Nitrates and calcium channel antagonists have been recom­mended for treatment of achalasia. The rationale behind the use of these medications is their potential to decrease LES tone by relaxing gastrointestinal smooth muscle. However, the limitations in the use of these drugs are several: they are short acting; they can have significant side effects such as headaches, hypotension and tachyphylaxis; and, although a decrease in LES pressure has been well documented by ma- nometry, symptom improvement has varied greatly among different studies. In general, most patients tend to opt for other, more satisfactory forms of treatment after they have been on these drugs for a few months.

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Achalasia was one of the first gastrointestinal motility disorders to be characterized, both clinically and manometrically. Failure of relaxation of the lower esophag- eal sphincter (LES) is the cardinal feature of this disease, thought to result from a relatively selective degeneration of the inhibitory neurons in the surrounding myenteric plexus (Figure 1). This leads to a functional obstruction of the esophagus that, along with aperistalsis in the body of the esophagus, is responsible for the major symptoms of achalasia: dysphagia for solids and liquids, regurgitation of undigested food and chest pain. All current methods of treatment are es­sentially palliative in nature and are focused on reducing the LES pressure. The main focus of this review will be on the use of botulinum toxin (BTX) for this condition and how it compares with other available therapies.

BTX

BTX blocks the calcium-dependent release of acetylcholine from presynaptic cholinergic nerve terminals. It is a neuro- toxin produced by Clostridium botulinum. Although several serotypes are known, the one used clinically is BTX type A. Pasricha et al were the first to demonstrate the appli­cation of BTX for the treatment of achalasia in a double- blind, randomized, placebo controlled study. Since then, multiple studies and several reviews have been published. BTX causes a significant reduction in resting base­line LES pressure, esophageal clearance and symptoms (Fig­ure 2). The efficacy ranges from 65% to 90% after a single injection, with the effect lasting anywhere from three months to more than one year. The main limitation to the use of BTX for achalasia is its lack of significant long term re­sults with a single injection. With repeat injections at an aver­age of every 10 months, Annese et al recently reported the highest long term efficacy rate to date (75% after a mean follow-up of 24±15 months).

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Parathyroid carcinoma is usually associated with more severe clinical manifestations of PHPT than parathyroid adenomas. The incidence of parathyroid cancer does not favor women but is matched between the sexes, and the age of onset is approx­imately earlier than in benign disease (mid-40yr instead of the mid-50yr). The principal histological features of parathyroid car­cinoma include mitoses, tick fibrous bands, and capsular and blood vessel invasion. However, the distinction between benign and malignant parathyroid tumors cannot be definitively established in the absence of local invasion or metastases. Nonetheless, these features are not always clearly pre­sent and certainly identify a late stage of the disease with a poor prognosis and low cure rate.

In 1994 Cryns et al. reported that inactivation of the Rb1 gene might be involved in the pathogenesis of parathyroid car­cinoma and that this finding might be a useful tool for the diag­nosis of parathyroid malignancy; since then, contradictory re­sults have been obtained by other investigators. Our group, recently, further investigated the role of the Rb1 gene in the differential diagnosis between benign and malignant parathyroid tumors by evaluating LOH at this locus and pRb immunohistochemistry. We show that Rb1 gene alter­ations are not specific for parathyroid cancer. Retention of Rb heterozygosity excludes such diagnosis, which is suggested by the combined finding of LOH and lack of pRb expression. How­ever, the same authors who previously reported that inactiva­tion of Rb1 is a key factor in the pathogenesis of many or most parathyroid carcinomas, showed no microdeletion, insertions or point mutations in the coding regions and promoter of the Rb1 gene in a small series of parathyroid carcinomas. Recent studies have found an involvement of HRPT2 gene in the pathogenesis of sporadic parathyroid cancer. Shat- tuck et al. found HRPT2 mutations in 10 of 15 patients with apparently sporadic parathyroid carcinoma; three of the patients had HRPT2 germline mutations. Howell et al. de­tected HRPT2 somatic mutation in four of four parathyroid car­cinoma. Our group identified HRPT2 mutations in six of seven parathyroid carcinomas. Thus HRPT2 mutation is patho­genic for most sporadic parathyroid carcinomas. Combining all the results the prevalence of HRPT2 mutations in sporadic parathyroid carcinomas is 77% (Table III). It is conceivable that inactivating mutation of non coding or regulatory regions could be also implicated in the pathogenesis of sporadic parathyroid cancer. Thus, HRPT2 mutation is central to the pathogenesis of most, and perhaps virtually all sporadic parathyroid carcino­ma.

To date cyclin D1/parathyroid adenomatosis gene 1 (PRAD1) together with the MEN1 is the only gene with an established role in the development of sporadic (nonfamilial) parathyroid adenomas.

The cyclin D1/parathyroid adenomatosis gene 1 oncogene

The cyclin D1/PRAD1 gene was identified as a parathyroid oncogene on chromosome 11 q13, clonally activated in a sub­set of parathyroid adenomas by tumor-specific DNA rearrange­ment with the parathyroid hormone (PTH) gene locus. The rearrangement separated the 5′ regulatory region and the noncoding exon 1 of the PTH gene from its coding exons, with different, non-PTH DNA, placed adjacent to each PTH gene section with a pericentromeric inversion of chromosome 11, bringing the PRAD1 (normally on 11q) under the control of the PTH gene 5′ flanking region (on 11 p) (Fig. 4). (The tumor cells has one intact PTH gene that accounted for expression of PTH by the tumor). This rearrangement causes transcriptional acti­vation and overexpression of the PRAD1 gene (Fig. 5). Consequent to its discovery as a parathyroid oncogene, cyclin D1 has become established as a major and broad con­tributor to other neoplasia such as breast cancer, multiple mieloma, B-cell lymphomas and others. The cyclin D1 gene encodes a 295 amino acid protein homolo­gous to members of cyclin class of proteins. Cyclins play an important role in the regulation of cell cycle progression, and human cyclins have been grouped in different types ac­cording to sequence similarity. The C, D and E type cy- clins appear to be G1 cyclins which regulate the progression throught G1 phase and the G1-S transition, determining whether initiation of a new cell cycle occurs. During G1, cyclin D1 com­plexes with and activates its kinase partner, cyclin-dependent kinase (CDK) CDK4 or CDK6, depending on tissue type. The activated kinase is involved in the phosphorylation and inacti­vation of retinoblastoma protein (pRb), determining progres­sion toward S-phase. It is thought, therefore, that overexpres­sion or deregulated expression of cyclin D1 could quite con­ceivably accelerate the cell’s progress through G1 into S phase, bypassing normal regulatory controls in committing to divide, and also be well tolerated by the cell during the remain­der of the cycle. Such a mechanism would provide an appeal­ing explanation for the benign nature of parathyroid adenomas, because it could yield excessive cellular proliferation without necessarily conferring the phenotype of invasiveness or metas­tasis to the tumor cell.

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FIHP is a clinically defined entity, based on the absence of ex­pression of the extra-parathyroid manifestations that character­ize other familial HPT syndromes. FIHP is genetically hetero­geneous, and can be caused by variant expressions of germline mutations in MEN1, HRPT2, CASR, and probably other genes.

One of the puzzling aspects of FIHP is the absence of some of the manifestations of the syndromic forms despite the fact that the same gene is affected. Several possible mechanisms might account for this finding: i) incomplete penetrance of some of the manifestations, as the gnathic and renal features in HPT- JT; ii) difference in the spectrum of mutations: it has been suggested that missense/in-frame deletion mutations may lead to incomplete MEN 1 phenotype, whereas truncating or nonsense mutations are more frequently observed in the full-blown syndrome. However, recent results from our and other groups have ruled out this possibility; iii) different mutations of the same gene may result in various degree of structure change and, accordingly, the capability of the mutated protein of interacting with other proteins may be variously affected. Indeed, either naturally occurring or engi­neered MEN1 gene mutations have been shown to affect dif­ferently binding of menin with JunD; iv) influences from en­vironmental factors and the presence of modifier genes that may contribute to phenotypic variations, as reported in familial adenomatous polyposis.

Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism

FHH is an autosomal dominant syndrome characterized by life­long moderate hypercalcemia, inappropriate serum PTH levels, and relative hypocalciuria. Parathyroid gland are normal in most patients with FHH. In some families, however, PTH is moderately elevated. The biochemical abnormality of FHH has been attributed to the increased renal retention of cal­cium that is not quite enough to overcome the decreased parathyroid sensitivity to calcium, so that PTH concentration is inappropriately normal. In rare cases PTH is moderately elevat­ed, suggesting that decreased parathyroid sensitivity to calci­um is accompanied by a moderate generalized parathyroid hy- perplasia. This observation suggests that the CASR may be involved in the control of parathyroid proliferation (see be­low).

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Germline gain-of-function mutations in the RET protooncogene cause MEN 2A. The RET protein is a receptor tyrosine ki­nase that normally transduces growth and differentiation sig­nals in developing tissues including those derived from the neural crest. This makes the RET gene, which encodes a tyro­sine kinase receptor, a candidate gene involved in nonfamilial hyperparathyroidism. There are both differences and much overlap in the specific RET gene mutations underlying MEN 2A and familial medullary thyroid cancer (FMTC); in contrast MEN 2B is caused by entirely distinct RET mutations. The rea­son for which parathyroid disease fails to develop in FMTC pa­tients who can bear identical RET mutations as found in MEN 2A remains unclear. Unlike the several different inactivating mutations of MEN1, which are typical of a tumor suppressor mechanism, RET mutations in MEN 2A are limited in number, reflecting the need for specific gain-of-function changes to acti­vate this oncogene. RET mutation at codon 634 seems to be highly associated with the expression of PHPT in MEN 2A. MEN2 type RET mutations have been implicated in the patho- genesis of some sporadic medullary thyroid carcinomas and pheocromocytomas. Up to date no RET mutations have been found in sporadic parathyroid adenomas. RET is expressed in both MEN 2A parathyroid adenomas and in spo­radic adenomas. This suggests that parathyroid disease is an integral part of the MEN 2A, but that RET do not play a role in the pathogenesis of sporadic parathyroid adenomas.

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Genetic studies on inherited tumor susceptibility disorders have increased our knowledge of tumorigenesis. PHPT is found in several disorders with an autosomal dominance inher­itance, such as multiple endocrine neoplasia type 1 (MEN 1) and 2A (MEN2A), hereditary hyperparathyroidism-jaw tumor (HPT-JT) syndrome, familial isolated hyperparathyroidism (FIHP), familial hypocalciuric hypercalcemia (FHH) and neona­tal severe hyperparathyroidism (NSHPT). The genetic charac­teristics of familial parathyroid diseases are shown in Table I.

Multiple endocrine neoplasia type 1

Genetic mapping studies in families with MEN 1 syndrome showed that the gene responsible is on chromosome 11 q13. By analogy with familial retinoblastoma, which involves in­heritance of mutations in the Rb gene, it was suggested that the MEN1 gene was a tumor suppressor gene. Inactivation of both alleles is required to completely deplete the gene’s anti­neoplastic product. A common inactivation mechanism is a so­matic deletion of a substantial proportion of chromosomal DNA that includes the relevant gene. This is revealed by a loss of heterozygosity (LOH) of DNA markers in tumor DNA relative to normal DNA of the same individual (Fig. 1). The evidence that the MEN1 was a tumor suppressor gene was provided by the demonstration of somatic genetic abnormalities in MEN1 tu­mors which inactivate one allele of a gene at 11q13 and so re­veal the inherited MEN1 mutation on the other allele (Fig. 2). LOH of polymorphic marker DNAs from this region has been found in the majority of MEN 1-associated tumors including those of parathyroids. Mutations of the MEN1 gene have been detected in >90% of MEN1 families. The mutations are scattered through the nine translated exons of the MEN1 gene, and approximately half the members of each family have a mutation unique to that family, making presymptomatic ge­netic testing laborious.

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