Meg Wolfe, MD

• Associate Professor of Surgery
• Department of Surgery
• University of California, San Francisco-Fresno
• Fresno, California

Advanced nasopharyngeal carcinoma causes neuropathies of the cranial nerves due to skull base involvement diabetes type 2 med discount actos 45 mg. Carcinomas of the oral cavity present as nonhealing ulcers diabetes symptoms in a 6 yr old 30 mg actos free shipping, changes in the fit of dentures diabetes type 2 unexplained weight loss purchase actos without prescription, or painful lesions diabetes mellitus hhns order generic actos pills. Tumors of the tongue base or oropharynx can cause decreased tongue mobility and alterations in speech diabetes symptoms dizzy 45 mg actos order otc. Cancers of the oropharynx or hypopharynx rarely cause early symptoms, but they may cause sore throat and/or otalgia. Hoarseness may be an early symptom of laryngeal cancer, and persistent hoarseness requires referral to a specialist for indirect laryngoscopy and/or radiographic studies. If a head and neck lesion treated initially with antibiotics does not resolve in a short period, further workup is indicated; to simply continue the antibiotic treatment may be to lose the chance of early diagnosis of a malignancy. Advanced head and neck cancers in any location can cause severe pain, otalgia, airway obstruction, cranial neuropathies, trismus, odynophagia, dysphagia, decreased tongue mobility, fistulas, skin involvement, and massive cervical lymphadenopathy, which may be unilateral or bilateral. Some patients have enlarged lymph nodes even though no primary lesion can be detected by endoscopy or biopsy; these patients are considered to have carcinoma of unknown primary. If the enlarged nodes are located in the upper neck and the tumor cells are of squamous cell histology, the malignancy probably arose from a mucosal surface in the head or neck. Tumor cells in supraclavicular lymph nodes may also arise from a primary site in the chest or abdomen. The physical examination should include inspection of all visible mucosal surfaces and palpation of the floor of the mouth and of the tongue and neck. In addition to tumors themselves, leukoplakia (a white mucosal patch) or erythroplakia (a red mucosal patch) may be observed; these "premalignant" lesions can represent hyperplasia, dysplasia, or carcinoma in situ and require biopsy. Search for occult primary with biopsies of tonsils, nasopharynx, base of tongue, and pyriform sinus. Lymph nodes are staged by size, number, and location (ipsilateral vs contralateral to the primary). Distant metastases are found in <10% of patients at initial diagnosis and are more common in patients with advanced lymph node stage; microscopic involvement of the lungs, bones, or liver is more common, particularly in patients with advanced neck lymph node disease. Modern imaging techniques may increase the number of patients with clinically detectable distant metastases in the future. In patients with lymph node involvement and no visible primary, the diagnosis should be made by lymph node excision. Comorbidities associated with tobacco and alcohol abuse can affect treatment outcome and define long-term risks for patients who are cured of their disease. These patients are treated with curative intent by either surgery or radiation therapy. The choice of modality differs according to anatomic location and institutional expertise. Radiation therapy is often preferred for laryngeal cancer to preserve voice function, and surgery is preferred for small lesions in the oral cavity to avoid the long-term complications of radiation, such as xerostomia and dental decay. Most recurrences occur within the first 2 years following diagnosis and are usually local. Such patients can also be treated with curative intent, but not with surgery or radiation therapy alone. Combined-modality therapy including surgery, radiation therapy, and chemotherapy is most successful. It can be administered as induction chemotherapy (chemotherapy before surgery and/or radiotherapy) or as concomitant (simultaneous) chemotherapy and radiation therapy. Most patients who receive three cycles show tumor reduction, and the response is clinically "complete" in up to half of patients. This "sequential" multimodality therapy allows for organ preservation (omission of surgery) in patients with laryngeal and hypopharyngeal cancer, and it has been shown to result in higher cure rates compared with radiotherapy alone. Concomitant Chemoradiotherapy With the concomitant strategy, chemotherapy and radiation therapy are given simultaneously rather than in sequence. Tumor recurrences from head and neck cancer develop most commonly locoregionally (in the head and neck area of the primary and draining lymph nodes). The concomitant approach is aimed at enhancing tumor cell killing by radiation therapy in the presence of chemotherapy (radiation enhancement) and is a conceptually attractive approach for bulky tumors. Toxicity 505 (especially mucositis, grade 3 or 4 in 70­80%) is increased with concomitant chemoradiotherapy. However, meta-analyses of randomized trials document an improvement in 5-year survival of 8% with concomitant chemotherapy and radiation therapy. Results seem more favorable in recent trials as more active drugs or more intensive radiotherapy schedules are used. In addition, concomitant chemoradiotherapy produces better laryngectomy-free survival (organ preservation) than radiation therapy alone in patients with advanced larynx cancer. The use of radiation therapy together with cisplatin has also produced improved survival in patients with advanced nasopharyngeal cancer. The success of concomitant chemoradiotherapy in patients with unresectable disease has led to the testing of a similar approach in patients with resected intermediate-stage disease as a postoperative therapy. Concomitant chemoradiotherapy produces a significant improvement over postoperative radiation therapy alone for patients whose tumors demonstrate higher risk features, such as extracapsular spread beyond involved lymph nodes, involvement of multiple lymph nodes, or positive margins at the primary site following surgery. Nevertheless, the integration of cetuximab into current standard chemoradiotherapy regimens has failed to show additional improvement in survival and is not recommended. Patients with recurrent and/or metastatic disease are, with few exceptions, treated with palliative intent. Some patients may require local or regional radiation therapy for pain control, but most are given chemotherapy. Response rates to chemotherapy average only 30­50%; the durations of response are short, and the median survival time is 8­10 months. Drugs targeting specific mutations are under investigation, but no such strategy has yet been shown to be feasible in head and neck cancer. Currently, the extent of surgery has been limited or completely replaced by chemotherapy and radiation therapy as the primary approach. Long-term complications include xerostomia, loss of taste, decreased tongue mobility, second malignancies, dysphagia, and neck fibrosis. The complications of chemotherapy vary with the regimen used but usually include myelosuppression, mucositis, nausea and vomiting, and nephrotoxicity (with cisplatin). Chapter 106 Head and Neck Cancer 506 the mucosal side effects of therapy can lead to malnutrition and dehydration. Many centers address issues of dentition before starting treatment, and some place feeding tubes to ensure control of hydration and nutrition intake. About 50% of patients develop hypothyroidism from the treatment; thus, thyroid function should be monitored. These tumors may recur regionally; adenoid cystic carcinoma has a tendency to recur along the nerve tracks. For metastatic disease, therapy is given with palliative intent, usually chemotherapy with doxorubicin and/or cisplatin. Incidence and mortality rates among Hispanics and Native and Asian Americans are approximately 40­50% those of whites. A deep sequencing study suggested that one genetic mutation is induced for every 15 cigarettes smoked. The risk of lung cancer is lower among persons who quit smoking than among those who continue smoking; former smokers have a ninefold increased risk of developing lung cancer compared to men who have never smoked versus the 20-fold excess in those who continue to smoke. The size of the risk reduction increases with the length of time the person has quit smoking, although generally even long-term former smokers have higher risks of lung cancer than those who never smoked. Cigarette smoking has been shown to increase the risk of all the major lung cancer cell types. Although cigarette smoking is the cause of the majority of lung cancers, several other risk factors have been identified, including occupational exposures to asbestos, arsenic, bischloromethyl ether, hexavalent chromium, mustard gas, nickel (as in certain nickel-refining processes), and polycyclic aromatic hydrocarbons. Occupational observations also have provided insight into possible mechanisms of lung cancer induction. For example, the risk of lung cancer among asbestos-exposed workers is increased primarily among those with underlying asbestosis, raising the possibility that the scarring and inflammation produced by this fibrotic nonmalignant lung disease may in many cases (although likely not in all) be the trigger for asbestos-induced lung cancer. Several other occupational exposures have been associated with increased rates of lung cancer, but the causal nature of the association is not as clear. The risk of lung cancer appears to be higher among individuals with low fruit and vegetable intake during adulthood. This observation led to hypotheses that specific nutrients, in particular retinoids and carotenoids, might have chemopreventative effects for lung cancer. In fact, studies found the incidence of lung cancer was increased among smokers with supplementation. Ionizing radiation is also an established lung carcinogen, most convincingly demonstrated from studies showing increased rates of lung cancer among survivors of the atom bombs dropped on Hiroshima and Nagasaki and large excesses among workers exposed to alpha irradiation from radon in underground uranium mining. Prior lung diseases such as chronic bronchitis, emphysema, and tuberculosis have been linked to increased risks of lung cancer as well. Smoking Cessation Given the undeniable link between cigarette smoking and lung cancer (not even addressing other tobacco-related illnesses), physicians must promote tobacco abstinence. Stopping tobacco use before middle age avoids more than 90% of the lung cancer risk attributable to tobacco. Moreover, smoking can alter the metabolism of many chemotherapy drugs, potentially adversely altering the toxicities and therapeutic benefits of the agents. Consequently, it is important to promote smoking cessation even after the diagnosis of lung cancer is established. Physicians need to understand the essential elements of smoking cessation therapy. The individual must want to stop smoking and must be part 7 Oncology and Hematology 107 neoplasms of the Lung Leora Horn, Christine M. Johnson Lung cancer, which was rare prior to 1900 with fewer than 400 cases described in the medical literature, is considered a disease of modern man. By the mid-twentieth century, lung cancer had become epidemic and firmly established as the leading cause of cancer-related death in North America and Europe, killing over three times as many men as prostate cancer and nearly twice as many women as breast cancer. This fact is particularly troubling because lung cancer is one of the most preventable of all of the major malignancies. Tobacco consumption is the primary cause of lung cancer, a reality firmly established in the mid-twentieth century and codified with the release of the U. Following the report, cigarette use started to decline in North America and parts of Europe, and with it, so did the incidence of lung cancer. To date, the decline in lung cancer is seen most clearly in men; only recently has the decline become apparent among women in the United States. Unfortunately, in many parts of the world, especially in countries with developing economies, cigarette use continues to increase, and along with it, the incidence of lung cancers is also rising. Although tobacco smoking remains the primary cause of lung cancer worldwide, approximately 60% of new lung cancers in the United States occur in former smokers (smoked 100 cigarettes per lifetime, quit 1 year), many of whom quit decades ago, or never smokers (smoked <100 cigarettes per lifetime). Moreover, one in five women and one in 12 men diagnosed with lung cancer have never smoked. Given the magnitude of the problem, it is incumbent that every internist has a general knowledge of lung cancer and its management. More than 225,000 individuals will be diagnosed with lung cancer in the United States in 2013, and over 150,000 individuals will die from the disease. The incidence of lung cancer peaked among men in the late 1980s and has plateaued in women. Lung cancer is rare below age 40, with rates increasing until age 80, after which the rate tapers off. The projected lifetime probability of developing lung cancer is estimated to be approximately 8% among males and approximately 6% among females. The incidence of lung cancer varies by racial and ethnic group, with the highest age-adjusted incidence rates among African Americans. The excess in age-adjusted rates among African Americans occurs only among men, but examinations of age-specific rates show that below age 50, mortality from lung cancer willing to work hard to achieve the goal of smoking abstinence. Self-help strategies alone only marginally affect quit rates, whereas individual and combined pharmacotherapies in combination with counseling can significantly increase rates of cessation. However, both drugs have been reported to increase suicidal ideation and must be used with caution. In a randomized trial, varenicline was shown to be more efficacious than bupropion or placebo. Prolonged use of varenicline beyond the initial induction phase proved useful in maintaining smoking abstinence. Of note, reducing cigarettes smoked before quit day and quitting abruptly, with no prior reduction, yield comparable quit rates. Therefore, patients can be given the choice to quit in either of these ways (Chap. Inherited Predisposition to Lung Cancer Exposure to environmental carcinogens, such as those found in tobacco smoke, induce or facilitate the transformation from bronchoepithelial cells to the malignant phenotype. The contribution of carcinogens on transformation is modulated by polymorphic variations in genes that affect aspects of carcinogen metabolism. However, because of their population frequency, the overall impact on lung cancer risk could be high. In addition, environmental factors, as modified by inherited modulators, likely affect specific genes by deregulating important pathways to enable the cancer phenotype. First-degree relatives of lung cancer probands have a two- to threefold excess risk of lung cancer and other cancers, many of which are not smoking-related. These data suggest that specific genes and/or genetic variants may contribute to susceptibility to lung cancer. Common gene variants involved in lung cancer have been recently identified through large, collaborative, genome-wide association studies. These studies identified three separate loci that are associated with lung cancer (5p15, 6p21, and 15q25) and include genes that regulate acetylcholine nicotinic receptors and telomerase production. Likewise, a susceptibility locus on chromosome 6q greatly increases risk lung cancer risk among light and never smokers. Although progress has been made, there is a significant amount of work that remains to be done in identifying heritable risk factors for lung cancer.

The patient should be advised to have other family members screened if either melanoma or clinically atypical moles (dysplastic nevi) are present metabolic disease symptoms in children actos 45 mg buy low price. Patients who fit into high-risk groups should be instructed to perform monthly selfexaminations diabetes mellitus ogtt purchase genuine actos line. Biopsy Any pigmented cutaneous lesion that has changed in size or shape or has other features suggestive of malignant melanoma is a candidate for biopsy diabetes symptoms bruising quality 45 mg actos. This facilitates pathologic assessment of the lesion blood sugar parameters generic actos 45 mg without prescription, permits accurate measurement of thickness if the lesion is melanoma diabetes test range numbers generic actos 15 mg on line, and constitutes definitive treatment if the lesion is benign. For suspicious lesions, every attempt should be made to preserve the ability to assess the deep and peripheral margins and to perform immunohistochemistry. Shave biopsies are an acceptable alternative, particularly if the suspicion of malignancy is low, but they should be deep and include underlying fat; cauterization should be avoided. The biopsy should be read by a pathologist experienced in pigmented lesions, and the report should include Breslow thickness, mitoses per square millimeter for lesions 1 mm, presence or absence of ulceration, and peripheral and deep margin status. Breslow thickness is the greatest thickness of a primary cutaneous melanoma measured on the slide from the top of the epidermal granular layer, or from the ulcer base, to the bottom of the tumor. In three of these types-superficial spreading melanoma, lentigo maligna melanoma, and acral lentiginous melanoma- the lesion has a period of superficial (so-called radial) growth during which it increases in size but does not penetrate deeply. It is during this period that the melanoma is most capable of being cured by surgical excision. The fourth type-nodular melanoma -does not have a recognizable radial growth phase and usually presents as a deeply invasive lesion that is capable of early metastasis. When tumors begin to penetrate deeply into the skin, they are in the so-called vertical growth phase. Melanomas with a radial growth phase are characterized by irregular and sometimes notched borders, variation in pigment pattern, and variation in color. An increase in size or change in color is noted by the patient in 70% of early lesions. Bleeding, ulceration, and pain are late signs and are of little help in early recognition. Superficial spreading melanoma is the most common variant observed in the white population. Lentigo maligna melanoma usually is confined to chronically sun-damaged sites in older individuals. Acral lentiginous melanoma occurs on the palms, soles, nail beds, and mucous membranes. Although this type occurs in whites, it occurs most frequently (along with nodular melanoma) in blacks and East Asians. A fifth type of melanoma, desmoplastic melanoma, is associated with a fibrotic response, neural invasion, and a greater tendency for local recurrence. Occasionally, melanomas appear clinically to be amelanotic, in which case the diagnosis is established microscopically after biopsy of a new or a changing skin nodule. Newer classifications will increasingly emphasize molecular features of each melanoma (see below). The molecular analysis of individual melanomas will provide a basis for distinguishing benign nevi from melanomas, and determination of the mutational status of the tumor will help elucidate the molecular mechanisms of tumorigenesis and be used to identify targets that will guide therapy. A comprehensive catalog of somatic mutations from a human melanoma revealed more than 33,000 base mutations with damage to almost 300 protein-coding segments compared with normal cells from the same patient. An understanding of the molecular changes that occur during the transformation of normal melanocytes into malignant melanoma would not only help classify patients but also would contribute to the understanding of etiology and aid the development of new therapeutic options. A genome-wide assessment of melanomas classified into four groups based on their location and degree of exposure to the sun has confirmed that there are distinct genetic pathways in the development of melanoma. The four groups were cutaneous melanomas on skin without chronic sun-induced damage, cutaneous melanomas with chronic sun-induced damage, mucosal melanomas, and acral melanomas. Thus, although the genetic changes are diverse, the overall pattern of mutation, amplification, and loss of cancer genes indicates they have convergent effects on key biochemical pathways involved in proliferation, senescence, and apoptosis. Chapter 105 Cancer of the Skin Duration of Known Existence, Years 5­20 or longera 1­7 Nodular melanoma Acral lentiginous melanoma a Months­<5 years 1­10 Color In flat portions, shades of brown and tan predominate, but whitish gray occasionally present; in nodules, shades of reddish brown, bluish gray, bluish black Shades of brown mixed with bluish red (violaceous), bluish black, reddish brown, and often whitish pink, and the border of lesion is at least in part visibly and/or palpably elevated Reddish blue (purple) or bluish black; either uniform in color or mixed with brown or black In flat portions, dark brown predominantly; in raised lesions (plaques), brown-black or blue-black predominantly During much of this time, the precursor stage, lentigo maligna, is confined to the epidermis. The anatomic site of the primary is also prognostic; favorable sites are the forearm and leg (excluding the feet), and unfavorable sites include the scalp, hands, feet, and mucous membranes. Older individuals, especially men over 60, have worse prognoses, a finding that has been explained in part by a tendency toward later diagnosis (and thus thicker tumors) and in part by a higher proportion of acral melanomas in men. The current melanoma staging criteria and estimated 15-year survival by stage are depicted in Table 105-3. The clinical stage of the patient is determined after the pathologic evaluation of the melanoma skin lesion and clinical/radiologic assessment for metastatic disease. Pathologic staging also includes the microscopic evaluation of the regional lymph nodes obtained at sentinel lymph node biopsy or completion lymphadenectomy as indicated. If signs or symptoms of metastatic disease are present, appropriate diagnostic imaging should be performed. At initial presentation, more than 80% of patients will have disease confined to the skin and a negative history and physical exam, in which case imaging is not indicated. Neither mutation by itself appears to be sufficient to cause melanoma; thus, they often are accompanied by other mutations. Targeted agents that inhibit these pathways have been developed, and some are available for clinical use (see below). For lesions on the face, hands, and feet, strict adherence to these margins must give way to individual considerations about the constraints of surgery and minimization of morbidity. In all instances, however, inclusion of subcutaneous fat in the surgical specimen facilitates adequate thickness measurement and assessment of surgical margins by the pathologist. Topical imiquimod also has been used, particularly for lentigo maligna, in cosmetically sensitive locations. The initial (sentinel) draining node(s) from the primary site is (are) identified by injecting a blue dye and a radioisotope around the primary site. The sentinel node(s) then is (are) identified by inspection of the nodal basin for the blue-stained node and/or the node with high uptake of the radioisotope. The identified nodes are removed and subjected to careful histopathologic analysis with serial section using hematoxylin and eosin stains as well as immunohistochemical stains. Patients with microscopically positive lymph nodes should be considered for adjuvant therapy with interferon or enrollment in a clinical trial. Each of these presentations is managed surgically, following which there 498 is the possibility of long-term disease-free survival. Isolated limb perfusion or infusion with melphalan and hyperthermia are options for patients with extensive cutaneous regional recurrences in an extremity. High complete response rates have been reported and significant palliation of symptoms can be achieved, but there is no change in overall survival. Patients rendered free of disease after surgery may be at high risk for a local or distant recurrence and should be considered for adjuvant therapy. Radiotherapy can reduce the risk of local recurrence after lymphadenectomy, but does not affect overall survival. Patients with large nodes (>3­4 cm), four or more involved lymph nodes, or extranodal spread on microscopic examination should be considered for radiation. Treatment is accompanied by significant toxicity, including a flulike illness, decline in performance status, and the development of depression. Side effects can be managed in most patients by appropriate treatment of symptoms, dose reduction, and treatment interruption. The high-dose regimen is significantly more toxic than peginterferon, but the latter requires 4 additional years of therapy. The recently approved immunotherapy and targeted agents are being evaluated in the adjuvant setting. Patients with oligometastatic disease should be referred to a surgical oncologist for consideration of metastasectomy, because they may experience long-term disease-free survival after surgery. Patients with solitary metastases are the best candidates, but surgery increasingly is being used even for patients with metastases at more than one site. Surgery can also be used as an adjunct to immunotherapy when only a few of many metastatic lesions prove resistant to systemic therapy. Patients continue treatment until they achieve maximal benefit, usually 4­6 cycles. Treatment is associated with long-term disease-free survival (probable cures) in 5% of treated patients. Checkpoint blockade with a monoclonal antibody results in improved T cell function with eradication of tumor cells in preclinical animal models. Historically, metastatic melanoma was considered incurable; median survival ranges from 6 to 15 months, depending on the organs involved. The prognosis is better for patients with skin and subcutaneous metastases (M1a) than for lung (M1b) and worst for those with metastases to liver, bone, and brain (M1c). Although historical data suggest that the 15-year survival of patients with M1a, M1b, and M1c disease is less than 10%, there is optimism that newer therapies will increase the number of melanoma patients with long-term survival, especially patients with M1a and M1b disease. The most common immune-related adverse events were skin rash and diarrhea (sometimes severe, life-threatening colitis), but toxicity could involve most any organ. Vigilance and early treatment with steroids that do not appear to interfere with the antitumor effects are required to manage these patients safely. Widespread use of ipilimumab has not been completely embraced by the oncology community because of the low objective response rate, significant toxicity (including death), and high cost (drug cost alone for a course of therapy is approximately $120,000 in 2013). Although the percentage of patients whose tumors regress following immunotherapy is lower than the response rate after targeted therapy (see below), the durability of immunotherapy-induced responses (>10 years in some cases) appears to be superior to responses after targeted therapy and suggests that many of these patients have been cured. Treatment is accompanied by manageable side effects that differ from those following immunotherapy or chemotherapy. Patients should be co-managed with a dermatologist as these skin cancers will need excision. Metastases have not been reported, and treatment can be continued safely following simple excision. Activating mutations in the c-kit receptor tyrosine kinase are found in a minority of cutaneous melanomas with chronic sun damage, but more commonly in mucosal and acral lentiginous subtypes. Analysis of a metastatic lesion is preferred, but any biopsy will suffice because there is little discordance between primary and metastatic lesions. The majority of patients still die from their melanoma, despite improvements in therapy. Therefore, enrollment in a clinical trial is always an important consideration, even for previously untreated patients. Therefore, a major focus of care should be the timely integration of palliative care and hospice. Because no discernible survival benefit has been demonstrated for routine surveillance, it is reasonable to perform scans only if clinically indicated. Although tumor registries do not routinely gather data on the incidence of basal cell and squamous cell skin cancers, it is estimated that the annual incidence is 1. There has also been an increase in the incidence of nonepithelial skin cancer, especially Merkel cell carcinoma, with nearly 5000 new diagnoses and 3000 deaths annually. There is a dose-response relationship between tanning bed use and the incidence of skin cancer. Tanning bed use as a teenager or young adult confers greater risk than comparable exposure in older individuals. Other associations include blond or red hair, blue or green eyes, a tendency to sunburn easily, and an outdoor occupation. The frequency of skin cancer is proportional to the level and duration of immunosuppression and the extent of sun exposure before and after transplantation. Borders are typically indistinct, and lesions can be subtle; thus, delay in treatment is common, and tumors can be more extensive than expected clinically. It is commonly mistaken for a wart or callous when the inflammatory response to the lesion is minimal. Squamous cell carcinoma is seen here as a hyperkeratotic crusted and somewhat eroded plaque on the lower lip. Sun-exposed skin in areas such as the head, neck, hands, and arms represent other typical sites of involvement. Actinic keratoses consist of hyperkeratotic erythematous papules and patches on sun-exposed skin. They arise in middle-aged to older adults and have some potential for malignant transformation. Metastatic carcinoma to the skin is characterized by inflammatory, often ulcerated dermal nodules. Mycosis fungoides is a cutaneous T cell lymphoma, and plaque-stage lesions are seen in this patient. Keratoacanthoma is a low-grade squamous cell carcinoma that presents as an exophytic nodule with central keratinous debris. This basal cell carcinoma shows central ulceration and a pearly, rolled telangiectatic tumor border. The margins of this tumor may be ill defined, and fixation to underlying structures may occur ("tethering"). Treatment of premalignant and in situ lesions reduces the subsequent risk of invasive disease. The degree of local destruction and risk of recurrence vary with the size, duration, location, and histologic subtype of the tumor. Large lesions and micronodular, infiltrative, and morpheaform subtypes may be more aggressive. Tumors arising on sun-damaged skin have a lower metastatic potential than do those on non-sunexposed areas. Large, poorly differentiated, deep tumors with perineural or lymphatic invasion, multifocal tumors, and those arising in immunosuppressed patients often behave aggressively. The therapy chosen depends on tumor characteristics including depth and location, patient age, medical status, and patient preference. Wide local excision with standard margins is usually selected for invasive, ill-defined, and more aggressive subtypes of tumors, or for cosmetic reasons.

However diabetes test conversion 15 mg actos visa, zinc has been shown to improve taste function secondary to hepatic deficiencies blood sugar 39 buy actos discount, and retinoids (bioactive vitamin A derivatives) are known to play an essential role in the survival of olfactory neurons diabetes symptoms of stomach cancer buy on line actos. One protocol in which zinc was infused with chemotherapy treatments suggested a possible protective effect against developing taste impairment diabetes mellitus meaning cheap actos 45 mg mastercard. Diseases of the alimentary tract can not only influence chemoreceptive function diabetes treatment journal buy actos with american express, but also occasionally influence vitamin B12 absorption. This can result in a relative deficiency of vitamin B12, theoretically contributing to olfactory nerve disturbance. Vitamin B2 (riboflavin) and magnesium supplements are reported in the alternative literature to aid in the management of migraine that, in turn, may be associated with smell dysfunction. Because vitamin D deficiency is a cofactor of chemotherapy-induced mucocutaneous toxicity and dysgeusia, adding vitamin D3, 1000­2000 units per day, may benefit some patients with smell and taste complaints during or following chemotherapy. A number of medications have reportedly been used with success in ameliorating olfactory symptoms, although strong scientific evidence for efficacy is generally lacking. A report that theophylline improved smell function was uncontrolled and failed to account for the fact that some meaningful improvement occurs without treatment; indeed, the percentage of responders was about the same (50%) as that noted by others to show spontaneous improvement over a similar time period. Alternative therapies, such as acupuncture, meditation, cognitivebehavioral therapy, and yoga, can help patients manage uncomfortable experiences associated with chemosensory disturbance and oral pain syndromes and to cope with the psychosocial stressors surrounding the impairment. By accentuating the other sensory experiences of a meal, such as food texture, aroma, temperature, and color, one can optimize the overall eating experience for a patient. Proper oral and nasal hygiene and routine dental care are extremely important ways for patients to protect themselves from disorders of the mouth and nose that can ultimately result in chemosensory disturbance. Patients should be warned not to overcompensate for their taste loss by adding excessive amounts of sugar or salt. Smoking cessation and the discontinuance of oral tobacco use are essential in the management of any patient with smell and/or taste disturbance and should be repeatedly emphasized. A major and often overlooked element of therapy comes from chemosensory testing itself. Confirmation or lack of conformation of loss is beneficial to patients who come to believe, in light of unsupportive family members and medical providers, that they may be "crazy. Thus, it is often therapeutic for an older person to know that, while his or her smell function is not what it used to be, it still falls above the average of his or her peer group. Without testing, many such patients are simply told they are getting old and nothing can be done for them, leading in some cases to depression and decreased self-esteem. The inner and outer hair cells of the organ of Corti have different innervation patterns, but both are mechanoreceptors. The afferent innervation relates principally to the inner hair cells, and the efferent innervation relates principally to outer hair cells. The motility of the outer hair cells alters the micromechanics of the inner hair cells, creating a cochlear amplifier, which explains the exquisite sensitivity and frequency selectivity of the cochlea. Beginning in the cochlea, the frequency specificity is maintained at each point of the central auditory pathway: dorsal and ventral cochlear nuclei, trapezoid body, superior olivary complex, lateral lemniscus, inferior colliculus, medial geniculate body, and auditory cortex. At low frequencies, individual auditory nerve fibers can respond more or less synchronously with the stimulating tone. At higher frequencies, phase-locking occurs so that neurons alternate in response to particular phases of the cycle of the sound wave. Intensity is encoded by the amount of neural activity in individual neurons, the number of neurons that are active, and the specific neurons that are activated. There is evidence that the right and left ears as well as the central nervous system may process speech asymmetrically. Generally, a sound is processed symmetrically from the peripheral to the central auditory system. However, a "right ear advantage" exists for dichotic listening tasks, in which subjects are asked to report on competing sounds presented to each ear. In most individuals, a perceptual right ear advantage for consonant-vowel syllables, stop consonants, and words also exists. Similarly, whereas central auditory processing for sounds is symmetric with minimal lateral specialization for the most part, speech processing is lateralized. There is specialization of the left auditory cortex for speech recognition and production, and of the right hemisphere for emotional and tonal aspects of speech. Left hemisphere dominance for speech is found in 95­98% of right-handed persons and 70­80% of left-handed persons. In general, lesions in the auricle, external auditory canal, or middle ear that impede the transmission of sound from the external environment to the inner ear cause conductive hearing loss, whereas lesions that impair mechanotransduction in the inner ear or transmission of the electrical signal along the eighth nerve to the brain cause sensorineural hearing loss. Conductive Hearing Loss the external ear, the external auditory canal, and the middle ear apparatus is designed to collect and amplify sound and efficiently transfer the mechanical energy of the sound wave to the fluid-filled cochlea. Factors that obstruct the transmission of sound or serve to dampen the acoustical energy result in conductive hearing loss. Conductive hearing loss can occur from obstruction of the external auditory canal by cerumen, debris, and foreign bodies; swelling of the lining of the canal; atresia or neoplasms of the canal; perforations of the tympanic membrane; disruption of the ossicular chain, as occurs with necrosis of the long process of the incus in trauma or infection; otosclerosis; or fluid, scarring, or neoplasms in the middle ear. Rarely, inner ear malformations or pathologies, such as superior semicircular canal dehiscence, lateral semicircular canal dysplasia, incomplete partition of the inner ear, and large vestibular aqueduct, may also be associated with conductive hearing loss. While small perforations often heal spontaneously, larger defects usually require surgical intervention. Tympanoplasty is highly effective (>90%) in the repair of tympanic membrane perforations. Lalwani Hearing loss is one of the most common sensory disorders in humans and can present at any age. Nearly 10% of the adult population has some hearing loss, and one-third of individuals age >65 years have a hearing loss of sufficient magnitude to require a hearing aid. Sound waves enter the external auditory canal and set the tympanic membrane (eardrum) in motion, which in turn moves the malleus, incus, and stapes of the middle ear. Movement of the footplate of the stapes causes pressure changes in the fluid-filled inner ear, eliciting a traveling wave in the basilar membrane of the cochlea. The tympanic membrane and the ossicular chain in the middle ear serve as an impedance-matching mechanism, improving the efficiency of energy transfer from air to the fluid-filled inner ear. Stereocilia of the hair cells of the organ of Corti, which rests on the basilar membrane, are in contact with the tectorial membrane and are deformed by the traveling wave. A point of maximal displacement of the basilar membrane is determined by the frequency of the stimulating tone. Drawing of modified coronal section through external ear and temporal bone, with structures of the middle and inner ear demonstrated. Cholesteatoma, a benign tumor composed of stratified squamous epithelium in the middle ear or mastoid, occurs frequently in adults. Theories of pathogenesis include traumatic immigration and invasion of squamous epithelium through a retraction pocket, implantation of squamous epithelia in the middle ear through a perforation or surgery, and metaplasia following chronic infection and irritation. On examination, there is often a perforation of the tympanic membrane filled with cheesy white squamous debris. The presence of an aural polyp obscuring the tympanic membrane is highly suggestive of an underlying cholesteatoma. A chronically draining ear that fails to respond to appropriate antibiotic therapy should raise suspicion of a cholesteatoma. Conductive hearing loss with a normal ear canal and intact tympanic membrane suggests either ossicular pathology or the presence of "third window" in the inner ear (see below). Fixation of the stapes from otosclerosis is a common cause of low-frequency conductive hearing loss. It occurs equally in men and women and is inherited as an autosomal dominant trait with incomplete penetrance; in some cases, it may be a manifestation of osteogenesis imperfecta. In women, the otosclerotic process is accelerated during pregnancy, and the hearing loss is often first noticeable at this time. Extension of otosclerosis beyond the stapes footplate to involve the cochlea (cochlear otosclerosis) can lead to mixed or sensorineural hearing loss. Fluoride therapy to prevent hearing loss from cochlear otosclerosis is of uncertain value. Disorders that lead to the formation of a pathologic "third window" in the inner ear can be associated with conductive hearing loss. There are normally two major openings, or windows, that connect the inner ear with the middle ear and serve as conduits for transmission of sound; these are, respectively, the oval and round windows. A third window is formed where the normally hard otic bone surrounding the inner ear is eroded; dissipation of the acoustic energy at the third window is responsible for the "inner ear conductive hearing loss. A common symptom is vertigo evoked by loud sounds (Tullio phenomenon), by Valsalva maneuvers that change middle ear pressure, or by applying positive pressure on the tragus (the cartilage anterior to the external opening of the ear canal). Patients with this syndrome also complain of being able to hear the movement of their eyes and neck. A large jugular bulb or jugular bulb diverticulum can create a "third window" by eroding into the vestibular aqueduct or posterior semicircular canal; the symptoms are similar to those of the superior semicircular canal dehiscence syndrome. Sensorineural Hearing Loss Sensorineural hearing loss results from either damage to the mechanotransduction apparatus of the cochlea or disruption of the electrical conduction pathway from the inner ear to the brain. Thus, injury to hair cells, supporting cells, auditory neurons, or the central auditory pathway can cause sensorineural hearing loss. Damage to the hair cells of the organ of Corti may be caused by intense noise, viral infections, ototoxic drugs. Congenital malformations of the inner ear may be the cause of hearing loss in some adults. Genetic predisposition alone or in concert with environmental exposures may also be responsible (see below). Presbycusis (age-associated hearing loss) is the most common cause of sensorineural hearing loss in adults. In the early stages, it is characterized by symmetric, gentle to sharply sloping high-frequency hearing loss. More importantly, the hearing impairment is associated with significant loss in clarity. There is a loss of discrimination for phonemes, recruitment (abnormal growth of loudness), and particular difficulty in understanding speech in noisy environments such as at restaurants and social events. Hearing aids are helpful in enhancing the signal-to-noise ratio by amplifying sounds that are close to the listener. Although hearing aids are able to amplify sounds, they cannot restore the clarity of hearing. Thus, amplification with hearing aids may provide only limited rehabilitation once the word recognition score deteriorates below 50%. Cochlear implants are the treatment of choice when hearing aids prove inadequate, even when hearing loss is incomplete (see below). The audiogram shows a moderate to severe downsloping sensorineural hearing loss typical of presbyacusis. The loss of high-frequency hearing is associated with a decreased speech discrimination score; consequently, patients complain of lack of clarity of hearing, especially in a noisy background. Histologically, there is distention of the endolymphatic system (endolymphatic hydrops) leading to degeneration of vestibular and cochlear hair cells. Although any pattern of hearing loss can be observed, typically, low-frequency, unilateral sensorineural hearing impairment is present. A 2-g/d low-salt diet is the mainstay of treatment for control of rotatory vertigo. Diuretics, a short course of glucocorticoids, and intratympanic gentamicin may also be useful adjuncts in recalcitrant cases. Surgical therapy of vertigo is reserved for unresponsive cases and includes endolymphatic sac decompression, labyrinthectomy, and vestibular nerve section. Both labyrinthectomy and vestibular nerve section abolish rotatory vertigo in >90% of cases. Sensorineural hearing loss may also result from any neoplastic, vascular, demyelinating, infectious, or degenerative disease or trauma affecting the central auditory pathways. Primary diseases of the central nervous system can also present with hearing impairment. Characteristically, a reduction in clarity of hearing and speech comprehension is much greater than the loss of the ability to hear pure tone. Hearing loss can accompany hereditary sensorimotor neuropathies and inherited disorders of myelin. Tumors of the cerebellopontine angle such as vestibular schwannoma and meningioma usually present with asymmetric sensorineural hearing loss with greater deterioration of speech understanding than pure tone hearing. Multiple sclerosis may present with acute unilateral or bilateral hearing loss; typically, pure tone testing remains relatively stable while speech understanding 220 fluctuates. Isolated labyrinthine infarction can present with acute hearing loss and vertigo due to a cerebrovascular accident involving the posterior circulation, usually the anterior inferior cerebellar artery; it may also be the heralding sign of impending catastrophic basilar artery infarction (Chap. A finding of conductive and sensory hearing loss in combination is termed mixed hearing loss. Mixed hearing losses are due to pathology of both the middle and inner ear, as can occur in otosclerosis involving the ossicles and the cochlea, head trauma, chronic otitis media, cholesteatoma, middle ear tumors, and some inner ear malformations. Trauma resulting in temporal bone fractures may be associated with conductive, sensorineural, or mixed hearing loss. If the fracture spares the inner ear, there may simply be conductive hearing loss due to rupture of the tympanic membrane or disruption of the ossicular chain. Profound hearing loss and severe vertigo are associated with temporal bone fractures involving the inner ear. A perilymphatic fistula associated with leakage of inner ear fluid into the middle ear can occur and may require surgical repair. Cerebrospinal fluid leaks that accompany temporal bone fractures are usually selflimited; the value of prophylactic antibiotics is uncertain. Tinnitus is defined as the perception of a sound when there is no sound in the environment. It may have a buzzing, roaring, or ringing quality and may be pulsatile (synchronous with the heartbeat). Tinnitus is often associated with either a conductive or sensorineural hearing loss. The cause of the tinnitus can usually be determined by finding the cause of the associated hearing loss.

Since pharyngeal exudate may be present on examination pregestational diabetes definition actos 15 mg order with amex, this condition can be difficult to differentiate from streptococcal pharyngitis diabetes type 1 antibodies cheap actos 15 mg without a prescription. However type 1 diabetes and xylitol generic actos 30 mg without a prescription, adenoviral pharyngitis is distinguished by the presence of conjunctivitis in one-third to onehalf of patients diabetes symptoms nerve pain actos 15 mg order without a prescription. The clinical features of acute pharyngitis caused by streptococci of groups A diabetes test price actos 30 mg purchase without a prescription, C, and G are similar, ranging from a relatively mild illness without many accompanying symptoms to clinically severe cases with profound pharyngeal pain, fever, chills, and abdominal pain. The most common presenting symptom is sore throat-one of the most common reasons for ambulatory care visits by both adults and children. The most important source of concern is infection with group A -hemolytic Streptococcus (S. The relative importance of the different pathogens can only be estimated, since a significant proportion of cases (~30%) have no identified cause. Coryzal manifestations, including cough, are typically absent; when present, they suggest a viral etiology. Diagnosis the primary goal of diagnostic testing is to separate acute streptococcal pharyngitis from pharyngitis of other etiologies (particularly viral) so that antibiotics can be prescribed more efficiently for patients in whom they may be beneficial. The most appropriate standard for the diagnosis of streptococcal pharyngitis, however, has not been established definitively. Throat swab culture is generally regarded as the most appropriate but cannot distinguish between infection and colonization and requires 24­48 h to yield results that vary with technique and culture conditions. Rapid antigen-detection tests offer good specificity (>90%) but lower sensitivity when implemented in routine practice. The sensitivity has also been shown to vary across the clinical spectrum of disease (65­90%). The Centers for Disease Control and Prevention, the Infectious Diseases Society of America, and the American Academy of Family Physicians do not recommend backup culture when adults have negative results from a highly sensitive rapid antigen-detection test, however, because of the lower prevalence and smaller benefit in this age group. Complications Although rheumatic fever is the best-known complication of acute streptococcal pharyngitis, the risk of its following acute infection remains quite low. Other complications include acute glomerulonephritis and numerous suppurative conditions, such as peritonsillar abscess (quinsy), otitis media, mastoiditis, sinusitis, bacteremia, and pneumonia-all of which occur at low rates. Some evidence supports antibiotic use to prevent the suppurative complications of streptococcal pharyngitis, particularly peritonsillar abscess, which can also involve oral anaerobes such as Fusobacterium. Abscesses usually are accompanied by severe pharyngeal pain, dysphagia, fever, and dehydration; in addition, medial displacement of the tonsil and lateral displacement of the uvula are often evident on examination. Oropharyngeal candidiasis (thrush) is caused by a variety of Candida species, most often C. Treatment, which usually consists of an oral antifungal suspension (nystatin or clotrimazole) or oral fluconazole, is typically successful. In these cases, therapy based on culture and susceptibility test results is ideal. Treatment consists of debridement and oral administration of penicillin plus metronidazole, with clindamycin or doxycycline alone as an alternative. Fever, dysarthria, and drooling also may be noted, and patients may speak in a "hot potato" voice. Recommended agents include ampicillin/sulbactam, clindamycin, or high-dose penicillin plus metronidazole. The illness typically starts as a sore throat (most commonly in adolescents and young adults), which may present as exudative tonsillitis or peritonsillar abscess. The magnitude of this benefit is fairly small, since rheumatic fever is now a rare disease, even among untreated patients. Nevertheless, when therapy is started within 48 h of illness onset, symptom duration is decreased modestly. An additional benefit of therapy is the potential to reduce the transmission of streptococcal pharyngitis, particularly in areas of overcrowding or close contact. Antibiotic therapy for acute pharyngitis is therefore recommended in cases in which S. Azithromycin can be used in place of penicillin, although resistance to azithromycin among S. Newer (and more expensive) antibiotics also are active against streptococci but offer no greater efficacy than the agents mentioned above. There is no evidence to support antibiotic treatment of group C or G streptococcal pharyngitis or pharyngitis in which mycoplasmas or chlamydiae have been recovered. For influenza, the armamentarium includes the adamantanes amantadine and rimantadine and the neuraminidase inhibitors oseltamivir and zanamivir. Administration of all these agents needs to be started within 48 h of symptom onset to reduce illness duration meaningfully. Among these agents, only oseltamivir and zanamivir are active against both influenza A and influenza B and therefore can be used when local patterns of infection and antiviral resistance are unknown. Septic thrombophlebitis of the internal jugular vein can result, with associated pain, dysphagia, and neck swelling and stiffness. Occasionally, the infection can extend along the carotid sheath and into the posterior mediastinum, resulting in mediastinitis, or it can erode into the carotid artery, with the early sign of repeated small bleeds into the mouth. The concomitant use of anticoagulants to prevent embolization remains controversial and is sometimes advised, with careful consideration of both the risks and the benefits. For a detailed discussion of this entity, the reader should consult a textbook of pediatric medicine. Because of the danger of airway obstruction, acute epiglottitis constitutes a medical emergency, particularly in children, and prompt diagnosis and airway protection are of the utmost importance. Etiology After the introduction of the Hib vaccine in the mid-1980s, disease incidence among children in the United States declined dramatically. Nevertheless, lack of vaccination or vaccine failure has meant that many pediatric cases seen today are still due to Hib. Clinical Manifestations and Diagnosis Epiglottitis typically presents more acutely in young children than in adolescents or adults. On presentation, most children have had symptoms for <24 h, including high fever, severe sore throat, tachycardia, systemic toxicity, and (in many cases) drooling while sitting forward. Symptoms and signs of respiratory obstruction also may be present and may progress rapidly. The somewhat milder illness in adolescents and adults often follows 1­2 days of severe sore throat and is commonly accompanied by dyspnea, drooling, and stridor. Conversely, oropharyngeal examination reveals infection that is much less severe than would be predicted from the symptoms-a finding that should alert the clinician to a cause of symptoms and obstruction that lies beyond the tonsils. The diagnosis often is made on clinical grounds, although direct fiberoptic laryngoscopy is frequently performed in a controlled environment. Laboratory tests characteristically document mild to moderate leukocytosis with a predominance of neutrophils. Acute laryngitis can also be associated with acute bacterial respiratory infections such as those caused by group A Streptococcus or C. Another bacterial pathogen thought to play a role (albeit unclear) in the pathogenesis of acute laryngitis is M. Chronic laryngitis of infectious etiology is much less common in developed than in developing countries. Laryngitis due to Mycobacterium tuberculosis is often difficult to distinguish from laryngeal cancer, in part because of the frequent absence of signs, symptoms, and radiographic findings typical of pulmonary disease. Candida species can cause laryngitis as well, often in association with thrush or esophagitis and particularly in immunosuppressed patients. Clinical Manifestations Laryngitis is characterized by hoarseness and also can be associated with reduced vocal pitch or aphonia. Direct laryngoscopy often reveals diffuse laryngeal erythema and edema, along with vascular engorgement of the vocal folds. Antibiotics are not recommended except when group A Streptococcus is cultured, in which case penicillin is the drug of choice. The choice of therapy for chronic laryngitis depends on the pathogen, whose identification usually requires biopsy with culture. Many adults have been managed with observation only since the illness is perceived to be milder in this age group, but some data suggest that this approach may be risky and probably should be reserved only for adult patients who have yet to develop dyspnea or stridor. Because rates of ampicillin resistance in this organism have risen significantly in recent years, therapy with a -lactam/-lactamase inhibitor combination or a second- or third-generation cephalosporin is recommended. Antibiotic therapy should be continued for 7­10 days and should be tailored to the organism recovered in culture. Infection of the retropharyngeal space also can be extremely dangerous, as this space runs posterior to the pharynx from the skull base to the superior mediastinum. Infections in this space are more common among children <5 years old because of the presence of several small retropharyngeal lymph nodes that typically atrophy by age 4 years. Infection is usually a consequence of extension from another site of infection-most commonly, acute pharyngitis. Retropharyngeal space infection also can follow penetrating trauma to the posterior pharynx. Patients with retropharyngeal abscess typically present with sore throat, fever, dysphagia, and neck pain and are often drooling because of difficulty and pain with swallowing. Many of these infections are life threatening but are difficult to detect at early stages, when they may be more easily managed. These spaces communicate with one another and with other important structures in the head, neck, and thorax, providing pathogens with easy access to areas that include the mediastinum, carotid sheath, skull base, and meninges. Infection of the lateral pharyngeal (or parapharyngeal) space is most often a complication of common infections of the oral cavity and upper respiratory tract, including tonsillitis, peritonsillar abscess, pharyngitis, mastoiditis, and periodontal infection. This space, situated deep in the lateral wall of 45 oral Manifestations of Disease Samuel C. Knowledge of the oral milieu and its unique structures is necessary to guide preventive services and recognize oral manifestations of local or systemic disease (Chap. Furthermore, internists frequently collaborate with dentists in the care of patients who have a variety of medical conditions that affect oral health or who undergo dental procedures that increase their risk of medical complications. Teeth start to develop in utero and continue to develop until after the tooth erupts. Normally, all 20 deciduous teeth have erupted by age 3 and have been shed by age 13. Permanent teeth, eventually totaling 32, begin to erupt by age 6 and 236 have completely erupted by age 14, though third molars ("wisdom teeth") may erupt later. The erupted tooth consists of the visible crown covered with enamel and the root submerged below the gum line and covered with bonelike cementum. Dentin, a material that is denser than bone and exquisitely sensitive to pain, forms the majority of the tooth substance, surrounding a core of myxomatous pulp containing the vascular and nerve supply. The tooth is held firmly in the alveolar socket by the periodontium, supporting structures that consist of the gingivae, alveolar bone, cementum, and periodontal ligament. A few millimeters of unattached or free gingiva (1­3 mm) overlap the base of the crown, forming a shallow sulcus along the gum-tooth margin. Dental Caries, Pulpal and Periapical Disease, and Complications Dental caries usually begin asymptomatically as a destructive infectious process of the enamel. Bacteria-principally Streptococcus mutans- colonize the organic buffering biofilm (plaque) on the tooth surface. If not removed by brushing or by the natural cleansing and antibacterial action of saliva, bacterial acids can demineralize the enamel. Fissures and pits on the occlusal surfaces are the most frequent sites of early decay. Surfaces between the teeth, adjacent to tooth restorations and exposed roots, are also vulnerable, particularly as individuals age. Over time, dental caries extend to the underlying dentin, leading to cavitation of the enamel. Without management, the caries will penetrate to the tooth pulp, producing acute pulpitis. At this stage, when the pulp infection is limited, the tooth may become sensitive to percussion and to hot or cold, and pain resolves immediately when the irritating stimulus is removed. Should the infection spread throughout the pulp, irreversible pulpitis occurs, leading to pulp necrosis. At this later stage, pain can be severe and has a sharp or throbbing visceral quality that may be worse when the patient lies down. Treatment of caries involves removal of the softened and infected hard tissue and restoration of the tooth structure with silver amalgam, glass ionomer, composite resin, or gold. Once irreversible pulpitis occurs, root canal therapy becomes necessary; removal of the contents of the pulp chamber and root canals is followed by thorough cleaning and filling with an inert material. Pulpal infection leads to periapical abscess formation, which can produce pain on chewing. If the infection is mild and chronic, a periapical granuloma or eventually a periapical cyst forms, either of which produces radiolucency at the root apex. Elderly patients, patients with diabetes mellitus, and patients taking glucocorticoids may experience little or no pain or fever as these complications develop. Periodontal Disease Periodontal disease and dental caries are the primary causes of tooth loss. Like dental caries, chronic infection of the gingiva and anchoring structures of the tooth begins with formation of bacterial plaque. Plaque and calculus (calcified plaque) are preventable by appropriate daily oral hygiene, including periodic professional cleaning. Left undisturbed, chronic inflammation can ensue and produce hyperemia of the free and attached gingivae (gingivitis), which then typically bleed with brushing. If this issue is ignored, severe periodontitis can develop, leading to deepening of the physiologic sulcus and destruction of the periodontal ligament. As the periodontium (including the supporting bone) is destroyed, the teeth loosen. A role for chronic inflammation due to chronic periodontal disease in promoting coronary heart disease and stroke has been proposed.

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