Category Archives: Stell Cell Genetics

General Information About Salivary Gland Cancer Incidence and Mortality

Salivary gland tumors are a morphologically and clinically diverse group of neoplasms, which may present significant diagnostic and management challenges. These tumors are rare, with an overall incidence in the Western world of approximately 2.5 cases to 3.0 cases per 100,000 per year.[1] Malignant salivary gland neoplasms account for more than 0.5% of all malignancies and approximately 3% to 5% of all head and neck cancers.[1,2] Most patients with malignant salivary gland tumors are in the sixth or seventh decade of life.[3,4]

Although exposure to ionizing radiation has been implicated as a cause of salivary gland cancer, the etiology of most salivary gland cancers cannot be determined.[2,3,5,6] Occupations associated with an increased risk for salivary gland cancers include rubber products manufacturing, asbestos mining, plumbing, and some types of woodworking.[3]

Tumors of the salivary glands comprise those in the major glands (e.g., parotid, submandibular, and sublingual) and the minor glands (e.g., oral mucosa, palate, uvula, floor of mouth, posterior tongue, retromolar area and peritonsillar area, pharynx, larynx, and paranasal sinuses).[2,7] Minor salivary gland lesions are most frequently seen in the oral cavity.[2]

Of salivary gland neoplasms, more than 50% are benign, and approximately 70% to 80% of all salivary gland neoplasms originate in the parotid gland.[1,2,8] The palate is the most common site of minor salivary gland tumors. The frequency of malignant lesions varies by site. Approximately 20% to 25% of parotid tumors, 35% to 40% of submandibular tumors, 50% of palate tumors, and more than 90% of sublingual gland tumors are malignant.[1,9]

Histologically, salivary gland tumors represent the most heterogenous group of tumors of any tissue in the body.[10] Although almost 40 histologic types of epithelial tumors of the salivary glands exist, some are exceedingly rare and may be the subject of only a few case reports.[1,11] The most common benign major and minor salivary gland tumor is the pleomorphic adenoma, which comprises about 50% of all salivary gland tumors and 65% of parotid gland tumors.[1] The most common malignant major and minor salivary gland tumor is the mucoepidermoid carcinoma, which comprises about 10% of all salivary gland neoplasms and approximately 35% of malignant salivary gland neoplasms.[1,12] This neoplasm occurs most often in the parotid gland.[2,12,13] This type and other histologic types of salivary gland neoplasms are reviewed in detail in the Cellular Classification of Salivary Gland Treatment section of this summary.

Most patients with benign tumors of the major or minor salivary glands present with painless swelling of the parotid, submandibular, or the sublingual glands. Neurological signs, such as numbness or weakness caused by nerve involvement, typically indicate a malignancy.[2] Facial nerve weakness that is associated with a parotid or submandibular tumor is an ominous sign. Persistent facial pain is highly suggestive of malignancy; approximately 10% to 15% of malignant parotid neoplasms present with pain.[8,14] (Refer to the PDQ summary on Pain for more information.) The majority of parotid tumors, both benign and malignant, however, present as an asymptomatic mass in the gland.[2,8]

Early-stage low-grade malignant salivary gland tumors are usually curable by adequate surgical resection alone. The prognosis is more favorable when the tumor is in a major salivary gland; the parotid gland is most favorable, then the submandibular gland; the least favorable primary sites are the sublingual and minor salivary glands. Large bulky tumors or high-grade tumors carry a poorer prognosis and may best be treated by surgical resection combined with postoperative radiation therapy.[15] The prognosis also depends on the following:[16,17]

Overall, clinical stage, particularly tumor size, may be the crucial factor to determine the outcome of salivary gland cancer and may be more important than histologic grade.[18]

Perineural invasion can also occur, particularly in high-grade adenoid cystic carcinoma, and should be specifically identified and treated.[19] Radiation therapy may increase the chance of local control and increase the survival of patients when adequate margins cannot be achieved.[20][Level of evidence: 3iiiDii] Unresectable or recurrent tumors may respond to chemotherapy.[21-23] Fast neutron-beam radiation therapy or accelerated hyperfractionated photon-beam schedules have been shown to be effective in the treatment of inoperable, unresectable, and recurrent tumors.[24-26]

Complications of surgical treatment for parotid neoplasms include facial nerve dysfunction and Frey syndrome also known as gustatory flushing and sweating and the auriculotemporal syndrome.[8] Frey syndrome has been successfully treated with injections of botulinum toxin A.[27-29]

Note: Other PDQ summaries containing information related to salivary gland cancer include the following:

Salivary gland neoplasms are remarkable for their histologic diversity. These neoplasms include benign and malignant tumors of epithelial, mesenchymal, and lymphoid origin. Salivary gland tumors pose a particular challenge to the surgical pathologist. Differentiating benign from malignant tumors may be difficult, primarily because of the complexity of the classification and the rarity of several entities, which may exhibit a broad spectrum of morphologic diversity in individual lesions.[1] In some cases, hybrid lesions may be seen.[2] The key guiding principle to establish the malignant nature of a salivary gland tumor is the demonstration of an infiltrative margin.[1]

The following cellular classification scheme draws heavily from a scheme published by the Armed Forces Institute of Pathology (AFIP).[3] Malignant nonepithelial neoplasms are included in the scheme because these neoplasms comprise a significant proportion of salivary gland neoplasms seen in the clinical setting. For completeness, malignant secondary tumors are also included in the scheme.

Where AFIP statistics regarding the incidence, or relative frequency, of particular histopathologies are cited, some bias may exist because of the AFIP methods of case accrual as a pathology reference service. When possible, other sources are cited for incidence data. Notwithstanding the AFIP data, the incidence of a particular histopathology has been found to vary considerably depending upon the study cited. This variability in reporting may be partially caused by the rare incidence of many salivary gland neoplasms.

The clinician should be aware that several benign epithelial salivary gland neoplasms have malignant counterparts, which are shown below:[3]

Histologic grading of salivary gland carcinomas is important to determine the proper treatment approach, though it is not an independent indicator of the clinical course and must be considered in the context of the clinical stage. Clinical stage, particularly tumor size, may be the critical factor to determine the outcome of salivary gland cancer and may be more important than histologic grade.[1] For example, stage I intermediate-grade or high-grade mucoepidermoid carcinomas can be successfully treated, whereas low-grade mucoepidermoid carcinomas that present as stage III disease may have a very aggressive clinical course.[4]

Grading is used primarily for mucoepidermoid carcinomas, adenocarcinomas, not otherwise specified (NOS), adenoid cystic carcinomas, and squamous cell carcinomas.[1,3] Various other salivary gland carcinomas can also be categorized according to histologic grade as follows:[3,5-8]

Low grade

Low grade, intermediate grade, and high grade

Intermediate grade and high grade

High grade

*[Note: Some investigators consider mucoepidermoid carcinoma to be of only two grades: low grade and high grade.[5]]

Mucoepidermoid carcinoma is a malignant epithelial tumor that is composed of various proportions of mucous, epidermoid (e.g., squamous), intermediate, columnar, and clear cells and often demonstrates prominent cystic growth. It is the most common malignant neoplasm observed in the major and minor salivary glands.[1,9] Mucoepidermoid carcinoma represents 29% to 34% of malignant tumors originating in both major and minor salivary glands.[3,5,10,11] In two large retrospective series, 84% to 93% of cases originated in the parotid gland.[12,13] With regard to malignant tumors of the minor salivary glands, mucoepidermoid carcinoma shows a strong predilection for the lower lip.[3,14] In an AFIP review of civilian cases, the mean age of patients was 47 years, with an age range of 8 years to 92 years.[3] Prior exposure to ionizing radiation appears to substantially increase the risk of developing malignant neoplasms of the major salivary glands, particularly mucoepidermoid carcinoma.[3,13]

Most patients are asymptomatic and present with solitary, painless masses. Symptoms include pain, drainage from the ipsilateral ear, dysphagia, trismus, and facial paralysis.[3] (Refer to the PDQ summary on Pain for more information.)

Microscopic grading of mucoepidermoid carcinoma is important to determine the prognosis.[1,12,15] Mucoepidermoid carcinomas are graded as low grade, intermediate grade, and high grade. Grading parameters with point values include the following:

Total point scores are 0 to 4 for low grade, 5 to 6 for intermediate grade, and 7 to 14 for high grade.

In a retrospective review of 243 cases of mucoepidermoid carcinoma of the major salivary glands, a statistically significant correlation was shown between this point-based grading system and outcome for parotid tumors but not for submandibular tumors.[12] Another retrospective study that used this histologic grading system indicated that tumor grade correlated well with prognosis for mucoepidermoid carcinoma of the major salivary glands, excluding submandibular tumors, and minor salivary glands.[13] A modification of this grading system placed more emphasis on features of tumor invasion.[16] Nonetheless, though tumor grade may be useful, stage appears to be a better indicator of prognosis.[3,16]

Cytogenetically, mucoepidermoid carcinoma is characterized by a t(11;19)(q1421;p1213) translocation, which is occasionally the sole cytogenetic alteration.[17-19] This translocation creates a novel fusion product, MECT1-MAML2, which disrupts a Notch signaling pathway.[20] Notch signaling plays a key role in the normal development of many tissues and cell types, through diverse effects on cellular differentiation, survival, and/or proliferation, and may be involved in a wide variety of human neoplasms.[21]

Rarely, mucoepidermoid carcinoma may originate within the jaws. This tumor type is known as central mucoepidermoid carcinoma.[3] The mandibular to maxillary predilection is approximately 3:1.[22]

Adenoid cystic carcinoma, formerly known as cylindroma, is a slow growing but aggressive neoplasm with a remarkable capacity for recurrence.[23] Morphologically, three growth patterns have been described: cribriform, or classic pattern; tubular; and solid, or basaloid pattern. The tumors are categorized according to the predominant pattern.[3,23-25] The cribriform pattern shows epithelial cell nests that form cylindrical patterns. The lumina of these spaces contain periodic acid-Schiff (PAS)-positive mucopolysaccharide secretions. The tubular pattern reveals tubular structures that are lined by stratified cuboidal epithelium. The solid pattern shows solid groups of cuboidal cells. The cribriform pattern is the most common, and the solid pattern is the least common.[26] Solid adenoid cystic carcinoma is a high-grade lesion with reported recurrence rates of as much as 100% compared with 50% to 80% for the tubular and cribriform variants.[25]

In a review of its case files, the AFIP found adenoid cystic carcinoma to be the fifth most common malignant epithelial tumor of the salivary glands after mucoepidermoid carcinomas; adenocarcinomas, NOS; acinic cell carcinomas; and PLGA.[3] Other series, however, report adenoid cystic carcinoma to be the second most common malignant tumor with an incidence or relative frequency of approximately 20%.[1] In the AFIP data, this neoplasm constitutes approximately 7.5% of all epithelial malignancies and 4% of all benign and malignant epithelial salivary gland tumors. The peak incidence for this tumor is reported to be in the fourth through sixth decades of life.[3]

This neoplasm typically develops as a slow growing swelling in the preauricular or submandibular region. Pain and facial paralysis develop frequently during the course of the disease and are likely related to the associated high incidence of nerve invasion.[3] (Refer to the PDQ summary on Pain for more information.) Regardless of histologic grade, adenoid cystic carcinomas, with their unusually slow biologic growth, tend to have a protracted course and ultimately a poor outcome, with a 10-year survival reported to be less than 50% for all grades.[1,27] These carcinomas typically show frequent recurrences and late distant metastases.[1,28] Clinical stage may be a better prognostic indicator than histologic grade.[28,29] In a retrospective review of 92 cases, a tumor size larger than 4 cm was associated with an unfavorable clinical course in all cases.[30]

Acinic cell carcinoma, also known as acinic cell adenocarcinoma, is a malignant epithelial neoplasm in which the neoplastic cells express acinar differentiation. By conventional use, the term acinic cell carcinoma is defined by cytologic differentiation towards serous acinar cells, as opposed to mucous acinar cells, whose characteristic feature is cytoplasmic periodic acid-Schiff (PAS)-positive zymogen-type secretory granules.[3] In AFIP data of salivary gland neoplasms, acinic cell carcinoma is the third most common salivary gland epithelial neoplasm after mucoepidermoid carcinoma and adenocarcinoma, NOS.[3] In these data, acinic cell carcinoma comprised 17% of primary malignant salivary gland tumors or about 6% of all salivary gland neoplasms; more than 80% occur in the parotid gland; women were affected more than men; and the mean age was 44 years. Other studies have reported a relative frequency of acinic cell carcinoma from 0% to 19% of malignant salivary gland neoplasms.[3]

Clinically, patients typically present with a slowly enlarging mass in the parotid region. Pain is a symptom in more than 33% of patients. (Refer to the PDQ summary on Pain for more information.) For acinic cell carcinoma, staging is likely a better predictor of outcome than histologic grading.[3] In a retrospective review of 90 cases, poor prognostic features included pain or fixation; gross invasion; and microscopic features of desmoplasia, atypia, or increased mitotic activity. Neither morphologic pattern nor cell composition was a predictive feature.[31]

PLGA is a malignant epithelial tumor that is essentially limited to occurrence in minor salivary gland sites and is characterized by bland, uniform nuclear features; diverse but characteristic architecture; infiltrative growth; and perineural infiltration.[3] In a series of 426 minor salivary gland tumors, PLGA represented 11% of all tumors and 26% of those that were malignant.[32] In minor gland sites, PLGA is twice as frequent as adenoid cystic carcinoma, and among all benign and malignant salivary gland neoplasms, only pleomorphic adenoma and mucoepidermoid carcinoma are more common.[3] In the AFIP case files, more than 60% of tumors occurred in the mucosa of either the soft or hard palates, approximately 16% occurred in the buccal mucosa, and 12% occurred in the upper lip. The average age of patients is reported to be 59 years, with 70% of patients between the ages of 50 and 79 years.[3] The female to male ratio is about 2:1, a proportion greater than for malignant salivary gland tumors in general.[3,33]

PLGA typically presents as a firm, nontender swelling involving the mucosa of the hard and soft palates (i.e., it is often found at their junction), the cheek, or the upper lip. Discomfort, bleeding, telangiectasia, or ulceration of the overlying mucosa may occasionally occur.[3] This salivary gland neoplasm typically runs a moderately indolent course. In a study of 40 cases with long-term follow-up, overall survival was 80% at 25 years.[34] Because of the unpredictable behavior of the tumor, some investigators consider the qualifying term, low grade, to be misleading and instead prefer the term, polymorphous adenocarcinoma.[1]

Adenocarcinoma, NOS, is a salivary gland carcinoma that shows glandular or ductal differentiation but lacks the prominence of any of the morphologic features that characterize the other, more specific carcinoma types. The diagnosis of adenocarcinoma, NOS, is essentially one of exclusion. In an AFIP review of cases, adenocarcinoma, NOS, was second only to mucoepidermoid carcinoma in frequency among malignant salivary gland neoplasms.[3] Other series have reported an incidence of 4% to 10%.[1] In AFIP files, the mean patient age was 58 years.[3] Approximately 40% and 60% of tumors occurred in the major and minor salivary glands, respectively. Among the major salivary gland tumors, 90% occurred in the parotid gland. Adenocarcinoma, NOS is graded in a similar way to extrasalivary lesions according to the degree of differentiation.[1] Tumor grades include low grade, intermediate grade, and high-grade categories.[3]

Patients with tumors in the major salivary glands typically present with solitary, painless masses.[35] Two retrospective studies indicate that survival is better for patients with tumors of the oral cavity than for those with tumors of the parotid and submandibular glands.[35,36] These studies differ regarding the prognostic significance of tumor grade.

Basal cell adenocarcinoma, also known as basaloid salivary carcinoma, carcinoma ex monomorphic adenoma, malignant basal cell adenoma, malignant basal cell tumor, and basal cell carcinoma, is an epithelial neoplasm that is cytologically similar to basal cell adenoma but is infiltrative and has a small potential for metastasis.[3] In AFIP case files spanning almost 11 years, basal cell carcinoma comprised 1.6% of all salivary gland neoplasms and 2.9% of salivary gland malignancies.[3] Nearly 90% of tumors occurred in the parotid gland.[3,37] The average age of patients is reported to be 60 years.[3]

Similar to most salivary gland neoplasms, swelling is typically the only sign or symptom experienced.[37] A sudden increase in size may occur in a few patients.[38] Basal cell carcinomas are low-grade carcinomas that are infiltrative, locally destructive, and tend to recur. The carcinomas occasionally metastasize. In a retrospective series that included 29 patients, there were recurrences in 7 patients and metastases in 3 patients.[37] In another retrospective review that included 72 patients, 37% of the patients experienced local recurrences.[38] The overall prognosis for patients with this tumor is good.[37,38]

Clear cell carcinoma, also known as clear cell adenocarcinoma, is a very rare malignant epithelial neoplasm composed of a monomorphous population of cells that have optically clear cytoplasm with standard hematoxylin and eosin stains and lack features of other specific neoplasms. Because of inconsistencies in the methods of reporting salivary gland neoplasms, meaningful incidence rates for this tumor are difficult to derive from the literature.[3] Most cases involve the minor salivary glands.[1,3,39-41] In the AFIP case files, the mean age of patients is approximately 58 years.[3]

In most patients, swelling is the only symptom. Clear cell adenocarcinoma is a low-grade neoplasm. As of 1996, the AFIP reported that no patient is known to have died as a result of this tumor.[3]

Cystadenocarcinoma, also known as malignant papillary cystadenoma, mucus-producing adenopapillary, or nonepidermoid, carcinoma; low-grade papillary adenocarcinoma of the palate; and papillary adenocarcinoma, is a rare malignant epithelial tumor characterized histologically by prominent cystic and, frequently, papillary growth but lacking features that characterize cystic variants of several more common salivary gland neoplasms. Cystadenocarcinoma is the malignant counterpart of cystadenoma.[3]

In a review that included 57 patients, the AFIP found that men and women are affected equally; the average patient age was approximately 59 years; and approximately 65% of the tumors occurred in the major salivary glands, and primarily in the parotid.[3] Most patients present with a slowly growing asymptomatic mass. Clinically, this neoplasm is rarely associated with pain or facial paralysis. Cystadenocarcinoma is considered to be a low-grade neoplasm.[3]

Sebaceous adenocarcinoma is a rare malignant epithelial tumor composed of islands and sheets of cells that have morphologically atypical nuclei, an infiltrative growth pattern, and focal sebaceous differentiation. This is a very rare tumor, as few cases have been reported in the literature.[3] Almost all cases occur in the parotid gland.[3] The average age of patients is reported to be 69 years.[42]

An equal number of patients present with a painless, slow-growing, asymptomatic swelling or pain. A few experience facial paralysis.[3] Most sebaceous adenocarcinomas are probably intermediate-grade malignancies. Tumor recurs in about 33% of cases.[43,44]

Sebaceous lymphadenocarcinoma is an extremely rare malignant tumor that represents carcinomatous transformation of sebaceous lymphadenoma. The carcinoma element may be sebaceous adenocarcinoma or some other specific or nonspecific form of salivary gland cancer.[3] Only three cases have been reported in the literature.[43,45] The three cases occurred in or around the parotid gland. All patients were in their seventh decade of life. Two of the three patients were asymptomatic. One had tenderness on palpation. Case reports suggest that this is a low-grade malignancy with a good prognosis.[44,45]

Oncocytic carcinoma, also known as oncocytic adenocarcinoma, is a rare, predominantly oncocytic neoplasm whose malignant nature is reflected both by its abnormal morphologic features and infiltrative growth. Oncocytic carcinoma represents less than 1% of almost 3,100 salivary gland tumors accessioned to the AFIP files during a 10-year period.[3] Most cases occur in the parotid gland. The average age of patients in the AFIP series was 63 years.[3]

Approximately 33% of the patients usually develop parotid masses that cause pain or paralysis.[46] Oncocytic carcinoma is a high-grade carcinoma. Tumors smaller than 2 cm have a better prognosis than larger tumors.[6]

Salivary duct carcinoma, also known as salivary duct adenocarcinoma, is a rare, typically high-grade malignant epithelial neoplasm composed of structures that resemble expanded salivary gland ducts. A low-grade variant exists.[47] Incidence rates vary depending upon the study cited.[3] In the AFIP files, salivary duct carcinomas represent only 0.2% of all epithelial salivary gland neoplasms. More than 85% of cases involve the parotid gland and approximately 75% of patients are men. The peak incidence is reported to be in the seventh and eighth decades of life.[3]

Clinically, parotid swelling is the most common sign. Facial nerve dysfunction or paralysis occur in more than 25% of patients and may be the initial manifestation.[3] The high-grade variant of this neoplasm is one of the most aggressive types of salivary gland carcinoma and is typified by local invasion, lymphatic and hematogenous spread, and poor prognosis.[3,7] In a retrospective review of 104 cases, 33% of patients developed local recurrence, and 46% of patients developed distant metastasis.[48]

Mucinous adenocarcinoma is a rare malignant neoplasm characterized by large amounts of extracellular epithelial mucin that contains cords, nests, and solitary epithelial cells. The incidence is unknown. Limited data indicate that most, if not all, occur in the major salivary glands with the submandibular gland as the predominant site.[3,49] These tumors may be associated with dull pain and tenderness.[3,49] This neoplasm may be considered to be low grade.[3]

The classification of malignant mixed tumors, includes three distinct clinicopathologic entities: carcinoma ex pleomorphic adenoma, carcinosarcoma, and metastasizing mixed tumor. Carcinoma ex pleomorphic adenoma constitutes the vast majority of cases, whereas carcinosarcoma, a true malignant mixed tumor, and metastasizing mixed tumor are extremely rare.[3]

Carcinoma ex pleomorphic adenoma, also known as carcinoma ex mixed tumor, is a carcinoma that shows histologic evidence of arising from or in a benign pleomorphic adenoma.[50] Diagnosis requires the identification of benign tumor in the tissue sample.[51] The incidence or relative frequency of this tumor varies considerably depending on the study cited.[1] A review of material at the AFIP showed carcinoma ex pleomorphic adenoma to comprise 8.8% of all mixed tumors and 4.6% of all malignant salivary gland tumors, ranking it as the sixth most common malignant salivary gland tumor after mucoepidermoid carcinoma; adenocarcinoma, NOS; acinic cell carcinoma; polymorphous low-grade adenocarcinoma; and adenoid cystic carcinoma.[3] The neoplasm occurs primarily in the major salivary glands.[52]

The most common clinical presentation is a painless mass.[3] Approximately 33% of patients may experience facial paralysis.[53] Depending on the series cited, survival times vary significantly: 25% to 65% at 5 years, 24% to 50% at 10 years, 10% to 35% at 15 years, and 0% to 38% at 20 years.[3] In addition to tumor stage, histologic grade and degree of invasion are important parameters to determine prognosis.[54]

Carcinosarcoma, also known as true malignant mixed tumor, is a rare malignant salivary gland neoplasm that contains both carcinoma and sarcoma components. Either or both components are expressed in metastatic foci. Some carcinosarcomas develop de novo while others develop in association with benign mixed tumor. This neoplasm is rare; only eight cases exist in the AFIP case files.[3] At one facility, only 11 cases were recorded over a 32-year period.[8] The majority of tumors occur in the major salivary glands.

Swelling, pain, nerve palsy, and ulceration have been frequent clinical findings. Carcinosarcoma is an aggressive, high-grade malignancy. In the largest series reported, which consisted of 12 cases, the average survival period was 3.6 years.[8]

Metastasizing mixed tumor is a very rare histologically benign salivary gland neoplasm that inexplicably metastasizes. Often a long interval occurs between the diagnosis of the primary tumor and the metastases. The histologic features are within the spectrum of features that typify pleomorphic adenoma.[3] The majority occur in the major salivary glands. The primary neoplasm is typically a single, well-defined mass. Recurrences, which may be multiple, have been reported to occur for as many as 26 years after excision of the primary neoplasm.[55]

Primary squamous cell carcinoma, also known as primary epidermoid carcinoma, is a malignant epithelial neoplasm of the major salivary glands that is composed of squamous (i.e., epidermoid) cells. Diagnosis requires the exclusion of primary disease located in some other head and neck site; indeed, most squamous cell carcinomas of the major salivary glands represent metastatic disease.[3] This diagnosis is not made in minor salivary glands because distinction from the more common mucosal squamous cell carcinoma is not possible.[3] Previous exposure to ionizing radiation appears to increase the risk for developing this neoplasm.[11,56,57] The median time between radiation therapy and diagnosis of the neoplasm is approximately 15.5 years.[11] The reported frequency of this tumor among all major salivary gland tumors has varied from 0.9% to 4.7%.[3,10] In AFIP major salivary gland accessions from 1985 to 1996, primary squamous cell carcinoma comprised 2.7% of all tumors; 5.4% of malignant tumors; and 2.5% and 2.8%, respectively, of all parotid and submandibular tumors.[3] The average age in the AFIP registry was 64 years.[3] This neoplasm occurs in the parotid gland almost nine times more often than in the submandibular gland.[3,57] There is a strong male predilection.[3,11,57-59] This tumor is graded in a similar way to extrasalivary lesions according to the degree of differentiation, namely, low grade, intermediate grade, and high grade.[1]

Most patients present with an asymptomatic mass in the parotid region. Other symptoms may include a painful mass and facial nerve palsy.[57] The prognosis for this neoplasm is poor. In a 30-year retrospective analysis of 50 cases of squamous cell carcinoma of the salivary glands, survival rates at 5 years and 10 years were 24% and 18%, respectively.[57]

Epithelial-myoepithelial carcinoma, also known as adenomyoepithelioma, clear cell adenoma, tubular solid adenoma, monomorphic clear cell tumor, glycogen-rich adenoma, glycogen-rich adenocarcinoma, clear cell carcinoma, and salivary duct carcinoma, is an uncommon, low-grade epithelial neoplasm composed of variable proportions of ductal and large, clear-staining, differentiated myoepithelial cells. The tumor comprises approximately 1% of all epithelial salivary gland neoplasms.[3,60] It is predominantly a tumor of the parotid gland. In the AFIP case files, the mean age of patients is about 60 years and about 60% of the patients are female.[3]

Localized swelling is commonly the only symptom, but occasionally patients experience facial weakness or pain.[61,62] Overall, epithelial-myoepithelial carcinoma is a low-grade carcinoma that recurs frequently, has a tendency to metastasize to periparotid and cervical lymph nodes, and occasionally results in distant metastasis and death.[60,62-64]

Anaplastic small cell carcinoma of the salivary glands was first described in 1972.[65] Subsequent histochemical and electron microscopic studies have supported the neuroendocrine nature of this tumor.[66,67] Microscopically, the tumor cells have oval, hyperchromatic nuclei and scant amount of cytoplasm and are organized in sheets, strands, and nests. The mitotic rate is high. Neuroendocrine carcinomas are more frequently found in the minor salivary glands and have a better survival rate compared with small cell carcinomas of the lung.[68] The undifferentiated counterpart of this neoplasm is the small cell undifferentiated carcinoma.

Undifferentiated carcinomas of salivary glands are a group of uncommon malignant epithelial neoplasms that lack the specific light-microscopic morphologic features of other types of salivary gland carcinomas. These carcinomas are histologically similar to undifferentiated carcinomas that arise in other organs and tissues. Accordingly, metastatic carcinoma is a primary concern in the differential diagnosis of these neoplasms.[3]

Small cell undifferentiated carcinoma, also known as extrapulmonary oat cell carcinoma, is a rare, primary malignant tumor that, with conventional light microscopy, is composed of undifferentiated cells and, with ultrastructural or immunohistochemical studies, does not demonstrate neuroendocrine differentiation. This is the undifferentiated counterpart of anaplastic small cell carcinoma (Refer to the anaplastic small cell carcinoma section in the Cellular Classification of Salivary Gland Cancer section of this summary for more information.)

In an AFIP review of case files, small cell carcinoma represented 1.8% of all major salivary gland malignancies; the mean age of patients was 56 years.[3] In 50% of the cases, patients present with an asymptomatic parotid mass of 3 months' or less duration.[68-70] This is a high-grade neoplasm. In a retrospective review of 12 cases, a tumor size of more than 4 cm was found to be the most important predictor of behavior. In another small retrospective series, estimated survival rates at 2 and 5 years were 70% and 46%, respectively.[68]

Large cell undifferentiated carcinoma is a tumor in which features of acinar, ductal, epidermoid, or myoepithelial differentiation are absent under light microscopy, though occasionally, poorly formed ductlike structures are found. This neoplasm accounts for approximately 1% of all epithelial salivary gland neoplasms.[3,53,71,72] Most of these tumors occur in the parotid gland.[70,72] In AFIP data, the peak incidence is in the seventh to eighth decades of life.[3]

Rapid growth of a parotid swelling is a common clinical presentation.[59] This is a high-grade neoplasm that frequently metastasizes and has a poor prognosis. Neoplasms 4 cm or larger may have a particularly poor outcome.[70,72]

Lymphoepithelial carcinoma, also known as undifferentiated carcinoma with lymphoid stroma and carcinoma ex lymphoepithelial lesion, is an undifferentiated tumor that is associated with a dense lymphoid stroma. An exceptionally high incidence of this tumor is found in the Eskimo and Inuit populations.[3,73] This neoplasm has been associated with Epstein-Barr virus infection.[74,75] Of the occurrences, 80% are in the parotid gland.[3]

In addition to the presence of a parotid or submandibular mass, pain is a frequent symptom, and facial nerve palsy occurs in as many as 20% of patients.[76] (Refer to the PDQ summary on Pain for more information.) Of the patients, more than 40% have metastases to cervical lymph nodes at initial presentation, 20% develop local recurrences or lymph node metastases, and 20% develop distant metastases within 3 years following therapy.[73,76-78]

Myoepithelioma carcinoma is a rare, malignant salivary gland neoplasm in which the tumor cells almost exclusively manifest myoepithelial differentiation. This neoplasm represents the malignant counterpart of benign myoepithelioma.[3] To date, the largest series reported involves 25 cases.[79] Approximately 66% of the tumors occur in the parotid gland.[3,74] The mean age of patients is reported to be 55 years.[79]

The majority of patients present with the primary complaint of a painless mass.[79] This is an intermediate grade to high-grade carcinoma.[3,79] Histologic grade does not appear to correlate well with clinical behavior; tumors with a low-grade histologic appearance may behave aggressively.[79]

Adenosquamous carcinoma is an extremely rare malignant neoplasm that simultaneously arises from surface mucosal epithelium and salivary gland ductal epithelium. The carcinoma shows histopathologic features of both squamous cell carcinoma and adenocarcinoma. Only a handful of reports have discussed this tumor.[3]

In addition to swelling, adenosquamous carcinoma produces visible changes in the mucosa including erythema, ulceration, and induration. Pain frequently accompanies ulceration. Limited data indicate that this is a highly aggressive neoplasm with a poor prognosis.[3]

Lymphomas and benign lymphoepithelial lesion

Lymphomas of the major salivary glands are characteristically of the non-Hodgkin type. In an AFIP review of case files, non-Hodgkin lymphoma accounted for 16.3% of all malignant tumors that occurred in the major salivary glands; disease in the parotid gland accounted for about 80% of all cases.[3]

Patients with benign lymphoepithelial lesion (e.g., Mikulicz disease), which is a manifestation of the autoimmune disease, Sjgren syndrome, are at an increased risk for development of non-Hodgkin lymphoma.[80-84] Benign lymphoepithelial lesion is clinically characterized by diffuse and bilateral enlargement of the salivary and lacrimal glands.[23] Morphologically, a salivary gland lesion is composed of prominent myoepithelial islands surrounded by a lymphocytic infiltrate. Germinal centers are often present in the lymphocytic infiltrate.[23] Immunophenotypically and genotypically, the lymphocytic infiltrate is composed of B-lymphocytes and T-lymphocytes, which are polyclonal. In some instances, the B-cell lymphocytic infiltrate can undergo clonal expansion and evolve into frank non-Hodgkin lymphoma. The vast majority of the non-Hodgkin lymphomas arising in a background of benign lymphoepithelial lesions are marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT).[81-84] MALT lymphomas of the salivary glands, like their counterparts in other anatomic sites, typically display relatively indolent clinical behavior.[3,85]

Primary non-MALT lymphomas of the salivary glands may also occur and appear to have a prognosis similar to those in patients who have histologically identical nodal lymphomas.[86,87] Unlike non-Hodgkin lymphoma, involvement of the major salivary glands by Hodgkin lymphoma is rare. Most tumors occur in the parotid gland.[3] The most common histologic types encountered are the nodular sclerosing and lymphocyte-predominant variants.[88,89]

Mesenchymal neoplasms

Mesenchymal neoplasms account for 1.9% to 5% of all neoplasms that occur within the major salivary glands.[90,91] These cellular classifications pertain to major salivary gland tumors. Because the minor salivary glands are small and embedded within fibrous connective tissue, fat, and skeletal muscle, the origin of a mesenchymal neoplasm from stroma cannot be determined.[3] The types of benign mesenchymal salivary gland neoplasms include hemangiomas, lipomas, and lymphangiomas.

Malignant mesenchymal salivary gland neoplasms include malignant schwannomas, hemangiopericytomas, malignant fibrous histiocytomas, rhabdomyosarcomas, and fibrosarcomas, among others; in the major salivary glands, these neoplasms represent approximately 0.5% of all benign and malignant salivary gland tumors and approximately 1.5% of all malignant tumors.[90,92,93] Of importance is to establish a primary salivary gland origin for these tumors by excluding the possibilities of metastasis and direct extension from other sites. In addition, the diagnosis of salivary gland carcinosarcoma should be excluded.[3] Primary salivary gland sarcomas behave like their soft tissue counterparts in which prognosis is related to sarcoma type, histologic grade, tumor size, and stage.[93,94] (Refer to the PDQ summary on Adult Soft Tissue Sarcoma Treatment for more information.) A comprehensive review of salivary gland mesenchymal neoplasms can be found elsewhere.[95]

Malignant neoplasms whose origins lie outside the salivary glands may involve the major salivary glands by:[3]

Direct invasion of nonsalivary gland tumors into the major salivary glands is principally from squamous cell and basal cell carcinomas of the overlying skin.

Approximately 80% of metastases to the major salivary glands may be from primary tumors elsewhere in the head and neck; the remaining 20% may be from infraclavicular sites.[96,97] The parotid gland is the site of 80% to 90% of the metastases, and the remainder involve the submandibular gland.[97,98] In a decade-long AFIP experience, metastatic tumors constituted approximately 10% of malignant neoplasms in the major salivary glands, exclusive of malignant lymphomas.[3] The majority of metastatic primary tumors to the major salivary glands are squamous cell carcinomas and melanomas from the head and neck that presumably reach the parotid gland via the lymphatic system; infraclavicular primary tumors, such as the lung, kidney, and breast, reach the salivary glands by a hematogenous route.[97-99] The peak incidence for metastatic tumors in the salivary glands is reported to be in the seventh decade of life.[3]

In general, tumors of the major salivary glands are staged according to size, extraparenchymal extension, lymph node involvement (in parotid tumors, whether or not the facial nerve is involved), and presence of metastases.[1-4] Tumors arising in the minor salivary glands are staged according to the anatomic site of origin (e.g., oral cavity and sinuses).

Clinical stage, particularly tumor size, may be the critical factor to determine the outcome of salivary gland cancer and may be more important than histologic grade.[5,6] Diagnostic imaging studies may be used in staging. With excellent spatial resolution and superior soft tissue contrast, magnetic resonance imaging (MRI) offers advantages over computed tomographic scanning in the detection and localization of head and neck tumors. Overall, MRI is the preferred modality for evaluation of suspected neoplasms of the salivary glands.[7]

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification to define salivary gland cancer.[5]

The minimum therapy for low-grade malignancies of the superficial portion of the parotid gland is a superficial parotidectomy. For all other lesions, a total parotidectomy is often indicated. The facial nerve or its branches should be resected if involved by tumor; repair can be done simultaneously. Growing evidence suggests that postoperative radiation therapy augments surgical resection, particularly for the high-grade neoplasms, when margins are close or involved, when tumors are large, or when histologic evidence of lymph node metastases is present.[1-8] Clinical trials, which have been completed in the United States and England, indicate that fast neutron-beam radiation therapy improves disease-free survival and overall survival in patients with unresectable tumors or for patients with recurrent neoplasms.[9-12] Facilities with fast neutron-beam radiation therapy are of limited availability in the United States. Accelerated hyperfractionated photon-beam radiation therapy has also resulted in high rates of long-term local regional controls.[13,14] The use of chemotherapy for malignant salivary gland tumors remains under evaluation.[15-19]

Low-grade stage I tumors of the salivary gland are curable with surgery alone.[1-3] Radiation therapy may be used for tumors for which resection involves a significant cosmetic or functional deficit or as an adjuvant to surgery when positive margins are present.[4] Neutron-beam therapy is effective in the treatment of poor-prognosis patients with malignant salivary gland tumors.[5-7]

High-grade stage I salivary gland tumors that are confined to the gland in which they arise may be cured by surgery alone, though adjuvant radiation therapy may be used, especially with the presence of positive margins.

Standard treatment options:

Standard treatment options:

Treatment options under clinical evaluation:

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage I salivary gland cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Low-grade stage II tumors of the salivary gland may be cured with surgery alone.[1-3] Radiation therapy as primary treatment may be used for tumors for which resection involves a significant cosmetic or functional deficit or as an adjuvant to surgery when positive margins are present.[4]

High-grade stage II salivary gland tumors that are confined to the gland in which they arise may be cured by surgery alone, though adjuvant radiation therapy may be used, especially if positive margins are present. Primary radiation therapy may be given for tumors that are inoperable, unresectable, or recurrent. Fast neutron-beam radiation therapy has been shown to improve disease-free survival and overall survival in this clinical situation.[5-7]

Standard treatment options:

Standard treatment options:

Read more:
Salivary Gland Cancer Treatment - National Cancer Institute

Practice Details Practice Number: 0175986 Qualifications: MBChB (Stell), MMed(Int)(Stell), DipHIVMan(CMSA), BScHons(MedSc)(Epidemiology&Statistics)(Stell) Office Contact Person: Hanli, Amelia or Fatima (Practice manager) Telephone No: 021948 4776 Fax No: 021948 3350 Cell No: 083292 4212 After Hours Telephone No: 083292 4212 Email Address: emille@egreid.com Website Address: Physical Address: Suite 4H, Fourth Floor, Riverside View, Netcare Kuils River, Van Riebeeck Road, Kuils River, 7580 Social Networks Postal Address: PO Box 150, Soneike, 7583 Detailed information and specialities Emille Reid is a specialist with an interest in Infectious Diseases. He runs a busy HIV clinic (as part of his general practice) and provide evidence-based in-hospital care as part of a supportive medical team of specialists at the Netcare Kuils River Hospital. He has a particular interest in caring for the critically ill whilst in icu as well as those suffering from HIV, TB and general- and tropical infections infections. He is a keen teacher who very often give lectures at medical school and provide training to nurses, general practitioners and specialists. Contact Form Please feel free to contact the doctor or if you have any questions for the doctor please fill in the form below: Map GPS Co-Ordinates: View Larger Map

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Dr Emille Reid | Physician | Kuils River | Cape Town

Cells are the basic building blocks of all living things. The human body is composed of trillions of cells. They provide structure for the body, take in nutrients from food, convert those nutrients into energy, and carry out specialized functions. Cells also contain the bodys hereditary material and can make copies of themselves.

Cells have many parts, each with a different function. Some of these parts, called organelles, are specialized structures that perform certain tasks within the cell. Human cells contain the following major parts, listed in alphabetical order:

Within cells, the cytoplasm is made up of a jelly-like fluid (called the cytosol) and other structures that surround the nucleus.

The cytoskeleton is a network of long fibers that make up the cells structural framework. The cytoskeleton has several critical functions, including determining cell shape, participating in cell division, and allowing cells to move. It also provides a track-like system that directs the movement of organelles and other substances within cells.

This organelle helps process molecules created by the cell. The endoplasmic reticulum also transports these molecules to their specific destinations either inside or outside the cell.

The Golgi apparatus packages molecules processed by the endoplasmic reticulum to be transported out of the cell.

These organelles are the recycling center of the cell. They digest foreign bacteria that invade the cell, rid the cell of toxic substances, and recycle worn-out cell components.

Mitochondria are complex organelles that convert energy from food into a form that the cell can use. They have their own genetic material, separate from the DNA in the nucleus, and can make copies of themselves.

The nucleus serves as the cells command center, sending directions to the cell to grow, mature, divide, or die. It also houses DNA (deoxyribonucleic acid), the cells hereditary material. The nucleus is surrounded by a membrane called the nuclear envelope, which protects the DNA and separates the nucleus from the rest of the cell.

The plasma membrane is the outer lining of the cell. It separates the cell from its environment and allows materials to enter and leave the cell.

Ribosomes are organelles that process the cells genetic instructions to create proteins. These organelles can float freely in the cytoplasm or be connected to the endoplasmic reticulum (see above).

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What is a cell? - Genetics Home Reference

Abstract

Five proteins are ejected from the bacteriophage T7 virion at the initiation of infection. The three known proteins of the internal core enter the infected cell; all three must both disaggregate from their structure in the mature virion and also almost completely unfold in order to leave the head and pass through the headtail connector. Two small proteins, the products of genes 6.7 and 7.3, also are ejected from the infecting virion. Gp6.7 and gp7.3 were not previously described as structural virion components, leading to a re-appraisal of the stoichiometry of virion proteins. Gp6.7 is found in tail-less particles and is defined as a head protein, whereas gp7.3 is localized in the tail. Gene 6.7 may be important in morphogenesis; mutants defective in this late gene yield a reduced burst of progeny. Gene 7.3 is essential for virion assembly but, although normally present, its product gp7.3 is not required in a mature particle. Particles assembled in the absence of gp7.3 contain tail fibers but fail to adsorb to cells.

The virions of bacteriophages T3 and T7 are very similar and have a fairly simple structure (Fig. 1). The icosahedral head has a diameter of 60 to 61 nm with a shell that is 2 nm thick (Stroud et al., 1981andRont et al., 1983). The outer shell is composed of two forms of the gene 10 protein, which are made via a programmed translational frameshift near the 3 end of the shorter gene 10A ( Dunn and Studier, 1983, Condreay et al., 1989, Condron et al., 1991aandCondron et al., 1991b). Inserted at one vertex is the headtail connector, composed of 12 gp8 molecules ( Carazo et al., 1986, Cerritelli and Studier, 1996, Kocsis et al., 1995andValpuesta et al., 1992). The connector has a 12-lobed wide domain inserted into the head cavity and a narrower domain that interacts with the tail ( Valpuesta et al., 1992andValpuesta et al., 2000). A channel, which is closed in mature virions, runs through the center of the connector (Donate et al., 1988). Inside the head, and attached to the headtail connector in the coaxial orientation, is a 26 nm21 nm cylindrical structure that is usually referred to as the internal core ( Serwer, 1976, Serwer et al., 1997andSteven and Trus, 1986). The core has recently been shown to exhibit 8-fold symmetry (Cerritelli et al., 2003), it consists of stacked rings and contains three distinct proteins, the products of genes 14, 15, and 16. The 40-kb genome is spooled around the internal core in six coaxial shells ( Cerritelli et al., 1997). Unlike most other tailed phages, the T7 tail is not assembled as a separate structure but forms directly on the DNA-filled head ( Studier, 1972, Serwer, 1976, Roeder and Sadowski, 1977andMatsuo-Kato et al., 1981). The stubby tail is 23 nm long, tapering from a diameter of 21 nm at the connector to 9 nm at its distal end, and is known to consist of two major proteins gp11 and gp12 ( Studier, 1972andSteven and Trus, 1986). Attached near the head proximal end of the tail are six symmetrically positioned tail fibers. Each fiber is composed of a trimer of gp17 that forms a kinked structure ( Kato et al., 1985, Kato et al., 1986andSteven et al., 1988). The N-terminal 150 residues of gp17 link the fiber to the tail, the next 117 residues fold into an -helix, forming a 16.4-nm rod that is flexibly joined to the 15.5-nm distal half fiber. The latter consists of a linear array of four globules that is thought to bind directly to the bacterial cell.

Bacteriophage T7 initiates an infection of Escherichia coli by the interaction of its tail fibers with the lipopolysaccharide (LPS) on the cell surface. Interaction of all six tail fibers with LPS would orient the phage tail perpendicular to the cell surface, conferring efficiency to subsequent stages of infection. However, the stubby T7 tail is too short to span the E. coli cell envelope and a channel needs to be made to allow the phage genome to travel from the virion into the cytoplasm. It was proposed that virion proteins are ejected into the cell, functionally endowing T7 with an extensible tail, in contrast to the well-known contractile tail of T4 and other Myoviridae ( Molineux, 2001). In testing this suggestion, we show here that five T7 proteins are ejected from the virion into the cell at the initiation of infection. Two of these proteins were not previously known to be part of the virion, an observation that prompted a re-evaluation of the protein composition of the T7 particle.

In order to determine which T7 virion proteins become irreversibly associated with the infected cell, adsorbed particles were gently eluted by extensive washing in pure water. Prior to infection, cells of the E. coli K-12 strain IJ1133 were treated with rifampicin so that phage development would be inhibited after the first 850 bp of the T7 genome had been translocated into the cell and there would be no phage gene expression ( Garca and Molineux, 1995, Garca and Molineux, 1996andStruthers-Schlinke et al., 2000). Adsorption of the T7 tail fibers to E. coli LPS occurs through electrostatic interactions ( Puck et al., 1951, Luria, 1953andTolmach, 1957), and the reduction in ionic strength during washing causes dissociation of the phage from the cell. A similar protocol was used to identify P22 proteins that are ejected into the host cell (Israel, 1977). Elution results in the removal of the majority of the major and minor forms of the T7 capsid protein gp10, the headtail connector gp8, and the tail proteins gp11, gp12, and gp17 (Fig. 2A). In contrast, the majority of the internal core proteins gp14, gp15, and gp16 remain stably associated with the cell during the elution regimen. At the initiation of infection, the internal core must therefore disaggregate in order to allow its constituent proteins to be ejected from the virion into the cell. Two small virion proteins, gp6.7 and gp7.3, are also ejected from the virion but are degraded in infected wild-type cells. The proteins can be stabilized when the multiply protease-deficient strain HM130 is infected (data not shown). It is not yet known which of degP, lon, tsp, or ptr, missing in strain HM130 ( Meerman and Georgiou, 1994), is responsible.

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Changes in bacteriophage T7 virion structure at the ...

Our Board of Directors is a group of volunteers committed to the Foundations mission to find a cure for retinitis pigmentosa, macular degeneration and related diseases of the retina. The Board includes representatives from the corporate and medical worlds, as well as individuals affected by vision loss.

Andrew Burke, Chair Partner, Stewart McKelvey Halifax, Nova Scotia

JoeGrech, Vice-Chair Vancouver, British Columbia

Rahn Dodick, Treasurer President, Dodick Landau Inc. Toronto, Ontario

Malcolm Hunter, Corporate Secretary President, Fred Deeley ImportsLtd. Vancouver, British Columbia

John Breen, Executive Officer SeniorExecutive Investment Officer, Sanabil Al-Saudia Investments

Catherine Tillmann, Executive Officer Director of Brand Image, Corporate Marketing, Four Seasons Hotels and Resorts(retired) Toronto, Ontario

Donna Green, Past Chair Principal, Greenrock Investments / Chief Executive Officer, Glittering Investments Limited Toronto, Ontario

Michel Cayouette, PhD Research Unit Director, Institut de recherches cliniques de Montreal (IRCM) Research Associate Professor, University of Montreal Montreal, Quebec

David Drury General Manager, IBM Canada Ltd. Toronto, Ontario

Sherif El-Defrawy, MD, PhD, FRCSC Chief of Ophthalmology, University of Toronto Toronto, Ontario

Peter FarmerDirector, Strategic Partnerships, Rogers CommunicationsToronto, Ontario

Jane Humphreys Toronto, Ontario

Peter J. Kertes, MD, FRCSC Vitreoretinal Surgeon/Ophthalmologist-in-Chief, Sunnybrook Health Sciences Centre Professor of Ophthalmology & Vision Sciences, University of Toronto Toronto, Ontario

Gary Mandel President, CEO, Independent Financial Concepts Group Ltd. Toronto, Ontario

Michael Ovens Process Analyst, Change Management, Bank of Montreal Toronto, Ontario

Lorna L. Rosenstein General Manager, Lotus Canada(retired) Toronto, Ontario

George Sheen Partner, PwC (retired) Toronto, Ontario

Raymond M. Stein, MD, FRCSC Medical Director, Bochner Eye Institute Toronto, Ontario

David D. Sweeny Director, RBC Capital Markets Toronto, Ontario

Deborah Tennant Toronto, Ontario

The Foundation Fighting Blindness Scientific Advisory Board (SAB) is a group of highly qualified and committed volunteers. These scientists bring a wide range of expertise to the FFBs scientific decision-making in genetics, molecular genetics, molecular biology, biochemistry and cell biology. All are actively engaged in sight-saving research.

The SAB is responsible for evaluating research applications submitted to the FFBs annual grant competition(s).

SAB members also aid in promoting retinal disease research amongst the scientific community and support the quality and accuracy of our educational programs and materials. Rigorous review for scientific merit by the SAB ensures that dollars donated to the FFB are used to fund the most productive and promising research projects, addressing crucial questions about the causes and treatment of retinal degenerative diseases. Thanks to the guidance of our scientific advisory boards, past and present, scientists funded by the FFB have consistently accomplished their research goals and have been responsible for major research breakthroughs.

Dr. Rod Bremner, PhD (Interim Chair) Senior Investigator, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital Professor of Ophthalmology; Laboratory Medicine & Pathobiology, University of Toronto

Dr. Seth Blackshaw, PhD Associate Professor in the Department of Neuroscience at the Johns Hopkins University School of Medicine, Baltimore

Dr. Sylvain Chemtob Sylvain Chemtob, MD, PhD Professor, Departments of Pediatrics, Ophthalmology and Pharmacology, University of Montreal

Dr. Brian Link Brian A. Link, PhD Associate Professor of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin

Dr. Orson Moritz Orson Moritz, PhD Associate Professor of Ophthalmology and Visual Science, University of British Columbia

Dr. Bill Stell Bill Stell, PhD (non-voting member) Expert Scientific Advisor for the Foundation Fighting Blindness Professor of Cell Biology and Anatomy; Ophthalmology; Neurosciences, University of Calgary

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The Foundation Fighting Blindness Leadership

Summary

The transport of calcium ions (Ca2+) to the cytosol is essential for immunoreceptor signaling, regulating lymphocyte differentiation, activation, and effector function. Increases in cytosolic-free Ca2+ concentrations are thought to be mediated through two interconnected and complementary mechanisms: the release of endoplasmic reticulum Ca2+ stores and store-operated Ca2+ entry via plasma membrane channels. However, the identity of molecular components conducting Ca2+ currents within developing and mature Tcells is unclear. Here, we have demonstrated that the L-type voltage-dependent Ca2+ channel CaV1.4 plays a cell-intrinsic role in the function, development, and survival of naive Tcells. Plasma membrane CaV1.4 was found to be essential for modulation of intracellular Ca2+ stores and Tcell receptor (TCR)-induced rises in cytosolic-free Ca2+, impacting activation of Ras-extracellular signal-regulated kinase (ERK) and nuclear factor of activated Tcells (NFAT) pathways. Collectively, these studies revealed that CaV1.4 functions in controlling naive Tcell homeostasis and antigen-driven Tcell immune responses.

CaV1.4 is required for store-operated calcium entry by naive CD4+ and CD8+ Tcells CaV1.4 regulates TCR-induced Ras-ERK and NFAT signaling CaV1.4 modulates the survival of naive CD4+ and CD8+ Tcells Cav1.4 is critical for pathogen-specific CD4+ and CD8+ Tcell responses

Calcium (Ca2+) ions act as universal second messengers in virtually all cell types, including cells of the immune system. In lymphocytes, Ca2+ signals modulate the activation of calcineurin-nuclear factor of activated Tcells (NFAT) and Ras-Mitogen-activated protein kinases (MAPK) pathways, serving to regulate cell activation, proliferation, differentiation, and apoptosis (Oh-hora, 2009andVig and Kinet, 2009). Tcell receptor (TCR) stimulation invokes rises in cytosolic Ca2+ through the activation of phospholipase C-1 (PLC1) and the associated hydrolysis of phosphatidylinositol-3,4-bisphosphate (PIP2) into inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). Subsequently, IP3 binds IP3 receptors in the endoplasmic reticulum (ER) and induces Ca2+ release from ER storesthus triggering store-operated Ca2+ entry (SOCE) from outside the cell via plasma membrane channels (Oh-hora, 2009andVig and Kinet, 2009). For Ca2+ signaling to affect Tcell fate or effector functions, sustained Ca2+ influx via plasma membrane channels is probably necessary for a number of hours, maintaining cytoplasmic Ca2+ concentrations higher than resting baseline (Oh-hora, 2009).

The identity and number of plasma membrane channels mediating sustained Ca2+ entry into Tcells is unclear (Kotturi etal., 2006). One well-characterized mechanism of entry is through Ca2+ release-activated calcium (CRAC) channels (Oh-hora, 2009). In the CRAC pathway, the Ca2+ sensor STIM1 responds to decreases in ER Ca2+ stores by associating with the CRAC channel pore subunit ORAI1 and activating SOCE. However, loss of ORAI1 in naive Tcells has been found to have minimal effects on their ability to flux Ca2+ or proliferate upon TCR stimulation (Gwack etal., 2008andVig etal., 2008). Other candidate plasma membrane Ca2+ channels operating in lymphocytes include the P2X receptor, transient receptor potential (TRP) cation channels, TRP vanilloid channels, TRP melastatin channels, and voltage-dependent Ca2+ channels (VDCC). It is unknown whether the repertoire of Ca2+ channels operating in Tcells remains constant or changes during various stages of development or differentiation.

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The CaV1.4 Calcium Channel Is a Critical Regulator of T ...

Dr. Meyer has been passionately involved with the CEREC (CAD/CAM) system for the past ten years. She specializes in front crowns and veneers (smile makeovers), and full mouth rehabilitations as well as teeth whitening. She understands the high aesthetic demands of her patients very well, and can meet them with her expertise and has a highly specialized dental practice. The most modern updated equipment includes CEREC 3D computers, milling units, lasers, baking ovens and the absolute state of the art X-ray Galileos CT unit. For more info on our services follow the links below: Teeth Whitening CEREC Crowns CEREC Veneers Dental Implants Stem Cell Harvesting

Dentistry, Full Mouth Rehabilitations, Gum Surgery Cosmetic Dentistry, CEREC Crowns, CEREC Veneers, Dental Implants, Gum Surgery, Tooth Whitening, Stem Cell Harvesting, Botox Tooth Decay, Broken/missing teeth, Old silver/amalgam fillings,Antibiotic stained, Chipped or mild crooked teeth,Yellow teeth,Loss of a tooth,Loose and/or ill fitting dentures,Severe grinding,Bad breath and/or periodontal (gum) disease CAD/CAM (computer aided design/computer aided milling) system, CEREC Cosmetic Dentist, Crowns, Veneers, Dental Implants, Dentist, Tooth Whitening, Tooth decay Most procedures can be done in +/- 1 hour in the dental chair, All procedures are fully computerized, Our practice is fitted and equipped with the latest state of the art technology and equipment that is available in the world today.

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Dr Ad Meyer | Cosmetic and Reconstructive Dentist ...

Description of Research Expertise:

I am a hematologist-oncologist with a specific research and clinical interest in plasma cell disorders and related dysproteinemias: multiple myeloma, immunoglobulin light chain (AL) amyloidosis, and Waldenstroms macroglobulinemia.

I also lead the multi-disciplinary Penn Amyloidosis Program. This is a cross-disciplinary program involving clinicians with expertise in amyloidosis from cardiology, nephrology, pathology and other disciplines.

I am involved in clinical, translational and epidemiologic research throughout the spectrum of plasma cell disorders. My primary research focus is on the myeloma precursor states: monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). I have previously established that both multiple myeloma (Weiss Blood 2009) and AL amyloidosis (Weiss J Clin Oncol 2014) have precursor states that are detectable for many years prior to diagnosis. I have also validated biomarkers for ultra-high risk SMM (Waxman Leukemia 2014) that have contributed to changing the diagnostic criteria for multiple myeloma requiring treatment (Rajkumar Lancet Oncol 2014).

I am currently performing trials to develop and test novel biomarkers for progression in the myeloma precursor states (MGUS and SMM). I am also participating in trials of early intervention in high risk SMM.

I am also conducting trials of novel agents for AL amyloidosis and relapsed and refractory multiple myeloma.

Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, Kumar S, Hillengass J, Kastritits E, Richardson P, Landgren O, Paiva B, Dispenzieri A, Weiss B, LeLeu X, Zweegman S, Lonial S, Rosinol L, Zamagni E, Jaganath S, Sezer O, Kristinsson SY, Caers J, Usmani SZ, Laheurta JJ, Johnsen HE, Beksac M, Cavo M, Goldschmidt H, Terpos E, Kyle RA, Anderson KC, Durie BGM, San Miguel JF: International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma Lancet Oncol 15 : e538-48,2014.

Weiss BM, Hebreo J, Cordaro DV, Roschewski MJ, Baker TP, Abbott KC, Olson SW: Increased Serum Free Light Chains Precede the Presentation of Immunoglobulin Light Chain Amyloidosis J Clin Oncol 32 (25): 2699-704,2014.

Waxman AJ, Mick R, Garfall AL, Cohen A, Vogl DT, Stadtmauer EA, Weiss BM: Classifying ultra-high risk smoldering myeloma Leukemia : 2014.

Weiss BM: Multiethnic myeloma Blood 121 (16): 3062-4,2013.

Fermand JP, Bridoux F, Kyle RA, Kastritis E, Weiss BM, Cook MA, Drayson MT, Dispenzieri A, Leung N; International Kidney and Monoclonal Gammopathy Research Group.: How I treat monoclonal gammopathy of renal significance (MGRS) Blood 122 (22): 3583-90,2013.

Minter AR, Simpson H, Weiss BM, Landgren O: Bone Disease From Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma: Pathogenesis, Interventions, and Future Opportunities. Seminars in Hematology 48 (1): 55-65,2011.

Weiss BM, Minter A, Abadie J, Howard R, Ascencao J, Schechter GP, Kuehl M, Landgren O: Patterns of Monoclonal Immunoglobulins and Serum Free Light Chains Are Significantly Different in African-American Compared to Caucasian MGUS Patients. American Journal of Hematology 86 (6): 475-8,2011.

Waxman AJ, Mink PJ, Devesa SS, Anderson WF, Weiss BM, Kristinsson SY, McGlynn KA, Landgren O: Racial disparities in incidence and outcome in multiple myeloma: a population-based study. Blood 116 (25): 5501-5506,2010.

Weiss BM, Abadie J, Verma P, Howard RS, Kuehl WM: A monoclonal gammopathy precedes multiple myeloma in most patients. Blood 113 (22): 5418-5422,2009.

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Brendan M. Weiss, MD profile| PennMedicine.org

Dominant Demyelinating CMT1A PMP-22 17p11.2-12 (duplication/point mutations) myelination, cell growth, differentiation progressive distal muscle weakness and atrophy, mostly at lower extremities, peroneal gait, areflexia MNCV< 38 m/s, median MNCV 15-30m/s, no conduction block CMT1B MPZ/P0 1q22 adhesion proteins onset in first decade, variable degree of progressive distal muscle weakness MNCV < 20 m/s (in patients with early onset) > 38 m/s (in patients with late onset) CMT1C LITAF/SIMPLE 16p13 protein degradation typical CMT1 MNCV 1625 m/s CMT1D EGR2/Krox20 10q21-22 transcription factor upregulation of myelin genes cranial nerve involvement progressive scoliosis MNCV 942 m/s CMT1F NEFL 8q21 neurofilaments organization, axonal transport onset in early childhood, delayed motor development, severe CMT1 phenotype, similar to DSS MNCV 1538 m/s Special forms: HNPP PMP-22 17p11.2-12 deletion/point mutations) episodes of painless weakness, calf hypertrophy, asymmetrical, CNS demyelination, dystonia rarely, corticosteroid efficient in some patients normal, or mild decreasing, conduction block at pressure site, prolonged distal latencies Neuropathy with hearing impairment connexin -31 (GJB3) 1p35.1 ion channel formation predominantly sensory neuropathy, variable disease severity, asymmetrical hearing loss MNCV and SNCV mildly reduced SNAPs and CMAPs mildly decreased Hypomyelinating neuropathy without clinical symptoms ARGHEF 10 8p23 development of peripheral nerve myelination clinically asymptomatic MNCV 2742 m/s, CMAPs and SNAPs normal Dominant:Axonal CMT2A MFN2 1p33-36 GTP-ase, axonal transport of mitochondria severe, early onset, hearing loss, CNS and pyramidal tract involvement very low CMAPs and SNAPs normal or slightly reduced NCV KIF1B 1p33-36 synaptic vesicle transport CMT2B RAB7 3q13-q22, intracellular membrane traffic sensory loss, feet ulcerations distal motor weakness, hyperkeratosis Normal MNCV CMT2C unknown 12q23-q24 diaphragmal and vocal cord paresis, death normal MNCV CMT2D GARS 7p15 translation process, motor neuron integrity small hand muscles atrophy normal MNCV CMT2E NEFL 8p21 axonal transport, neurofilament organization sensory loss of all modalities MNCV 13-38 m/s CMT2F HSPB1 (HSP27) 7q11-q21 protection of the structure of cell proteins sensory loss, motor impairment of different severity, small hand muscles atrophy later in the course of disease reduced or absent CMAPs CMT2G unknown 12q12-13.3 slowly progressive walking difficulties, preserved knee jerks, absent triceps surae jerks MNCV normal or mildly reduced CMT2H/K GDAP1 8q13-21.1 mitochondrial protein expressed mostly in neurons, regulation of mitochondrial dynamics mild clinical phenotype, vocal cord paralysis, slowly progressive course MNCV slightly decreased or in intermediate range CMT 2I/J MPZ 1q22-23 deafness, Adie pupils MNCV <38 m/s, progress to reduced MNCV CMT2L HSPB8/HSP22 12q24.3 mild sensory loss, scoliosis normal MNCV Dominant:Intermediate DI-CMTA unknown 10q24.1-q25.1 CMT phenotype of moderate severity MNCV 25-45 m/s DI-CMTB dynamin 2 19q12-q13.2 vesicular traffic, endocytosis protein synthesis normal or increased tendon reflexes neutropenia DI-CMTC YARS 1p34-p35 CMT phenotype of moderate severity DI-CMTD MPZ 1q22 variable and moderate severity Dominant: X-linked CMTX1 GJB1 Xq13.1 encodes connexin32, transfer of low weight material between cells hand/thenar muscles, CNS involvement, deafness, visual impairment, white matter lesion conduction block, temporal dispersion MNCV 30-40 m/s in males, MNCV 10-37 m/s in severely affected males MNCV 3050 m/s in females, low CMAPs CMT 3A (DSS) PMP22 17p11.2-12 onset<3y,palpable nerves, ataxia, progressive weakness, severe disability, increased CSF protein content, short stature NCV <10 m/s, fibrillation, positive denervation waves CMT 3B MPZ 1q22-23 onset in infancy, hypotonia, respiratory insufficiency and early deaths occasionally MNCV < 15 m/s CMT 3C unknown 8q23-q24 Charcot joints decreased MNCV DSS-EGR EGR2 10q21-22 phenotype consistent with DSS, cranial nerve involvement, respiratory difficulties MNCV < 8 m/s CMT 3D or CMT 4F periaxin 19q13.1 q13.2 maintenance of the peripheral nerve myelin extracelular matrix signaling unusual facies, deafness very slow MNCV Recessive:demyelinating CMT 4A GDAP1 8q13-21.1 early onset, severe motor retardation, progressive scoliosis MNCV 2535 m/s CMT 4B-1 MTMR2 11q22 transcription and cell proliferation cranial nerves affection, blindness, glaucoma, severe disability MNCV 922m/s CMT 4B-2 MTMR13/SBF2 11p15 onset at 5 years, early onset glaucoma, similar to CMT4B1 phenotype MNCV 1530 m/s CMT 4C KIAA1985 5q23-33 unknown function early onset, severe motor retardation, scoliosis respiratory insufficiency MNCV 1034 m/s CMT 4D (HSMN-Lom) NDRG1 8q24.3 cell growth arrest and differentiation deafness, tongue atrophy Roma population MNCV 920 m/s CMT 4E EGR2 10q 21.1-22 17p onset presented at birth, generalized hypotonia, arthrogryposis, cranial nerves involvement MNCV< 8m/s CMT 4F periaxin 19q13.1-q13.3 maintenance of peripheral nerve myelin, extracellular matrix signaling severe DSS or CMT1 phenotype, curvilinear inclusions in nerves MNCV <15 m/s, CMAPs absent or very low CMT 4G (Russe) unknown 10q23.2 severe distal muscle weakness, prominent sensory loss, frequently in Roma population MNCV 3035 m/s CMT 4H unknown 12p11.21 delay in motor development, scoliosis MNCV < 15 m/s low amplitudes CMT 4J FIG4 6q21 phosphoinositides content vesicular trafficking early onset, coordination disorder, severe disability MNCV 27 m/s CMAPs reduced CCFDN CTDP1 18q23 regulation of proteins involved in transcription and mRNA processing congenital cataract, mental retardation, facial dysmorphism, growth retardation, chorea, tremor, rhabdomyolisis, more frequently in Roma population MNCV 1933 m/s Recessive:Axonal CMT4C1 or AR CMT 2B1 lamin A/C 1q21.2-q21.3 nuclear lamina component, gene transcription rapid evolution involvement of proximal muscles reduced CMAPs, normal MNCV CMT4C2 or AR-CMT 2C or AR CMT 2H unknown 8q21.3 brisk patellar and upper limbs reflexes, ankle reflexes absent, plantar anattainable normal or mildly reduced MNCV, reduced CMAPs amplitude CMT4C3 Or AR CMT2B2 ARC 92/ACID1 (MED 25) 19q13.3 mediator complex associated with RNA polymerase II typical CMT2 phenotype reduced CMAPs mild decrease of MNCV CMT4C4 Or AR CMT 2K GDAP1 8q13-21.1 early onset, hypotonia, kyphoscoliosis, progressive course, hoarse voice, vocal cord paralysis, respiratory insufficiency MNCV> 40 m/s, absent CMAPs Recessive-X-linked CMTX2 unknown Xq 22.2 areflexia, pes cavus, mental retardation, unaffected females decreased NCV, low CMAPs CMTX3 unknown Xq26.3-q27.1 onset 313 years, progressive muscle weakness, normal mental development low CMAPs and median MNCV 2557 m/s CMTX4 Chowchock syndrome unknown X q24-q26.1 onset in infancy, deafness, mental retardation in 60% MNCV 3356 m/s, decreased sensory NCV CMTX5 unknown Xq21.32-q24 hearing loss, optic neuropathy, females unaffected low or absent CMAPs, mild decreasing of MNCV (4351 m/s) Dominant:axonal CMT (AD) with pyramidal features (HMSN V) mitofusin 2 (MFN2) 1p36.2 mitochondrial GTP-ase regulator of mitochondrial fussion and transport ankle jerk absent, tendon jerks present or increased MNCV decreased, low SNAPs and CMAPs amplitudes CMT with optic atrophy (HMSN VI or CMT 6) MFN2 1p36.2 early onset, optic atrophy MNCV slightly decreased Dominant:distal motor Distal HMN I unknown early onset 220 years, reflexes present or increased, ankle jerks absent, distal weakness and wasting MNCV normal or mildly decreased, SNAPs mildly reduced Distal HMN II HSP22, HSP27 12q24.3, 7q11-21 development of thermotolerance onset 1520 years, rapid progression, exstensor muscle weakness MNCV normal, CMAPs normal or reduced, SNCV normal Distal HMN V (HMN 5A) GARS 7p15 protein biosynthesis, role in translation phase pronounced hand muscles wasting and weakness, spasticity on lower extremities MNCV and CMAPs, normal or mildly reduced Distal HMN V- Silver's syndrome (HMN 5B) BSCL2, seipin 11q12q14 involved in RNA transport and glycosylation pronounced hand muscles wasting and weakness, mild lower extremities spasticity, no sensory/autonomic dysfunction reduced CMAPs, normal or mild reduction of MNCV Distal HMN VII B dynactin 2p13 role in prevention of neurodegeneration adult onset, bilateral vocal cord paralysis, progressive facial weakness and atrophy of hand muscles and distal legs normal MNCV, low CMAPs distally Distal HMN VII A unknown 2q14 onset in second decade, unilateral or bilateral vocal cord paralysis, breathing difficulties, weakness and atrophy of, hands and distal legs muscles Dist. HMN ALS4 SETX 9q34 possible role in RNA processing early onset, pyramidal tract involvement MNCV normal, CMAPs reduced Recessive:distal HMN Distal HMN III unknown telomeric to IGHMBP2 11q13 infantile onset, diaphragmal hypomobility CMAPs low, MNCV normal or mildly reduced Distal HMN IV unknown 11q13 mild neuropathy of late onset in third decade CMAPs low, MNCV normal or mildly reduced Distal HMN VI (SMARD1) IGHMBP2 11q13.2-13.4 RNA processing diaphragmal paresis, IURG, infantile onset, respiratory insufficiency, death low/absent CMAPs, mild decreased MNCV Distal HMN-J unknown 9p21.1-p12 onset between 610 years, first brisk reflexes and Babinski sign followed by areflexia and absent Babinski sign MNCV normal to mildly reduced, CMAP reduced amplitudes SNAP normal Cong. distal SMA unknown 12q23-q24 antenatal onset, arthrogryposis, severe course, paraplegia, scoliosis, trunk weakness MNCV normal X-linked distal HMN unknown Xq13-q21 juvenile onset, mild distal weakness and wasting CMAP amplitudes reduced, MNCV mildly reduced, and SNCV normal HSAN:Autosomal dominant HSAN I SPTLC1 9q22.1-q22.3 sphingolipid synthesis common features of all HSAN types: arthropathy, mutilating, paronychia, ulcers of fingers, pathological fractures, prolonged QT, syncopes, convulsions decreased SNCV HSAN 1B associated with cough and gastroesophageal reflux (GER) unknown 3p22-p24 cough, hoarse voice, syncopes, retinal detachment, hearing loss, GER, rarely ulcers, sensory loss decreased SNCV HSAN:Recessive HSAN II HSN 2 12p13.33 loss of pain, touch and temperature sensation, finger ulcerations, loss of tendon reflexes, mild muscle weakness SNCV decreased, SNAPs absent HSAN III or Riley-Day syndrome IKBKAP 9q31 transcription process onset at birth, hypotonia, defect in lacrimation, thermal dysregulation, postural hypotension, prominent autonomic dysfunction, gastrooesophageal reflux, chronic lung disease, ataxia, convulsions SNCV decreased, SNAPs absent or reduced HSAN IV TRKA/NGF NTRK1 1q21-q22 NGF signaling, thermal regulation via sweating, nociceptive system development pain insensitivity, anhydrosis normal reflexes, mild mental retardation normal MNCV and CMAPs, SNAPs and SNCV mildly reduced HSAN V TRKA/NGF NGF 1q21-q22 1p13.2-11.2 NGF signaling, CNS and peripheral pain pathways development onset at birth, pain insensitivity, bone/joint fractures, episodes of hyperpyrexia, anhydrosis less pronounced than in HSAN IV, hyperkeratosis, normal mental development NCV normal HSAN with deafness and global delay unknown unknown hypotonia, areflexia, developmental delay, hearing loss, dysmorphic features, renal tubular acidosis sensory neuropathy HSAN with spastic paraplegia unknown 5q15.31-14.1 severe sensory neuropathy, trophic ulcers and mutilation, MRI spinal cord atrophy axonal sensory neuropathy, SNAPs amplitudes reduced or absent, MNCV normal or mildly reduced X-linked HSAN associated with deafness (AUNX1) unknown AUNX1 locus Xq23-27.3 progressive auditory neuropathy, decreased otoacustic emission, progressive sensory neuropathy SNAPs reduced or absent, mildly reduced sensory NCV, normal MNCV

Read the original:
Charcot-Marie-Tooth Disease: A Clinico-genetic Confrontation

Biological processes are all ultimately how chemical processes react with their surroundings. The more detail that is known about a process, the greater our ability to modify it. Myopia is a complex interplay of many factors that result in an eyeball being too long for the focal plane of light entering the eye. Why this happens will ultimately be understood as the interplay of many molecular processes and the study of the very basic parts of this process will eventually allow us to greatly modify, if not control, myopia.

These references are mostly, but not exclusively, related to the lower levels of juvenile myopia. More references can be found by searching for your own articles using the PubMed (National Library of Medicine) database. Just enter some terms such as "myopia gene". There were 629 such articles listed on 04 October 2011.

MyopiaPrevention.org comment: Subtitled Myopia Control with Atropine 0.01% Eyedrops. From the conclusions: "Over 5 years, atropine 0.01% eyedrops were more effective in slowing myopia progression with less visual side effects compared with higher doses of atropine."

Read the commentary by Jeffrey Cooper: Practice Update. Eye Care. Expert Comment. August 25, 2015. "This study completes a series of clinical trials demonstrating the efficacy of atropine in slowing the progression of myopia and makes a strong case for clinical use of atropine in young patients."

MyopiaPrevention.org comment: The data is now five years old, but it shows that atropine use increased over the years while the concentration of the drop used decreased. In 2007, approximately 50% of children diagnosed with myopia were prescribed atropine, 40% of those getting .1% atropine. Among 9-10 year olds with myopia, 60% were prescribed atropine. Over the seven year period, atropine use increased 34%.

MyopiaPrevention.org comment: This ATOM2 followup of the ATOM1 study sought to determine if concentrations weaker than the previously studied 1% would have a similar effect. A dose as low as .01% was shown to slow myopia clinically at the same rate as 1% with "negligible effect on accommodation and pupil size, and no effect on near visual acuity." There were no reports of allergic conjunctivitis or dermatitis. This is a significant finding that could change how myopia is treated.

MyopiaPrevention.org comment: The abstract talks about the gene mutation identified in a specific population: "Bedouin Israeli consanguineous kindred." In other words, a very small, specific population. Such studies allow researchers to more easily determine the actions of a specific gene. Further research is then needed to determine if this action is somehow impaired in myopic individuals who do not have the specific mutation.

MyopiaPrevention.org comment: A retrospective study of controlled clinical trials. Atropine slowed myopic progression by .773D/yr compared to placebo. Effects of .5% and 1% were similar.

MyopiaPrevention.org comment: While atropine (a muscarinic antagonist) has been shown to reduce myopic progression, the specific receptor that mediates the effect has not been identified. This study indicates that "muscarinic antagonists prevent myopia progression through an M4-receptor mediated mechanism, most likely located in the retina."

This is important in that, if proven true, it would permit the development of a more targeted drug for myopia control than the more broad acting atropine.

MyopiaPrevention.org comment: This study of 22 subjects aged 13 to 25 found that myopes had slightly lower levels of Vitamin D in their blood compared to non-myopes when adjusted for age and diet, but the results were questioned because the study did not find that outdoor time was related to myopia.

MyopiaPrevention.org comment: A comprehensive review of the drugs used to study myopia progression involving various receptor targets within the eye. Various models for myopia progression are discussed. "...new bioengineering approaches for drug delivery" are called for.

MyopiaPrevention.org comment: Not yet read. The abstract states that "The findings that have resulted from this study have not only provided greater insight into the role of genes and other factors involved in myopia but have also gone some way to uncovering the aetiology of other refractive errors."

MyopiaPrevention.org comment: This is a study that looked at varying the dosage of atropine based on the season, with the idea of increasing the dose when the sun exposure is the least. It was found to be effective and tolerable to the students.

MyopiaPrevention.org comment: Insulin-like growth factor-1 (IGF-1) "may play a role in control of eye growth" and this study found a "genetic association between IGF-1 and high-grade myopia."

MyopiaPrevention.org comment: The study shows the type of work needed to identify a genetic component to myopia progression. A single gene was studied and was found to be associated with both hyperopia and myopia. No attempt is made to identify how the gene might create its influence.

MyopiaPrevention.org comment: Just like the title says. This is different than has been found in other populations.

MyopiaPrevention.org comment: In simplified terms, glucose levels in the body are regulated by insulin (lowers glucose) and glucagon (raises glucose). Chick eyes were studied for the effect of these two hormones and their ability to control ocular elongation and choroidal thickness, both responsible for emetropization and myopic development. The relationship is complicated. "the simplest view of how glucagon and insulin might control emmetropization would be that insulin stimulates the eye to elongate and the choroid to thin, thus acting like a negative lens, whereas glucagon does the reverse, slowing the elongation and causing the choroid to thicken, thus acting like a positive lens. We conclude the situation is considerably more complex." It appears that this more simplistic action is maintained if the eye is compensating for defocus during which time the eye is less responsive to the drug that would be expected to slow the process in either direction.

MyopiaPrevention.org comment: Pirenzepine was shown to slow myopia to .58 diopters over two years vs. .99 diopters for the placebo group, thus cutting the progression approximately in half. An editorial in the same edition (How should we try to affect myopic progression?) by Sherwin J. Isenberg notes that although atropine and pirenzepine have the best results "in properly conducted clinical trials" for myopia control, the former is an "off-label" use and the later is not available in the United States.

MyopiaPrevention.org comment: "The experiments reported here demonstrate that both unselective blocking of potassium channels and selective inhibition of the sodium-potassium-chloride symporter can produce dramatic interference with refractive compensation to optically induced blur." "The action of bumetanide appears to combine a defocus-sensitve inhibition of refractive compensation under conditions that would normally lead to myopia"

MyopiaPrevention.org comment: This adenosine antagonist (in tablet form) was tested in a study of 68 children of average age 11 for three years. The first year half the students received the tablets, the second year all students were given the choice of once a day or twice a day tablets and the third year all medication was stopped. The authors conclude that 7-mx is efficient in retarding myopia, but I don't see that from their results and study design.

MyopiaPrevention.org comment: Paired box gene 6 (PAX6) showed no association with myopia. COL2A1 (a collagen gene) was indicated as possibly associated with myopia.

MyopiaPrevention.org comment: In the chick eye, the perception of blur does not drive emmetropization but rather the energy at high spatial frequencies in an image, leading them to conclude that amacrine cells within the retina may be sufficient to drive emmetropization.

MyopiaPrevention.org comment: The title says it all.

MyopiaPrevention.org comment: Melatonin is a hormone that "transmits daily and seasonal timing information to a variety of tissues in essentially all vertebrate species." Application of systemic melatonin altered the growth of various ocular tissues where receptors have been identified. Further study is called for to elicit more specific data.

MyopiaPrevention.org comment: A pdf of the slides presented at a lecture for ARVO's (Association for Research in Vision and Ophthalmology) symposium. A discussion of the biochemical signals controlling growth that are operating within the retina.

MyopiaPrevention.org comment: Abstract in Polish translated into English on Pubmed.com. The abstract is perhaps most interesting for the listing of potential chemicals for myopia prevention.

MyopiaPrevention.org comment: Glucagon, a chemical messenger in the body, was investigated to see whether it is involved with signaling the eye to change its growth in response to plus lenses. It was shown to thicken the choroid and may contribute to myopia prevention by reducing sclera growth.

MyopiaPrevention.org comment: "That the combination of apomorphine and atropine were not additive suggests that combining dopaminergic and muscarinic agents is not a useful strategy for improving the efficacy of these antimyopia drug treatments."

MyopiaPrevention.org comment: A study of genes within a region previously identified as associated with high myopia. No significant gene was found. Includes a good summary of the incidence of eye problems associated with increased myopia in the section "Ocular Morbidity" including such facts as the lifetime risk of retinal detachment is 9.3% for those with myopia over 5.00 D. A necessary read for anyone thinking that identifying the genetic component of myopia should be easy.

MyopiaPrevention.org comment: Pirenzepine appeared to be safe to use in children but the study did not attempt to determine if it was effective in myopia prevention.

MyopiaPrevention.org comment: 331 children aged 6-12 studied over two years showed that myopia progressed 1.20 diopters in the control (placebo drops) group and .25 diopters in the group given 1% atropine drops daily. Results for axial elongation (another measure of myopia progression) were similar.

MyopiaPrevention.org comment: A summary of many of the issues in myopia research.

MyopiaPrevention.org comment: The concern is that long term atropine use might cause either toxic problems or lead to increased light damage to the eye due to atropine dilating pupils. This study did multifocal electroretinograms (mfERG) to determine if such damage was detectable for those who had used atropine for two years. The results showed slight changes of unknown significance in the atropine group. The author states "The clinical implications of these findings need to be further explored."

MyopiaPrevention.org comment: A review of the molecular techniques being used to study myopia.

MyopiaPrevention.org comment: Pirenzepine (a selective muscarinic antagonist) studied in 353 Asian children ages 6-12. 2% drops twice a day (progressed -.47 D), once a day (progressed -.70 D) and placebo(progressed -.84 D), thus showing a 43% drop in myopic progression for 2% pirenzepine drops given twice a day. Side effects included follicles and papillae (bumps on the inner lids) that were stated to be usually symptom free with overall "minimal anti-muscarinic safety issues."

MyopiaPrevention.org comment: An extensive review of the pharmacology of myopia presented at the 9th International Myopia Conference. You must be able to read .ppt files. From Dr. Wildsoet's web site.

MyopiaPrevention.org comment: Three groups (total 188 students age 6-13): Atropine + multifocal glasses, multifocal glasses, and single vision glasses. Followed for 18 months. Progression was least for atropine+multifocals (.40 D), and more for multifocals (1.19 D) and single vision lenses (1.40 D). Although the two glasses group did differ from each other, it was not felt the difference was strong enough to say multifocals were better at prevention than single vision glasses.

MyopiaPrevention.org comment: Amacrine cells within the retina "respond differentially" depending on whether the eye is myopic or hyperopic and thus may be important in emmetropization.

MyopiaPrevention.org comment: 168 children, age 6-13 were treated with either of .5%, .25% or .1% atropine drops nightly for up to two years. Myopic progression rates were .04, .45 and .47 Diopters/year respectively compared to a control of 1.06 Diopters/year. The .5% was the most effective.

MyopiaPrevention.org comment: A study of 214 students in Olmsted County, Minnesota (USA) received atropine for various lengths of time, from 18 weeks to 11.5 years. Photophobia and blurred vision were frequently reported, but the author did not classify those as "serious side effects". The atropine group had very little myopic change (.05 units/year) vs the "no-drug" group (.36 units/year). The article has a fairly extensive discussion of atropine in various myopia control studies and background data on myopia in general. Forty five pages.

The same article appears as Kennedy RH, Dyer JA, Kennedy MA, Parulkar S, Kurland LT, Herman DC, McIntire D, Jacobs D, Luepker RV.(2000) Reducing the progression of myopia with atropine: a long term cohort study of Olmsted County students. (ABSTRACT) Binocul Vis Strabismus Q. 2000;15(3 Suppl):281-304.

MyopiaPrevention.org comment: Injected atropine in chick eyes dramatically slowed myopic progression but did not reduce accommodation. Atropine eye drops would not stop myopic progression by affecting accommodation, further proof that accommodation or reading does not by itself cause myopia.

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Myopia Medications and Genetics - MYOPIA * Prevention