimazole troches depending on the degree of xerostomia (8­10). Patients should be encouraged to follow a soft diet and to receive an adequate caloric and nutrition intake. For patients in whom the tongue is involved, dysphagia may occur, lessening motivation to eat (2). In such patients, a nasogastric feeding tube or a percutaneous gastrostomy may be considered. The acute and long-term side effects of radiation therapy to the oral cavity are summarized in Table 22. This is done preferably with custom-made dental trays applied for at least 1 hour. The severity of xerostomia depends on the total dose of radiation, the source, the fractionation and poor dose delivery. Radiation results in atrophy of salivary gland elements, causing cessation of normal saliva production. The problem is compounded when the patient receives chemotherapy concurrently with radiation. Pharmacologic agents such as pilocarpine and amifostine have been investigated with mixed results for relief of xerostomia. However, most patients obtain symptomatic relief through frequent use of water (1). Other long-term sequelae are related to effects on soft tissue, bone and blood vessels. Irradiation of the extrinsic muscles of mastication can produce fibrosis, which leads to trismus over time. It is crucial for the clinician to bring forth the importance of preventing trismus at every opportunity because difficulty in opening the mouth not only affects the quality of life, but also interferes with adequate post-treatment monitoring of the oral cavity and oropharynx for recurrence or new cancer. Patients should begin to perform this exercise before radiation therapy commences and if the exercises are stopped during treatment they must be resumed as soon as the acute side effects of radiation therapy have subsided. Dental caries and periodontal disease leading to extractions are the most common precipitating factors. Prevention of this complication by rigorous oral hygiene is crucial because conservative measures such as antibiotics, debridement and curettage are effective only in the early stage of this disease process before bone necrosis takes place. Sporadic reports appear in the literature about reactivation of a tumor in this setting. The trial was aborted at 1 year since the placebo group had better outcomes than the treatment group. This is particularly important for extraction of molars since radiation exposure is usually the highest at the angle of the mandible. Alternatively, they may be treated with root canal therapy and then allowed to exfoliate on their own. If extractions are required, it is important to discuss the location of the teeth with respect to the radiation field with the radiation oncologist. Teeth within the field of radiation should be extracted without raising a surgical flap when possible. In addition, the use of low epinephrine-containing local anesthetic and perioperative systemic antibiotics is recommended (12). Serial extraction of teeth a few at a time allows the dentist to observe the progression of wound healing.

Shoulder pain and function after neck dissection with or without preservation of the spinal accessory nerve herbals stock photos 30 caps himplasia order visa. The Frey syndrome: a review and double blind evaluation of the topical use of a new anticholinergic agent klaron herbals generic 30 caps himplasia. Radionecrosis of the mandibula: a retrospective analysis of the incidence and risk factors herbals dictionary generic 30 caps himplasia amex. Resection and immediate microvascular reconstruction in the management of osteoradionecrosis of the mandible herbals good for the heart purchase generic himplasia line. The oral cavity serves as the entryway to the gastrointestinal tract where the process of digestion is initiated with mastication herbals for anxiety order himplasia without a prescription, salivation and propulsion of the food bolus into the pharynx. As mobile structures, the lips ensure oral competence by preventing spillage of contents. The tongue is a mass of skeletal muscle used for grasping food, maneuvering it within the oral cavity and propelling it into the oropharynx in swallowing. The movements of the tongue also help to articulate laryngeal sounds into comprehensible speech. The tongue surface, in addition to having tactile sensation, contains specialized receptors for the specialized function of taste. The oral cavity is bounded above by the hard palate and laterally by the buccal surface of the cheeks. It is lined by a mucosal layer that is adherent to underlying deeper structures such as the periosteum of the hard palate and the cheek musculature. The pliability of the cheek mucosa allows for food pocketing, preventing chewed food from spilling out of the oral cavity during deglutition. In terms of esthetics, the aim of reconstruction should be to resurface/reconstitute the surgical defect so that external facial contour and symmetry are maintained to the greatest degree possible. Since oral cavity cancers are locally invasive they do not respect anatomical boundaries. Due to the high functional requirements of the oral cavity, these specialized tissues should be restored individually as best as possible to preserve function. The traditional reconstructive mantra "replace like with like" holds true for oral cavity reconstruction, perhaps more than in any other region of the body. For example, a combined buccal mucosa and tongue defect may be better reconstructed with a skin graft for the defect of the buccal mucosa and a free flap for the tongue rather than using a single flap for both. Reconstruction in such a way reflects the separate functional and anatomic roles of these two sites. The patient should undergo a complete medical and surgical history as well as a physical examination. For example, the advanced elderly may have conditions precluding lengthy surgery due to a higher 399 400 Reconstructive surgery incidence of postoperative medical complications. They may be better candidates for a pedicled rather than free flap reconstruction or even non-surgical management. Routine imaging is not a necessary part of strictly soft tissue reconstructive planning in most cases; however, in some circumstances, it may be beneficial. Patients with prior neck dissection, radiotherapy or reconstruction may not have useable recipient vessels available. Computed tomography or magnetic resonance angiography suggest vessel patency in advance, while secondarily minimizing unnecessary dissection in the operating room. As virtual surgical planning for osseus mandible and maxillary reconstruction is gaining popularity, imaging of the fibula and other donor sites will become a more common part of the reconstructive workup. Once the details of the extirpation and reconstruction plan are formulated, only then is the patient taken to the operating room. The ideal situation is one in which there are two surgical teams: one responsible for tumor extirpation and a second for reconstruction. Having a single surgeon perform both the tumor ablation and the reconstruction is an enormous and exhausting undertaking. It is often possible for both the ablative and reconstructive teams to operate concurrently, thereby speeding up the surgical procedures and minimizing the length of anesthesia time. Both skin graft types are advantageous in that they are easy to harvest, readily available in abundance and can be used to resurface large defects. Disadvantages include a poor color and contour match, limited neovascularization on structures such as bone or radiated tissues and susceptibility to local trauma. Perhaps the most important aspect of skin grafts is that they are prone to contraction, with negative effects on tissue range of motion, pliability and compliance (1). Small and superficial mucosal defects of the oral cavity can be left open to granulate with spontaneous epithelialization, but with even greater contraction than a graft. Areas with rigid bony support to counteract contraction are most amenable to grafting or secondary healing, particularly the hard palate. They have been used to resurface intraoral defects of the tongue, maxillary oral vestibule, mandible, floor of the mouth and hard palate. Success rates up to 90% have been achieved, with complete epithelialization achieved by 4 weeks. The advantages of acellular dermal matrices over skin grafts include lower potential cost, absence of donor site morbidity, a natural-appearing mucosal surface and comparable functional status. Grafts serve a valuable role in reconstruction because of their simplicity, but the ability to heal needs to be carefully scrutinized in patients who have had prior radiotherapy or will need postoperative radiotherapy. Adjuvant treatments are an integral part of the multimodal treatment plan, particularly for advanced-stage tumors, and that should be taken into consideration while planning reconstructive surgery. An open wound following a failed skin graft reconstruction may delay the timely delivery of radiotherapy with a negative impact on patient outcome. Expeditious healing should be a goal contemplated at the time of planning of reconstruction. Split- or full-thickness skin grafts are straightforward and popular means of resurfacing superficial defects of the hard palate, buccal mucosa, floor of the mouth or tongue. As long as the wound base is vascularized, a skin graft should take reasonably well. Depending upon the defect location, bolsters to minimize skin graft movement are necessary. However, securing the bolster may be difficult in some locations, since it may produce airway obstruction, making some areas more favorable than others. Compared to partialthickness grafts, full-thickness grafts have less secondary contracture, but a higher metabolic requirement to ensure Vascularized tissue can be transferred into ablative defects in a number of ways. Local flaps are elevated from a donor site immediately adjacent to the area requiring reconstruction, whereas regional flaps are brought in from more remote sites. The most common examples of local flaps are cutaneous flaps such as those used to resurface small defects following skin cancer removal. They are generally small, survive via a random blood supply and usually have length to width ratios no greater than 2:1. For this reason, axial flaps can be safely elevated with greater reliability and with length to width ratios of as much as 5:1. Examples of local flaps in the oral cavity include mucosal advancement flaps such as those used for resurfacing of vermilion defects (random blood supply) versus axial mucoperiosteal flaps based on the greater palatine vessels for palatal reconstruction. Local flaps have limited use in the oral cavity since most small defects amenable to these reconstructions can often be closed primarily. Furthermore, small amounts of tension at either the flap donor or recipient site can have significant functional compromise on either speech or swallowing, so a careful balance must be achieved in local flap selection. Depending on the flap length, they reach a significant distance away from the donor site. Regional flaps used for oral cavity reconstruction can be harvested from other intraoral sites. Because they are entirely dependent on an intact blood supply, the flap reach is limited. There is also a paucity of available pedicle flaps that can reach the oral cavity for reconstruction. For example, flaps from the upper torso such as the pectoralis major and supraclavicular flaps lose much of their volume in the distance that is required to reach the oral cavity. The portion of the flap that ultimately provides the reconstruction is at the distal portion of the flap where blood supply is most tenuous. Pedicle flaps usually need to be tunneled into the recipient defect in the oral cavity, creating unwanted bulk in cosmetically sensitive areas such as the neck. Tunneling can also be a source of vascular pedicle constriction leading to flap ischemia. Finally, the direct communication between the intraoral inset and the donor site is an opportunity for donor site bacterial contamination or fistula development. With the advent of the operating microscope and the development of vascular surgery techniques, specialized microsurgical instruments and suture materials were developed, leading to the field of microvascular surgery. Microvascular free tissue transfer, with the ability to repair small vessels accurately, has become a very powerful technique within the reconstructive armamentarium (2). Free flaps have their blood supply temporarily divided at a distant donor site and reconstituted at the recipient site. Such an ability does away with the inherent constraints of pedicled flaps, significantly changing the way in which oral cavity reconstruction is approached. As long as there are adequate recipient vessels, nearly any defect can be reconstructed using a free flap of specialized tissues from around the body. Reconstruction of tongue defects is aimed at restoring the bulk that is lost following resection. Tongue convexity is necessary to contact the palate for speech articulation and to push the food bolus into the oropharynx (3). Small tongue defects can be closed primarily as long as there is no tethering or compromise to mobility. Resection involving greater than a third of the tongue is ideally reconstructed with free tissue transfer. Free flaps can be made sensate by harvesting them with a cutaneous nerve for coaptation with the lingual nerve stump; however, it remains unclear if this has any proven benefit in speech or swallowing (5). Low-volume free flaps, such as a radial forearm, have some spontaneous sensation recovery even in the absence of nerve repair. If the oral cavity defect includes bone in addition to soft tissue, then a decision needs to be made as to whether or not an osteocutaneous free flap is required. Other less widely used osseous flaps include the radial forearm, scapula and iliac crest. As mandible defects involve increasing amounts of soft tissue relative to bone, the balance may shift away from bone in favor of a musculocutaneous flap to obliterate surgical dead space and ensure reliable healing. The only area where bone is an absolute necessity is for the anterior mandible to avoid creation of the Andy Gump deformity. Careful measurements need to be taken, especially of the surface area, as well as the depth of the defect so that a volume assessment can be made. Isolated defects of the buccal mucosa or floor of the mouth generally involve a large surface area, but are small in volume. Fasciocutaneous flaps are also useful because they are pliable, allowing them to conform to contour changes from one part of the oral cavity to another. The alternative option is to combine a fibula with a second flap such as either a free radial forearm or pectoralis. Composite defects of the oral cavity include the intraoral lining, intervening musculoskeletal tissues and external skin. Reconstruction can be performed with a folded multi-island free flap or two separate reconstructions for the internal and external portions. Depending upon the defect location and surface area to volume ratio required, either a thin or thick flap can be used. When more than one skin paddle is required, a flap with multiple perforators is favorable to allow maximal flexibility in the reconstruction. For this reason, the vertical rectus flap or radial forearm flap are preferred because of the ample number of supplying vessels to the skin islands emanating from the axial pedicle. An alternative to creating two independent skin islands is to de-epithelialize an intervening section to create "pseudo-islands," although the degree of mobility is restricted. Because of its large size, it can be used as a donor source of tissue to resurface small defects of the palate, tonsils, alveolar ridge, floor of the mouth and lip vermillion. Tongue flaps can be based dorsally, laterally or from the ventral surface of the tongue. The tongue has a robust blood supply, so these flaps can be harvested safely and reliably. If the surgical history includes a prior neck dissection, patency of the lingual artery should first be confirmed (8). The first stage consists of flap elevation and partial inset into the area requiring resurfacing. Approximately 2­3 weeks thereafter, the second stage is performed with flap division and donor site closure. As an axial pattern flap with an extended length to width ratio, the facial artery must be included along the entire length of the flap (9). Wider flaps can be problematic because of increased donor site complications at the buccal mucosa closure. Prior to flap elevation, the course of the facial artery is verified using a Doppler ultrasound. Inferiorly based flaps are vascularized by the facial artery, whereas the superiorly based flap is nourished retrograde via the angular vessel. If the surgical history includes a prior submandibular gland resection or neck dissection, the facial artery is likely ligated, precluding an inferiorly based flap.

This observation is not entirely surprising because of the bias that would be expected in selecting patients for reconstruction; for instance banjara herbals generic himplasia 30 caps on-line, surgical defects in smaller T3 lesions are more likely to be closed primarily than those in larger T3 lesions jovees herbals cheap himplasia 30 caps with amex, which would be reconstructed with a free flap herbs list himplasia 30 caps buy amex. On a practical basis herbalshopcompanynet buy himplasia 30 caps fast delivery, free flaps have become standard of care following major resection and in this setting the use of free tissue transfer adds tremendously to the functional and esthetic outcome herbs that lower blood sugar proven himplasia 30 caps. While free flap reconstruction of the tongue does not add mobility to or sensation of the flap skin, it prevents tethering of the remnant tongue, fills up the soft tissue defect and retains mobility of the remnant tongue. The use of adjuvant postoperative radiation therapy can also influence functional outcome. Although alterations in speech were reported in one study, patients who received postoperative radiation therapy showed poorer swallowing function than those who did not (7). Again, the selection bias inherent to such a retrospective study does not allow meaningful interpretation of the data since the patients who need postoperative radiation therapy are more likely to have had larger and more ominous primary tumors. Finally, in one study, the benefit of rehabilitation treatment in the form of range of motion exercises was evaluated. It was demonstrated that a benefit in swallowing function was seen in those patients who performed range of motion exercises throughout their rehabilitative process (3). This certainly argues for the routine use of such exercises after treatment of oral cavity tumors. With regard to reconstruction of the surgical defect, several general principles can be applied. The reconstructive procedure of first choice should be the simplest option likely to provide maximal restoration of form and function. Likewise, if a small superficial defect can be adequately resurfaced with a split-thickness skin graft or allowed to heal by secondary re-epithelialization, then the use of free tissue transfer is unwarranted. The second principle in the reconstruction of surgical defects of the oral cavity is to replace like with like. With the evolution of free tissue transfer, this aim is much more readily achievable. The variety of donor sites with their unique composition of bone, muscle, skin and even neural innervation allows most defects to be reconstructed with a satisfactory restoration of form and even sensation (20,21). The challenges that remain in the oral cavity for the reconstructive surgeon include the restoration of intricate sensory and motor function of the resected structures as well as the complex three-dimensional tissues of critical regions such as the oral commissure. It should be realized that the balance in achieving these two overriding principles is often at odds. Striking a balance between the principles of simplicity and sufficiency is governed by the surgical defect, its functional and esthetic implications and the resources available to the head and neck surgeon. Regardless of the clinical situation, a variety 460 Functional outcomes and rehabilitation Table 20. Once the surgical defect has been adequately reconstructed, rehabilitative efforts are directed toward maximizing the function of the residual and transposed tissue. The initial aspects of this rehabilitation process occur shortly after surgery as the operative bed heals and residual sensation and mobility return. Additionally, if innervated free tissue flaps have been utilized, sensation will often return to these tissues with time. During this early postoperative period, it is critical for the patient to maintain maximal mobility. Often progressive increase in the movements of the jaws and tongue over time will prevent fibrosis and longer-term restriction in movement. A special note must be made with regard to the preservation of the ability to open the mouth widely and the prevention of trismus. The prevention of trismus is obviously critical to all aspects of the rehabilitation of speech and swallowing after treatment of tumors of the oral cavity. Any patient who undergoes treatment of a lesion in the oral cavity/oropharynx is at risk for the development of trismus. Performing exercises in which the mouth is opened as widely as possible several times a day can prevent trismus. An easy method of actively promoting jaw excursion is to instruct the patient to use fingers to pull the mandible and maxilla in opposite directions as frequently as possible during the post-treatment phase. A stack of wooden tongue depressors may also be used to progressively widen the interincisoral opening over time. A simple device called a "Cork Screw" fabricated by the dentist is easy to use and is effective in the prevention of trismus. Finally, various commercial devices, such as TheraBite and the Jaw Dynasplint System, are available to act as aids that facilitate active opening of the mouth. If an anatomical defect persists following surgery and adequate healing, prosthetics can often be used to further restore form and function. One area where great success has been observed with this approach is the use of a palatal obturator in the rehabilitation of the post-maxillectomy defect. The obturator restores velopharyngeal competence, prevents nasal regurgitation and preserves the esthetic contour of the cheek. Similarly, a palatal drop prosthesis can be fabricated in those patients who do not have sufficient tongue volume to approximate to the hard palate during the bolus transport phase of swallowing. The sophisticated nature and scope of the speech and swallowing evaluation performed by the speech pathologist is beyond the scope of this text. In simple terms, however, an examination is conducted to investigate any structural or functional deficits. This may include radiographic examination of the swallowing process in the form of a modified barium swallow, flexible endoscopic evaluation of swallowing with sensory testing using a fiberoptic nasolaryngoscope or informal observation. This will likely include various exercises and treatment techniques to maximize the function of the remaining structures as well as to facilitate the adaptation of compensatory strategies. A considerable degree of patience, perseverance and compliance is necessary on the part of both the patient and the caregiver to achieve the goal of optimal rehabilitation. Finally, it should be noted that the best postoperative rehabilitation will not overcome the deficits caused by poor surgical planning that does not respect the functional subunits of the oral cavity. A vivid illustration of this fact is the impact on function of the method of closure of the surgical defect after resection of early anterior tongue lesions. When a transverse wedge of tissue is resected that encompasses the tumor and is closed primarily, minimal functional or esthetic deficits result. In contrast, when the same lesion is resected in a longitudinal fashion resulting in a serpentine elongated tongue, significant effects on speech and swallowing are often seen. Radiation therapy and chemotherapy were also associated with significantly worse outcomes in eating and social disruptions (24). Patients without psychosocial issues mainly attributed their readjustment to the fact that they are grateful to be alive with the elimination of the disease (23,26). There have been some discrepancies in the literature as to the severity or existence of psychosocial issues; some report patients getting worse over time, while others report patients getting better over time (23,27,28). Despite these discrepancies, recognition of the possibility of psychosocial issues following treatment for oral and oropharyngeal cancers is important. For many patients, poor coping techniques have been associated with worse quality of life. However, in most cases, these issues had potential for improvement with appropriate support (22). One study reports that two-thirds of outpatient referrals are young females and suggests that this might be a highrisk group (29). Establishing tools to identify these high-risk patients in a postoperative setting may be useful in order to help patients return to their preoperative mental status. This scale was created by prospectively studying a cohort of patients with squamous cell carcinoma of the oral cavity. Factor analysis was used to relate questions and to develop four major categories: shame with appearance, sense of stigma, regret and social/speech concerns. These categories can be used to identify the specific type of intervention to be recommended. Timely recognition of individuals who will be helped by psychological intervention is crucial to avoiding long-term social or mental effects and thereby achieving the goal of restoring overall health after treatment of oral and oropharyngeal cancer. These changes can cause patients to feel ashamed or uncomfortable in social situations, which may lead to psychological issues such as depression, anxiety or isolation (22). The inability to eat normally or speak correctly can cause patients embarrassment to the point where they prefer to eat alone and avoid social outings (23). These concerns are less, however, with older patients who have significantly better views of their esthetics and mental health (24). Prognostic factors for swallowing rehabilitation following head and neck cancer surgery. Surgical variables affecting postoperative swallowing efficiency in oral cancer patients: a pilot study. Speech and swallowing function after anterior tongue and floor of mouth resection with distal flap reconstruction. Speech and swallowing function after oral and oropharyngeal resections: one-year follow-up. Speech and swallowing in irradiated and nonirradiated postsurgical oral cancer patients. Sensory recovery in noninnervated radial forearm free flaps in oral and oropharyngeal reconstruction. Sensory recovery of innervated and non-innervated radial forearm free flaps: functional implications. Sensation recovery on innervated radial forearm flap for hemiglossectomy reconstruction by using different recipient nerves. A comparison of donor and recipient site sensation in free tissue reconstruction of the oral cavity. Functional results of primary closure vs flaps in oropharyngeal reconstruction: a prospective study of speech and swallowing. A systematic review of patient-reported outcome measures in head and neck cancer surgery. Functional evaluation following microvascular oromandibular reconstruction of the oral cancer patient: a comparative study of reconstructed and nonreconstructed patients. The restoration or preservation of sensation in the oral cavity following ablative surgery. Psychosocial considerations of the post-treatment of head and neck cancer patients. Psychological distress in head and neck cancer patients 7­11 years after curative treatment. A prospective study on quality of life of patients with cancer of the oral cavity or oropharynx treated with surgery with or without radiotherapy. Anxiety: coping strategies, and coping behaviors in patients undergoing head and neck cancer surgery. Preliminary evaluation of the reliability and validity of the shame and stigma scale in head and neck cancer. William Halsted, the father of surgical oncology, theorized that cancer progression follows an orderly, stepwise process beginning from primary tumor formation to distant theorized metastasis, passing through regional lymph nodes (1). This simple concept of stepwise tumor progression was widely used in the first part of the 20th century and has essentially shaped the way we view and comprehend the behavior of a malignant tumor. It has also influenced the way we diagnose cancer, treat it and predict its course. The first systematic approach to stage cancer in a consistent way was done at Institut Gustave Roussy by Pierre Denoix. From 1942 to 1952, Denoix developed a system to stage solid malignancy based mainly on three anatomic characteristics: tumor (T), lymph node spread (N) and distant metastasis (M) (3). Although the main T, N and M categories remain almost unchanged since their initial conception, the staging system has been periodically fine-tuned to incorporate newer anatomical prognostic factors. Examples include more detailed T4 categories for head and neck cancers; the introduction of sentinel lymph node and isolated tumor cells in the N categories of breast cancer (8,9); and the depth of invasion, ulceration and mitotic rate as major T determinants in malignant melanoma (10). Examples of this trend 465 466 Prognostic nomograms include the incorporation of age and histology into thyroid cancer staging in 1983 (11); histological grade into soft tissue sarcoma and bone tumor staging in 1988 (12); and serum markers in testicular cancer, gestational trophoblastic tumors and prostate cancer in 1997 (13,14). It has been called anachronistic, and its use as the gold standard of cancer staging is accepted as "good enough" rather than optimal (15). Many disadvantages have been highlighted: lack of predictive power, lack of balance and differentiation between groups, failure to account for other tumors and host factors. The design of the current system unfortunately does not allow for easy addition of further variables without compromising on its biggest advantage: simplicity and user-friendliness. The challenge facing us now is to find a solution that can strike the ideal balance between complexity and user-friendliness (16). This information can generally be derived largely from clinical examination and radiographic imaging studies. The data points used for staging can be extracted from patient records even by personnel with minimal training and this user-friendliness has been pivotal in its worldwide popularity. Ironically, the simplicity of the system is at once its main advantage and also its greatest limitation. The rigid "bin" configuration means that any attempts to include new variables or categories would exponentially increase the number of bins, multiply the stages and make the system unwieldy. This would detract from its very core advantage of simplicity and user-friendliness. Any increase in the number of bins would also require a sufficient number of patients in each bin in order to maintain the predictive value of the system. Addition of variables would generate changes in the previous system, causing upward or downward "stage migration," requiring a complete redefinition of the staging system itself (19,20). However, the inclusion of other endpoints such as disease-specific survival, local control or regional control are more relevant to assessment of treatment results and differences among therapeutics options (16). Before we consider changing a system that has served us so well for several decades, it would be useful to examine the characteristics of an ideal staging system. Based on these three broad categories, patients with cancer are assigned into distinct categories. The T category (Tis, T1, T2, T3 and T4), N category (N0, N1, N2 and N3) and the M category (M0 and M1) are then combined into different "bins" (stage groupings). For most tumors, excluding the M1 category, this amounts to around 20 bins (T = 5 × N = 4).

Laminin is a non-collagenous high-molecular-weight (106) protein that interacts with glycosaminoglycans and promotes adhesion of various cell types jiva herbals 30 caps himplasia order mastercard. Laminin receptors occur on cells that normally interact with basement membranes shivalik herbals purchase himplasia overnight delivery, as well as on cells that extravasate quality herbals order on line himplasia, for example herbs used for healing order himplasia 30 caps, metastasizing cancer cells herbs nyc himplasia 30 caps buy fast delivery, macrophages, and leukocytes (Lopes et al. Aumailley (2013) has published a recent review on the Laminin family of glycoproteins. Fibronectin, another constituent of basement membrane, may also be an effective constituent for promoting extravascular migration of particulate matter (Newman et al. Fibronectin has been demonstrated to have potential applications as a material for clinical wound healing and tissue repair (Hsiao et al. Heparin sulfates, the side-chain moieties of cell surface proteoglycans, are important factors in cell recognition phenomena. The proteoheparin sulfates are ubiquitous cell surface proteoglycan components of the cell coat or glycocalyx. Lipoprotein lipase also attaches to endothelial cells through heparin sulfate interaction on the cell surface and is released by heparin through a detachment from this binding site (Shimada et al. Anionic sites on the lumenal surface of pulmonary microvascular endothelium have been shown to bind cationic ferritin in isolated, perfused rat lung studies (Pietra et al. The cationic ferritin is taken up by vesicles and discharged into the capillary membrane. Similar anionic sites are also present on alveolar epithelial surfaces (Vaccaro and Brody 1981). In some cases, cell surface expression of certain species can be induced; for example, interleukin-1 has been shown to induce the biosynthesis and cell surface expression of procoagulant activity in human vascular endothelial cells (Bevilacqua et al. Millions of lives of patients with diabetes have been saved since the introduction of insulin therapy. However, several daily injections of insulin are required to maximize glucose control in diabetic patients. Insulin is administered by subcutaneous injection, but this route of administration has a slow onset and subsequent prolonged duration of action. These limitations show up more when higher doses of insulin are injected, which results in a long duration of action and forces the patients to consume additional amounts of food to limit the risk of hypoglycemia (Anderson et al. This limitation has been reduced by the availability of newer, short-acting insulin analogues (Lispro, Aspart, and Glulisine). The formulation is designed for efficient transport of insulin across the intact respiratory epithelium into the systemic circulation (Owens 2002); its duration of action is more than 3 hours, and maximal serum insulin levels can be reached within 13 minutes after inhalation (Steiner et al. Bioadhesive agents have been hypothesized to interact with endothelial or epithelial cell surface determinants, inducing the cell to undergo transient separation or opening, thereby exposing subcellular determinants for which the agent may also have binding affinity. The interaction results in an acceleration of transport across at least one of the associated endothelial and epithelial structures or subcellular structures into a proximal tissue compartment. The basic premise is that this phenomenon will result in an improvement in the therapeutic index so that a reduced total dose of drug (or diagnostic agent) is required to obtain pharmacological effects comparable to significantly higher doses of free drug (or diagnostic agent). The results indicate that preferential and rapid uptake in the lung occurs with both sub-embolizing and embolizing particle diameters. Such a rapid and efficient uptake was not observed for dextran and agarose placebo particles that lack the heparin surface coat. Histochemical analysis of lung deposition showed the amphotericin B to be distributed in the alveoli, pulmonary interstitium, respiratory epithelium, and bronchial and tracheal lymph nodes, thus indicating extensive tissue percolation of the drug carrier; no significant kidney deposition was observed. In the same study, intravenous injection of Ulex europaeus 1 lectin microspheres were shown to be specifically taken up by lung endothelial cells and rapidly underwent migration into the extravascular tissues and into the airspace within 5 minutes­10 minutes after injection, with 90% of the injected dose being identified in the lung. Liver and kidney deposition was negligible to very low, showing that stabilized heparin nanosphere carriers with heparin surfaces are taken up by epithelial transport and that a high proportion of the dose becomes localized in lungs relative to other organs when administered by the airways. This novel example of epithelial uptake provides a rationale for administering drug-bioadhesive carrier conjugates by the inhalation route and may be particularly useful for the topical or systemic delivery of highly toxic drugs. Recently, it has become evident that monoclonal antibody (mAb) biotechnology is effective in a wide range of disease states. The application of antibodies is broad ranging and includes therapeutics, Drug Targeting to the Lung: Chemical and Biochemical Considerations 63 diagnostic tools, and research tools. The first therapeutic antibodies were mouse monoclonal antibodies that were selected against cytokines and cell surface proteins of proinflammatory, immunologic, or cancer cells (Takács et al. The development of monoclonal antibodies to human tumor-associated antigens has been achieved, and this has led to a renewed interest in the use of drug-antibody conjugates for cancer therapy (Stephens et al. There are several questions that need to be addressed before considering the use of drug-monoclonal antibody conjugates. Is there evidence that such antibodies will localize only in lung tissues and not in other tissues in vivo Do the antibodies contain appropriate functionalities to enable covalent linkage of drug molecules, and, if so, will the conjugated antibody exhibit targeting characteristics similar to those of the parent antibody Will the formation of an antibody-drug conjugate result in an immunologically active entity on repeated administration With regard to these considerations, it is important to determine whether, after either regional or systemic administration, a drug-antibody conjugate can deliver potentially therapeutic doses of the drug. This may depend on the loading of drug at multiple sites of conjugation on the antibody surface. In this respect, the greater the number of drug molecules conjugated to each antibody molecule, the more ineffective the resultant molecule might be, because attachment of drug molecules near or around the antibody-antigen binding site or at locations that compromise the three-dimensional integrity of the antibody will lead to decreased tissue specificity or increased immunological activity, respectively. Thus, an evaluation of the therapeutic index of the conjugate must be undertaken to determine whether it is superior to the free drug. When considering the targeting of therapeutic agents to lung tissue by this approach, the choice of cell surface antigens would appear to be most appropriate, although there is evidence that antibodies that can recognize in vivo antigens that are expressed extracellularly (Chan et al. A recombinant humanized mAb to human IgE has been found to inhibit mast-celldependent airway narrowing and other components of the asthmatic inflammatory response (Milgrom et al. Currently, omalizumab is undergoing clinical testing for a number of indications, including asthma. Omalizumab (Xolair) is a monoclonal anti-IgE antibody that specifically recognizes human IgE (Easthope and Jarvis 2001, Belliveau 2005). It is used for the treatment of moderate to severe allergic asthma in adults and adolescents that is inadequately controlled by inhaled corticosteroids (Chipps et al. The most commonly used route of administration for antibody-drug conjugates has been the intravenous route, but intracavity administration has also been investigated; and, generally, localization of antibody conjugates in the targeted tissue by this latter route appears to be superior to the intravenous route (Colcher et al. The mechanism of antibody-drug delivery at the cellular level is believed to involve initial binding to the specific cell surface antigen. This binding is followed by internalization and endocytosis into lysosomes, where digestion of the conjugate by lysosomal proteinases would release free drug from where it would diffuse to the site of action (de Duve et al. As mentioned previously, a significant reduction in antibody reactivity is often observed after multiple sites of conjugation of drug with antibody. This has led to the development of carriers that, when covalently linked to antibody, are able in turn to covalently bind many drug molecules to appropriate carrier functionalities. Obviously, such a gross molecular modification of the parent antibody may well affect its overall properties, and this often leads to significant differences in biodistribution of an antibody-carrier-drug complex relative to the parent antibody. In addition, for reasons stated previously, such a structural derivatization may also result in lower tissue specificity and increased toxicity. This approach uses hybrid antibodies with dual specificity (bifunctional/bispecific antibodies), one site binding with, say, a cell surface antigen, and the other with drug or cytotoxic agent. Such bispecific antibodies are prepared by reassociation of enzyme-prepared fragments of two antibodies or by hybridization of two existing hybridomas, one producing antibody to cell antigen, and the other producing antibody to drug. The application of this strategy to the development of therapeutic agents could be twofold: bispecific antibody would be initially administered, resulting in specific tissue localization. The concept of pre-targeting is not new and has been investigated for diagnostic tumor imaging with the high-affinity avidinbiotin system (Hnatowich et al. In this system, antibody conjugated to avidin was evaluated for localization in tumors followed by administration of radiolabeled biotin. It is conceivable that such a system may be useful for the pre-targeting of drugs to the lung, perhaps by using a biotin-drug conjugate in place of biotin. The use of drug-antibody fragments has been examined as a means for tissue targeting (Andrew et al. Generally, fragments appear to be poorer targeting agents than intact antibody, although they do exhibit relatively faster overall clearance and catabolism, which may result in less systemic toxicity. However, studies indicate that the increased clearance and kidney metabolism of antibody fragments may lead to renal toxicity (Rowland et al. The use of antibody fragments lacking a more immunogenic portion of the intact antibody molecule has generally not resulted in a decrease in immunogenic properties. Some earlier reports involving monoclonal antibodies directed against epithelial and endothelial cell surface components suggest that this approach to drug targeting in the lung may have good potential. Antibody location was shown to be on the basement membranes of glomeruli, alveoli (pronounced), choroids plexus, liver, and blood vessels and in epidermal junctions (Wick et al. The results suggested that this conjugate may be useful for targeted therapy to epidermal growth factor receptor-hyperproducing squamous carcinoma. After intravenous administration, these monoclonal antibodies exhibited good tumor localization with primary bronchial carcinoma patients, thus indicating that monoclonal antibodies directed against oncogene products may provide novel selective tools for diagnosis and targeted therapy of cancer. In a similar manner, mAb 6A3 selectively binds a membrane glycoprotein of rat lung capillary endothelia and has been shown to inhibit specific adhesion of lung endothelial vesicles to lung metastatic breast cancer cells. Because most monoclonal antibodies that have been studied for tissue targeting are from mouse or, occasionally, from rat, the problem of antibody production to such foreign proteins always exists. Molecular engineering has therefore been utilized to replace the foreign components of the murine antibody with human antibody sequences to overcome their immunogenicity (Birch and Lennox 1995). Numerous successful procedures have been developed for preparing humanized and fully human monoclonal antibodies (Takács et al. Future directions for the more effective utilization of monoclonal antibodies as drug targeting agents must focus on a more rational design of the antibody-drug conjugate. In particular, these studies have shown that the chemistry of the linker groups in relation to release mechanisms at the site of action must be carefully evaluated. In addition, chemical entities that could be incorporated into the conjugate structure that may influence its biodistribution should also be investigated. Also, more emphasis should be placed on determining the precise mechanism of action to avoid misinterpretation of in vivo data. In instances where a therapeutic effect has been observed, little attempt has been made to determine whether site specificity has been achieved by the proposed mechanism. Finally, with the increasing availability of human monoclonal antibodies, it is clear that drug-antibody conjugates have even greater potential for clinical therapy, although the cost of manufacturing and purifying monoclonal antibodies still limits their clinical utility. Much emphasis will continue to be focused on the respiratory tract as a suitable entry point for proteins and peptides for delivery into the systemic circulation. The use of macromolecule- and monoclonal antibody-drug conjugates will almost certainly increase with the advent of new nanoformulations (for some recent reviews see van Rijt et al. However, these advances may well be tempered unless parallel progress is made in other important areas. An area that still requires attention is determining the distribution of metabolizing enzymes throughout the respiratory tract. An in-depth study of the distribution of pulmonary metabolizing enzymes is necessary to achieve a greater cellular selectivity by the activation of appropriately designed prodrugs or drug conjugates in the vicinity of the target cell or a more efficient inactivation to minimize the systemic absorption of the drug. A greater emphasis will also need to be placed on elucidating epithelial membrane transport mechanisms, especially with regard to improving the epithelial transport of macromolecules. Studies are presently focusing on the microstructural aspects of macromolecular transport across pulmonary epithelia; the results of these investigations will certainly be of value in pulmonary drug-targeting strategies. The discovery of new epithelial and endothelium membrane receptors and proteins, the identification of selective materials for binding, or adhering to these receptors/proteins will also aid in the targeting of drugs to the respiratory tract. Specific targeting of drugs to other pulmonary targets, such as the alveolar macrophages, which lie in contact with the surfactant lining of the alveoli (Weibel and Gil 1968) and which have welldefined surface membrane receptors for initiating particle attachment and phagocytosis (Rowlands and Daniele 1975), may also be exploitable for improving selectivity. If one considers the inhalation route as a means for delivery of drugs to the systemic circulation, then inhaled drugs must enter the circulatory system principally by diffusion or transport across the alveolar capillary membrane. It is likely that such cells would be exposed to high concentrations of inhaled drugs. The sequestering in the lung is associated with pulmonary hypertension and lung injury, and, in some cases, it is not related to particle size. Thus, the future of pulmonary drug targeting remains promising, and although drug discovery efforts will no doubt lead to the development of agents with greater selectivity for pulmonary receptors, a greater emphasis will be placed on cell targeting and the development of new macromolecular vectors and cellular targets for this purpose. A preliminary review of its pharmacodynamic properties and therapeutic efficacy in asthma and rhinitis. Drug Targeting to the Lung: Chemical and Biochemical Considerations 69 Corvalan J. In Proceedings of the Congress of the European Academy of Allergology and Clinical Immunology. A preliminary review of its pharmacological properties and therapeutic efficacy in reversible obstructive airways disease. A comparison of the protective effect of sch 1000 and fenoterol against bronchoconstriction induced by histamine and methacholine. Drug Targeting to the Lung: Chemical and Biochemical Considerations 73 Miettinen M. Absorption of several peptidase-resistant, synthetic polypeptides: Poly-(2-hydroxyethyl)-aspartamides. Comparisons of systemic activity and safety among different inhaled corticosteroids. From this equation, it is seen that as far as particle properties go, it is the value of d2 that determines particle behavior. Because of the importance of d2, it is common to define the aerodynamic diameter of a particle, dae, as: dae = (/ref)1/2 d (4.

Yet no uniform agreement exists in what should be the scope of economic evaluations of pharmacogenomic testing herbs direct discount 30 caps himplasia with mastercard. For example herbs thai bistro himplasia 30 caps purchase online, is demonstration of value of testing genetic variants before drug administration compared to no testing (in 392 14 herbs nyc cake order 30 caps himplasia with visa. On the other hand lotus herbals 4 layer facial generic himplasia 30 caps buy line, would it be reasonable to expect a demonstration of the value of testing genetic variants with the drug compared to other treatment modalities In addition herbals on deck himplasia 30 caps buy overnight delivery, how should the impact of an improper diagnosis, especially psychiatric in nature, be incorporated into any economic model to analyze the cost-effectiveness In addition, the review of evidence presented in the aforementioned sections also identified some gaps in economic evaluations and/or issues for consideration. First, undoubtedly the adherence of the clinicians to the pharmacogenomic test results and recommendations would have an impact on the effectiveness of the tests and/or decision-making regarding implementation, but are seldom addressed in cost-effectiveness analysis. Furthermore, the adherence to recommendation would likely be affected by the time frame of test results availability for decision-making but the information for test results turnaround time is seldom provided or assumed immediately available, which is unrealistic. Second, most of the evaluations focus on cost-effectiveness analysis at the time of the study, without considering potential impacts on future health costs. Yet that potential cost saving is seldom incorporated into economic analysis of pharmacogenomic data, and the impact of this potential future use of genetic information will be compounded several fold with the combinatorial pharmacogenomic testing approach discussed in earlier sections. Third, is it realistic to require clinical utility and cost-effectiveness evidence for every genetic variant Another related example would be that are specific or highly prevalent for one specific ethnic group. Fourth, when applicable, the issue of variation among study populations and/or disease type needs to be considered for study design, as cost-effectiveness could be also dependent on genetic variation for specific variant, even among study populations residing in the same geographical location. These results highlight the relevance of the prevalence of alleles of interest in specific populations [28] and/or disease types [29­31] when evaluating potential cost benefits associated with genetic screening. Even though most of the available utility and cost-effectiveness is associated with some of the usual study limitations, such as lack of randomization and blinding, baseline differences between study groups, and inclusion of multiple diagnoses [4,5,34], these arguably represent intrinsic components of routine clinical practice. As such, these study results should not be simply dismissed as low-quality data that cannot be used for supporting a role of pharmacogenomic panel for optimization of drug therapy. Nevertheless, the level of evidence currently demanded by many investigators is, on one hand, rigorous but yet not very well defined in terms of specificity. What is clear is that, given no unified agreement as to what should be assessed in clinical utility and costeffectiveness data [22,25,35,36], perhaps a silver lining of the critical review of current literature on pharmacogenomics-guided antidepressant treatment is the highlighting of what still needs to be done for confirming clinical utility with improved health outcomes and demonstrating evidence-based cost-effectiveness [25]. Multiplex assay for comprehensive genotyping of genes involved in drug metabolism, excretion, and transport. A prospective, randomized, double-blind study assessing the clinical impact of integrated pharmacogenomic testing for major depressive disorder. A naturalistic study of the effectiveness of pharmacogenetic testing to guide treatment in psychiatric patients with mood and anxiety disorders. Improved antidepressant remission in major depression via a pharmacokinetic pathway polygene pharmacogenetic report. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. Does pharmacogenomic testing improve clinical outcomes for major depressive disorder Health technology assessments in personalized medicine: illustrations for cost-effectiveness analysis. Pharmacogenomics-based tailored versus standard therapeutic regimen for eradication of H. Psychiatric pharmacogenomics predicts health resource utilization of outpatients with anxiety and depression. Economic utility: combinatorial pharmacogenomics and medication cost savings for mental health care in a primary care setting. Clinical utility of combinatorial pharmacogenomics-guided antidepressant therapy: evidence from three clinical studies. Cost-effectiveness of combinatorial pharmacogenomic testing for treatment-resistant major depressive disorder patients. Extension of a pilot study: impact from the cytochrome P450 2D6 polymorphism on outcome and costs associated with severe mental illness. Rapid evidence review of the comparative effectiveness, harms, and cost-effectiveness of pharmacogenomics-guided antidepressant treatment versus usual care for major depressive disorder. Improved efficacy with targeted pharmacogenetic-guided treatment of patients with depression and anxiety: a randomized clinical trial demonstrating clinical utility. How attractive does a new technology have to be to warrant adoption and utilization Many challenges have slowed progress in this arena and are broad in scope, pertaining to evidence, cost, infrastructure, test interpretation, and education, among others [1­3]. In particular, the process of translating a genotype result into a clinical action can be complicated, even with appropriate training. Therefore, evidencebased clinical practice guidelines are necessary to facilitate routine use of pharmacogenetics test results in patient care. Some argue that one of the greatest challenges to integrating personalized medicine into healthcare is the lack of education and awareness among providers and patients [2,4]. Providers require education to understand how to effectively apply pharmacogenomics guidelines to clinical practice, which includes using that information in the context of other clinical variables. Patients need to be informed about the availability, utility, and limitations of pharmacogenetics tests, as well as about the implications of their specific test results. Current implementation efforts clearly demonstrate that clinical practice guidelines and clinician/patient education are critical to the advancement of precision medicine in everyday clinical practice [5­7]. In this article, we will explore currently available international consensus guidelines for pharmacogenomics as well as educational strategies for both clinicians and patients. These guidelines are based on systematic literature review and expert opinion and aim to provide evidence-based recommendations regarding selection of drug and dose based on genetics. Differences in genetic test interpretation and clinical recommendations exist between these guidelines and are discussed in a recent publication [9]. Although this process may appear trivial at first glance, 95% of clinicians indicate that this process is one of the most challenging aspects of implementing pharmacogenomics in routine clinical care [4]. No No Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Continued 398 15. Experts with significant financial conflicts are not included on the writing committee and any potential conflicts of interest are reported in the guideline. Published guidelines are updated whenever critical new evidence emerges that changes test interpretation or prescribing recommendations. Therapeutic recommendations are graded as "strong" in which "the evidence is high quality and the desirable effects clearly outweigh the undesirable effects"; "moderate" in which "there is a close or uncertain balance as to whether the evidence is high quality and the desirable clearly outweigh the undesirable effects"; "optional" in which "the desirable effects are closely balanced with undesirable effects, or the evidence is weak or based on extrapolations and there is room for differences in opinion as to the need for the recommended course of action"; and "no recommendation" in which "there is insufficient evidence, confidence, or agreement to provide a recommendation to guide clinical practice at this time" [4]. Each recommendation also includes an assessment of its usefulness in pediatric patients [4]. Guideline Writing Process the guideline writing process consists of a number of steps. Members continuously propose gene­drug pairs and the compiled list is prioritized during group meetings that are organized four to six times per year. Identified papers are assessed for two core parameters based on a previously described method [18]: · Level of evidence of the gene­drug interaction. This indicates the quality of the evidence found in literature for the gene­drug interaction and is scored on a scale ranging from 0 (lowest evidence) to 4 (highest evidence). This scale is originally derived from the National Cancer Institute Common Toxicity Criteria v2. Results are then used to synthesize a so-called risk evaluation report, presenting an overview of key findings of selected literature articles and scores of level of evidence and clinical relevance. After final assessment of the information presented in the report, it is then decided whether a gene­drug pair is indeed present and whether a therapeutic (dose) recommendation is necessitated. Composed therapeutic recommendations include (1) dose adjustments, (2) advice on therapeutic strategy. Calculation of these recommendations is based on the following rules: · Only pharmacokinetic data from articles with a level of evidence of 3 or 4 are used. However, dose recommendations are calculated only if statistically significant data are available. Dose recommendations for other genotypes and phenotypes were calculated by using analogous equations with the exception of prodrugs. In the Netherlands, the G-standard, a unique national drug database, is used by all electronic prescribing and medication surveillance systems. Operational knowledge can be specific for an institution and targeted to specific workflows or initiatives. Clinical knowledge can be targeted to specific drug­gene pairs or general genomic information. These two domains facilitate implementation of pharmacogenomics by informing clinicians on both how and when to use pharmacogenomics. Regardless on which domain is focused, some features to consider when developing education are the needs of the target audience, delivery methods, and potential barriers and challenges. Potential Needs the potential educational needs of the target audience are dependent on multiple factors including: their care role, prior knowledge, and educational delivery method. General information on pharmacogenomics is a reasonable starting point for any educational program and should include content regarding the clinical value and importance of pharmacogenomics and information regarding available resources. Clinicians report needing help communicating with patients about pharmacogenomics [3,24]. Providing predetermined answers for commonly asked patient questions can help reduce clinician resistance and increase clinical uptake. From the operational side, general information about what additional resources are available, such as consultant services and how to access these resources, is important. Once clinicians have been presented the potential value of pharmacogenomics, education on specific gene­drug pairs that is more detailed is more likely to be useful. Utilization of pharmacogenomics testing and referral services increased in the wake of education efforts, but the response was not sustained, highlighting the need for continual education [23]. Institutions commonly report using multiple methods for education because of the various types of material to be covered. Operationally, these providers will need to know the next step in patient care in their system. Some clinicians may need to be competent in areas such as interpreting test results, drug metabolism, and ethical concerns related to genetic testing [28,29]. The level of detail provided for this clinical and operational education will depend on previous education and the delivery method. Delivery Methods There are various delivery methods for pharmacogenomics education in both domains. Independent of the delivery methods, practical examples such as case series can be used to teach both clinical and operational knowledge [30]. Providing a layered approach with increasing amount of details can ensure the needs of your entire audience are met regardless of the delivery method. In-person education can be in the form of lectures such as Grand Rounds, interactive practice site-based educational meetings, and focused one-on-one sessions. These resources can be updated over time as new content is generated and reused, particularly as staff evolves in size and composition. For operational knowledge, timely emails or handouts can be used to alert clinicians to upcoming changes to workflow or functionality. These tools allow clinicians to receive education at a time when it might be most impactful: alongside patient-care activities. Barriers and Challenges Creating all of the necessary educational material is an enormous barrier to implementing pharmacogenomics. There are a number of online resources to help organizations develop this material (Table 15. Although clinical knowledge may easily be applied from online resources without modification, learning how and why another institution applied pharmacogenomics (operational knowledge) can also be valuable. Utilizing shared online resources are a key piece to a sustainable education program. Once the materials are created, having the resources to deliver them is a challenge. Although methods that use humans as the primary mode for delivering education may be preferred by learners, they are resource intensive and difficult to scale [37]. Additionally, motivating clinicians to participate in education activities is commonly reported as a challenge for successful programs [24]. When these two challenges combine, an ineffective education program can be the result. Another challenge is determining the right time and place to deliver the education. For operational knowledge, if education is delivered too late, a clinician may be faced with a situation in which they cannot provide effective clinical care resulting from a clinician not knowing how to resolve an interruptive alert. If the education is delivered too early, the clinician may forget how to resolve the interruptive alert before it is encountered. Clinical education delivered too early may not be as impactful to the provider because it is not yet relevant. Clinical education delivered too late may result in an adverse outcome because a provider did not know the importance of pharmacogenomics. If a clinician is faced with a specific therapeutic interaction, providing general pharmacogenomics education may prove worthless and providing too-detailed education 406 15. This website contains links to gene-specific pharmacogenetics competencies tailored to pharmacists. This website contains links to publications, presentations, and competencies related to pharmacogenomics. Finding the optimum combination of effective education methods is a major challenge for developing a successful education program. Clinician Education in Professional Schools As clinical adoption of pharmacogenomics grows, healthcare providers with skills to integrate this knowledge into their practice will be important.

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