MEN2 phenotype in a family with germline heterozygous rare RET K666N variant.

Summary: Multiple endocrine neoplasia type 2 (MEN2) is a hereditary cancer syndrome caused by germline-activating pathogenic variants in the RET proto-oncogene. MEN2A is the most common subtype, with a risk for medullary thyroid cancer (MTC), pheochromocytoma (PHEO), and primary hyperparathyroidism (PHPT), whereas MEN2B is less common and associated with MTC and PHEO along with mucosal neuromas. Little is known about the specific RET germline heterozygous variant K666N. This variant has been described in very few families, and in most cases, patients were diagnosed with a very indolent MTC as the only feature. There is one case of MTC and bilateral PHEO. The RET K666N variant is not stratified yet by the American Thyroid Association, and data are limited on pathogenicity; therefore, appropriate screening and treatment of asymptomatic RET K666N carriers are unclear. Here, we report a family with a heterozygous germline RET K666N variant. The proband was identified when she experienced cardiogenic shock and multi-organ failure after an elective hysterectomy and subsequently was found to have PHEO, with genetic testing revealing the RET K666N germline variant. Patient consent was obtained through IRB protocol COMIRB #15-0516. Learning Points: The specific RET germline heterozygous variant K666N is rare and described in very few families, and in most cases, patients were diagnosed with a very indolent MTC as the only feature. Our proband is much younger and has PHEO, MTC, and PHPT. The RET K666N germline variant appears to be a low penetrance variant for MEN2.

External beam radiation therapy (EBRT) for patients with malignant pheochromocytoma and non-head and -neck paraganglioma: combination with 131I-MIBG.

In patients with malignant pheochromocytoma and paraganglioma, 131I-MIBG radiotherapy can achieve an objective response rate of 30-50% with the dose limiting toxicity being hematologic. Patients with disseminated disease, who also have a few index bulky or symptomatic lesions, may benefit from the addition of targeted external beam radiotherapy alone or in combination with systemic 131I-MIBG. The records of patients with malignant paraganglioma who were treated with external beam radiotherapy at the University of Pennsylvania from February 1973 to February 2011 were reviewed in an institutional review board approved retrospective study. Of the 17 patients with tumors in the thorax, abdomen, or pelvis, 76% had local control or clinically significant symptomatic relief for at least 1 year or until death. As expected, the predominant toxicity was due to irradiation of tumor-adjacent normal tissues without clinically significant hematologic toxicity. Due to widespread systemic metastases with areas of bulky, symptomatic tumor, 5 of the 17 patients were treated with sequential 131I-MIBG (2 mCi/kg per treatment) and external beam radiotherapy to 9 sites. In these patients, all areas that were irradiated with external beam radiotherapy showed durable objective response despite all patients eventually experiencing out-of-field systemic progression requiring other treatment. Four of these patients remain alive with excellent performance status 16, 18, 23, and 24 months after external beam radiotherapy. External beam radiotherapy can be highly effective in local management of malignant paraganglioma and can be used in conjunction with 131I-MIBG due to nonoverlapping toxicities with excellent control of locally bulky tumors.

On the possibility of creating a magnetic field with a given degree of spatial inhomogeneity.

Proposed here is a method for constructing systems of circular thin Helmholtz coils (conic coils), which makes it possible to obtain a magnetic field with any degree of inhomogeneity by doubling the number of coils. A functional relationship is obtained between the currents of the coils and their distances to the center, which allows zeroing all derivatives in the expansion of the magnetic field in a series in spatial variables in the center of the system to a derivative of arbitrary order. An analytical expression is obtained for the magnitude of the magnetic field of the systems along the axis of symmetry. All the systems considered here have the same parity (oddness) of the projections of the magnetic field with respect to spatial variables and equal inhomogeneity in all directions in the center of symmetry.

DDT: participation in ultraviolet-detectable, charge-transfer complexation.

The chlorophenyl groups of DDT and several of its metabolites are capable of participating in a charge-transfer interaction with tetracyanoethylene detectable in the ultraviolet region of the spectrum. In addition, during a change of state DDT undergoes ultraviolet spectral alterations that closely resemble those previously claimed to support the hypothesis suggesting charge-transfer interaction between this pesticide and a component of insect nerve tissue. The pesticide DDT possesses structural characteristics that would permit it to participate in several types of molecular association.

Potential hazards of fumigant residues.

A spectrum of fumigants (primarily ethylene dibromide, 1,2-dibromo-3-chloropropane, ethylene oxide, symdibromotetetrachloroethane, 1,3-dichloropropene, dichlorovos, carbon tetrachloride, methyl bromide) as well as their degradation products in foodstuffs and soil have been examined mainly in regard to the potential mutagenicity of their residues.

Overview of potential mutagenic problems posed by some pesticides and their trace impurities.

This review principally addresses a number of aspects of usage of pesticides as well as populations at potential risk and attempts to highlight categories of pesticides whose structures or those of their metabolites and/or trace impurities, degradation and transformation products suggest an a priori mutagenic and/or carcinogenic risk. The pesticides considered include: DDT, hexachlorobenzene (HCB), 2,4,5-T, pentachlorophenol, and various herbicidal precursors (e.g., carbamates, triazines) of nitrosamines and nitroso derivatives. Structural features of a number of halo-unsaturated pesticides (e.g., dichloropropenes) were also reviewed from a viewpoint of contrasting their potential mutagenicity with that of vinyl chloride and vinylidene chloride. Additionally the mutagenicity of the organophosphorus pesticide Trichlorophon is contrasted with that of its degradation products.

Sources, transport and alterations of metal compounds: an overview. I. Arsenic, beryllium, cadmium, chromium, and nickel.

An overview is presented of the current state of knowledge of the salient aspects of the sources, transport, and alterations of arsenic, beryllium, cadmium, chromium, and nickel. This information is considered vital for a better assessment of the scope of potential human hazard to these ubiquitous toxicants and their compounds. Stress is focused on both natural and industrial activities, particularly on the latter's projected trends. Increasing use patterns per se of most of these metals, as well as aspects of waste disposal and the anticipated increased combustion of fossil fuels for power generation and space heating (particularly in the United States), are major causes of potential health concern. Additionally, attention is drawn to the need for increased research to fill the gaps in our knowledge in these vital areas, all in the hope of permitting a more facile identification and quantification of the potential hazard to exposure to these agents.

Contribution of organic particulates to respiratory cancer.

This paper presents some of the issues that remain to be resolved in order to assess the risk of cancer related to exposure to organic particulates. Most reviews of the effects of organic particulates from the outdoor environment on the risk of lung cancer show that this source seems to play a minor role. However, as fuel use and chemical composition of air pollutants change, the contribution of outdoor pollution as a cause of cancer may also change. Indoor air pollution is a more important source of exposure to organic particulates than is outdoor exposure. Although there is clear evidence that in occupational settings organic particulates cause human cancer, there has been almost no study of exposure to these types of particulates within indoor settings. Previous research has focused on cigarette smoke as the major indoor pollutant, but more specific characterization of contaminants in both the workplace and the home is required. The health effects of the higher levels of some of these contaminants in the workplace should be evaluated and the results extrapolated to populations exposed to lower levels in the home. Extensive research is needed to characterize organic particulate mixtures appropriately and test them for carcinogenicity. Studies on the health risks of nitropolynuclear aromatic hydrocarbons and polychlorinated dibenzodioxins and dibenzofurans are reviewed, but their contribution to the overall burden of respiratory cancer in humans cannot be estimated at this time. Characterization of mixtures, assessment of exposures, and linkage of exposures to health effects are the objectives of the recommendations proposed for further research.

Approaches for assessing health risks from complex mixtures in indoor air: a panel overview.

Critical to a more definitive human health assessment of the potential health risks from exposure to complex mixtures in indoor air is the need for a more definitive clinical measure and etiology of the health effects of complex mixtures. This panel overview highlights six of the eight presentations of the conference panel discussion and features a number of the major topical areas of indoor air concern. W. G. Meggs assessed clinical research priorities with primary focus on the role of volatile organic chemicals in human health, recognizing the areas where definitive data are lacking. By recognizing many types of chemical sensitivity, it may be possible to design studies that can illuminate the mechanisms by which chemical exposure may cause disease. The critically important topic of multiple chemical sensitivity was discussed by N. A. Ashford, who identified four high risk groups and defined the demographics of these groups. P. A. Schulte addressed the issue of biological markers of susceptibility with specific considerations of both methodological and societal aspects that may be operative in the ability to detect innate or inborne differences between individuals and populations. Three case studies were reviewed. H. Anderson discussed the past and present priorities from a public health perspective, focusing on those issues dealing with exposures to environmental tobacco smoke and formaldehyde off-gassing from materials used in mobile home construction. J. J. Osborne described several case studies involving wood smoke exposure to children, with emphasis on the significantly greater occurrence of chronic respiratory symptoms and acute chest illness for children from homes heated with woodburning stoves.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and pharmacodynamic effects of nicotine nasal spray devices on cardiovascular and pulmonary function.

BACKGROUND: A nasal spray form of nicotine replacement therapy (Nicotrol NS, McNeil Consumer Products Co, Fort Washington, Pa) has been approved and, because of its rapid absorption across the nasal mucosa, may be more effective than nicotine gum or transdermal patches. We tested the hypothesis that the nicotine absorbed into the nasal mucosa would produce significant changes in hemodynamics and pulmonary function in 20 healthy, nonsmoking men and women. METHODS: In this double-blind, randomized study of Nicotrol NS versus placebo, we measured serum nicotine concentrations, blood pressure, heart rate, and indices of pulmonary function at timed intervals before and after nasal spray administration of 3 mg of nicotine. RESULTS: A peak serum nicotine concentration of 4.71 +/- 3.16 ng/mL occurred 10 minutes after drug administration. The maximum change in systolic blood pressure occurred 5 minutes after dosing and was significantly related to nicotine administration (7.1 +/- 9.4% for the nicotine group vs -1.6 +/- 7.3% for the placebo; P = 0.03). In contrast, neither diastolic blood pressure (P = 0.8) nor heart rate (P = 0.07) changed significantly after nicotine administration, when compared with placebo. Pulmonary function was not altered acutely by a single inhalation of nicotine. Pharmacokinetic modeling revealed a classic one-compartment model in which nicotine is absorbed into the systemic circulation by a zero-order process and eliminated by a first-order process. CONCLUSIONS: In this population of nonsmokers, hemodynamic effects of the nicotine nasal spray were observed shortly after administration and before the peak serum nicotine concentration.

Industrial mutagens and potential mutagens I. Halogenated aliphatic derivatives.

The halogenated aliphatic hydrocarbons represent one of the most important categories of industrial chemicals from a consideration of volume, use categories, environmental and toxicological considerations and hence most importantly, potential population risk. The major halocarbons reviewed, primarily in terms of their occurrence, utility, stability, distribution, and levels of exposure as well as their metabolism, carcinogenicity and mutagenicity included: vinylchloride, vinylidene chloride, trichloroethylene, perchloroethylene, ethylene dichloride, ethylene dibromide, chloroprene, chloroform, carbon tetrachloride, fluorocarbons (trichlorofluoromethane and dichlorodifluoromethane), epichlorohydrin, halohydrins (2-chloro- and 2-bromoethanol) and haloethers (bis(chloromethyl); chloromethyl'-methyl; bis(2-chloroethyl)-and bis(2-chloroisopropyl)ether. In many instances, data were not available to assess world production, populations at risk and degrees of exposure. With the exception of vinylchloride, vinylidene chloride, epichlorohydrin and 2-halo ethanols, there is an acknowledged paucity of definitive mutagenicity data concerning the majority of halogenated hydrocarbons. Their ubiquitous distribution, and in a number of cases, their carcinogenicity both in man and animals, dictates the urgent need to more exhaustively investigate their potential mutagenicity.

Chemicals used in the rubber industry. An overview.

Hundreds of chemicals illustrative of many structural and use categories are employed in the rubber industry. The present overview has centered on the structural features of a number of compounds representative of several select use categories, eg, vulcanizing agents, accelerators, antioxidants, antiozonants, and blowing agents, with focus on the nature of their impurities, their chemical degradation, and by-products, as well as on those chemicals that can be converted to N-nitrosamines.

Exposure from occupational versus other sources.

There is an increasing need to consider the various routes of exposure to individuals in occupational settings, as well as the exposure of the general public to a broad spectrum of carcinogens. The need to consider indoor environments is increasingly recognized in light of the amount of time spent indoors by a large majority of the population and the recognition that levels of certain toxicants are higher indoors than outdoors. This overview highlights (i) a general comparison of exposure to indoor and outdoor levels of 12 volatile organic compounds and (ii) the exposure of workers and the general public to benzene, 1,3-butadiene, formaldehyde, styrene, tetrachloroethylene, phthalate esters, polychlorinated dibenzofurans, radon, and electromagnetic fields.

Technological changes in cancer prevention.

Exposures and technologies in the workplace are changing due to a variety of factors, including newly developed technologies, mechanization and automation, and improvements in industrial hygiene primarily effected in many developed countries. In addition substitution and removal of carcinogenic constituents in the workplace and general environment are increasing in a number of instances, particularly in North America, Western Europe, and Japan, and they are being accompanied as well by remediation either by source reduction, recycling, or compliance to more stringent national and international regulations and standards. This overview highlights some of the strategies employed in the technological changes in cancer prevention and cites examples in source reduction, changes in formulation, product or process changes, recycling, and hazardous materials management.

An overview of environmental and toxicological aspects of aromatic hydrocarbons. II. Toluene.

The salient aspects of the exposure to toluene were reviewed via an initial examination of the production, use, occurrence and disposition of toluene, as well as populations at potential risk. Special note should be taken as to the increasing use of toluene as a "safe" replacement for benzene in solvent applications and its increasing use in many consumer products. There is a broad potential for exposure by industrial workers and the general public (via vehicle exhausts and consumer products). The effects on humans and animals as well as the genetic effects of toluene were also reviewed following an initial consideration for its absorption and elimination. The narcotic and neurotoxic properties of toluene represent the main recognized health hazards to humans.

An overview of environmental and toxicological aspects of aromatic hydrocarbons. III. Xylene.

The commercial product "mixed xylenes" (a technical product generally containing approximately 40% m-xylene and 20% each of o-xylene, p-xylene and ethylbenzene, as well as small quantities of toluene) analogously to toluene is an agent of major chemical and occupational significance. It is produced in very large quantities and is extensively employed in a broad spectrum of applications, primarily as a solvent for which its use is increasing as a "safe" replacement for benzene, and in gasoline as part of the BTX component (benzene-toluene-xylene); xylenes are also frequently used in the rubber industry with other solvents such as toluene and benzene. As individual isomers they are extensively employed in the synthesis of synthetic agents, for example phthalic acid, isophthalic acid, terephthalic acid and dimethylterephthalate, which have very broad applications in the further preparation of phthalate ester plasticizers and components of polyester fiber, film and fabricated items. There is a broad potential for exposure both to industrial workers in the production and use of the xylenes and to the general public (via vehicle exhausts, consumer products, etc). Compared with benzene and toluene, very much less is known of the human health hazards, particularly the chronic effects of xylenes, either as mixed xylenes, as individual isomers or in admixture with other alkylbenzenes. It is of importance to note that coal-based solvents (e.g., xylene) have been suggested to be possible potent lymphocytic leukemogens, such as benzene, in a limited study of the relationship between lymphocytic leukemia and exposures to benzene and other solvents in the rubber industry. Available animal data on the carcinogenicity of xylene(s) are inadequate to permit an evaluation. Mixed xylenes are currently being investigated in a chronic bioassay by the National Toxicology Program. In limited studies thus far, the individual isomers have not been found genotoxic when tested in a number of short-term tests.

An overview of environmental and toxicological aspects of aromatic hydrocarbons. I. Benzene.

The salient aspects of the exposure to benzene were reviewed via an initial examination of the production, use, occurrence and dispersion of benzene, as well as populations at potential risk. Although benzene is ubiquitous in the environment, the major source of benzene in ambient air is via its use and occurrence in gasolines and subsequent emissions. Exposure to benzene in the general population is suggested to be several orders of magnitude less than to occupational cohorts. Levels of benzene exposure in the workplace have dropped considerably from that which was manifest in the 1940-1950 decade (e.g., 10-100 ppm) also due to the decreasing use of benzene as a solvent. The effects on humans and animals as well as genetic effects of benzene were also reviewed following an initial consideration of its absorption and elimination. The toxic effects on the hemopoietic system were cited with special consideration to the long-term exposure to benzene and the occurrence of leukemia.

An overview of environmental and toxicological aspects of aromatic hydrocarbons. IV. Ethylbenzene.

The solvent aspects of exposure to ethylbenzene are reviewed via an initial examination of the production, use, occurrence, and disposition of ethylbenzene as well as populations potentially at risk. While occupational exposure to ethylbenzene during its production and subsequent conversion to styrene is believed to be minimal, the broader occupational exposure to ethylbenzene during the production and use of 'mixed xylenes' is another area of concern. The general public can be exposed to ethylbenzene in ambient air as a result of its occurrence in motor vehicle exhaust. Additional exposure can arise in indoor environments, mostly from passive exposure to cigarette smoke. Ethylbenzene is primarily an irritant to the skin and mucous membranes and possesses narcotic properties at high concentrations.

Chemicals used in the rubber industry.

Hundreds of chemicals and mixtures illustrative of many structural and use categories are employed in the rubber industry. Global utilization of natural rubber and synthetic elastomers as well as rubber-processing chemicals are projected to increase in the foreseeable future. Primary focus is centered on the major rubber processing chemicals and elastomer monomers in regard to their utility, production trends, structural characteristics, nature of potential impurities, and toxicology (primarily carcinogenicity and genotoxicity). Additionally, areas of specific exposure concern and epidemiology in the rubber industry are considered.

Overview of some aspects of occurrence, formation and analysis of nitrosamines.

This review principally addresses a number of aspects of the occurrence and formation of the nitrosamines, highlighting principal areas of potential concern ranging from the spectrum of nitrosatable moieties found in the environment (e.g., secondary and tertiary amines, quaternary ammonium compounds, ureas, carbamates and guanidines), specific examples of nitrosamines found in food, alcoholic beverages, feed (and their significance for carcinogenesis bioassays), air and water. The factors influencing in vitro and in vivo nitrosation and the evidence for the latter in man are also discussed. Additionally, germane areas of the analysis of nitrosamines are reviewed with a focus on the major areas of concern and requirements of extreme sensitivity and selectivity in addition to the problems of artifacts in the analytical procedures.