Rapidly recurrent recalcitrant Rathke Cleft Cyst: Case report and review of the literature.

BACKGROUND: Rathke Cleft Cysts (RCC) are cystic sellar or suprasellar nonneoplastic lesions that are thought to originate from remnants of the rathke pouch. Postoperatively, RCCs have a tendency to reaccumulate, after which preoperative symptoms may recur. However, there exists very little evidence on which treatments are most effective in these patients. CASE-DESCRIPTION: In this report, we present a unique case of a symptomatic RCC that recurred four times after initial transsphenoidal surgery. Following each surgery, the patient had significant visual improvement with post-op imaging displaying decompression of the neural elements. However, RCC reaccumulated in strikingly rapid time intervals of 1.5 months, 0.5 months, 1.5 years, and 5 months after each respective prior surgery. Repeat interventions with transsphenoidal, pterional and supraorbital approaches were unsuccessful in providing a durable treatment response. The patient ultimately underwent radiotherapy after a final surgical marsupialization of the cyst and has since displayed stable imaging with improved vision. This patient represented a 'perfect storm' of factors that may contribute to cyst recurrence, including substantial visual field deficits, large cyst size, peripheral wall enhancements on MRI, an intraoperative CSF leak, use of a fat graft, subtotal resection of the portion of cyst wall that adhered to important suprasellar structures, squamous metaplasia noted in cyst wall, and suprasellar extension. CONCLUSIONS: We demonstrate that different surgical approaches through repeat surgeries may not assist in prevention of further recurrence; instead, we propose that radiotherapy should be offered early in the treatment course of recurrent cases that have additional risk factors for further reoccurrence.

Supratentorial dural-based hemangioblastoma not associated with von Hippel Lindau complex.

Hemangioblastomas are rarely found in a supratentorial location and are commonly associated with the von Hippel-Lindau complex. Therefore, patients with such tumors must be evaluated for both other hemangioblastomas within the central nervous system as well as for this complex via physical examination, radiographic examination, and genetic testing. We report the seventh case of a patient with an isolated supratentorial dural based hemangioblastoma not associated with the von Hippel-Lindau complex.

An evaluation of the carcinogenic hazard of 1,4-dichlorobenzene based on internationally recognized criteria.

1,4-Dichlorobenzene (1,4-DCB) was shown to induce the formation of male rat renal tubule tumors and male and female mouse liver tumors when administered in a chronic bioassay. Since the original carcinogenicity findings, an extensive body of mechanistic information has been developed to elucidate the mode of action by which 1,4-DCB induces these effects and to evaluate the human relevance of the observed animal tumors. In addition, some regulatory and authoritative bodies (U.S. EPA and IARC) have developed rigorous scientific criteria for the amount and types of evidence needed to establish that a material causes kidney toxicity and tumors in male rats through a specific mechanism, alpha-2u-globulin nephropathy. This paper summarizes the mechanistic data developed for 1,4-DCB, which affords an understanding of the lack of human relevance of the male rat renal tubule tumors and mouse liver tumors; assesses that mechanistic data set utilizing the defined set of evaluation criteria formulated by U.S. EPA and IARC for alpha-2u-globulin nephropathy; and discusses the predictive power of mechanistic data developed to elucidate the mode of action of 1,4-DCB in inducing mouse liver tumors. Finally, there is a discussion of how some, but not all, regulatory and authoritative bodies have incorporated this substantial mechanistic data set for 1, 4-DCB into their cancer hazard evaluations and concluded that 1, 4-DCB presents little, if any, cancer hazard to humans.

Evaluation of unscheduled DNA synthesis (UDS) and replicative DNA synthesis (RDS) following treatment of rats and mice with p-dichlorobenzene.

p-Dichlorobenzene (PDCB) has been reported to produce tumors in the male and female mouse liver and in the male rat kidney in 2-year gavage studies (NPT, 1987). To elucidate the possible mechanisms of carcinogenicity more fully, UDS and RDS were evaluated in B6C3F1 mouse hepatocytes and F-344 rat kidney cells by autoradiography following in vivo administration of PDCB. All corn oil gavage doses of PDCB (300, 600, and 1,000 mg/kg) and the negative control resulted in < 0 net grains/nucleus (NG) in the mouse liver and rat kidney, indicating that PDCB does not induce UDS in either tissue. Compared to controls with < or = 0.29% hepatocytes in S-phase (%S), treatment of mice induced 0.46, 1.90, and 1.52 %S (males) and 2.61, 1.18, and 4.45 %S (females), which indicates that PDCB acts as an inducer of cell proliferation in the liver. In male rat kidney cells, the same doses produced 0.87, 0.67, and 1.01 %S (0.38% in controls) and in females 0.48, 0.43, and 0.32 %S (0.52% in controls), indicating that PDCB induces cell replication in the male but not the female rat kidney. Therefore, these data demonstrate that PDCB is not genotoxic in the mouse liver or rat kidney at single oral doses comparable to the daily doses given in the National Toxicology Program (NTP) bioassay (NTP, 1987). Furthermore, the increases in RDS support the hypotheses that mouse liver tumor formation occurs via stimulation of hepatocyte proliferation and male rat kidney carcinogenesis via increased renal cell proliferation.

Mixture risk assessment: a case study of Monsanto experiences.

Monsanto employs several pragmatic approaches for evaluating the toxicity of mixtures. These approaches are similar to those recommended by many national and international agencies. When conducting hazard and risk assessments, priority is always given to using data collected directly on the mixture of concern. To provide an example of the first tier of evaluation, actual data on acute respiratory irritation studies on mixtures were evaluated to determine whether the principle of additivity was applicable to the mixture evaluated. If actual data on the mixture are unavailable, extrapolation across similar mixtures is considered. Because many formulations are quite similar in composition, the toxicity data from one mixture can be extended to a closely related mixture in a scientifically justifiable manner. An example of a family of products where such extrapolations have been made is presented to exemplify this second approach. Lastly, if data on similar mixtures are unavailable, data on component fractions are used to predict the toxicity of the mixture. In this third approach, process knowledge and scientific judgement are used to determine how the known toxicological properties of the individual fractions affect toxicity of the mixture. Three examples of plant effluents where toxicological data on fractions were used to predict the toxicity of the mixture are discussed. The results of the analysis are used to discuss the predictive value of each of the above mentioned toxicological approaches for evaluating chemical mixtures.

Dose- and time-dependent expression of transforming growth factor-beta 1 mRNA and protein in mouse epidermis and papillomas after repeated topical application of benzo[a]pyrene.

Topical weekly application of 64 micrograms of benzo[a]pyrene (BAP) for 4 wk induced transforming growth factor (TGF)-beta 1 mRNA in the epidermis of Swiss (ICR) mice, with a maximum at 6-12 h after the last treatment. The increase in TGF-beta 1 mRNA concentration was accompanied by an increase in immunohistochemically detectable intracellularly localized TGF-beta 1 protein in the suprabasal epidermis and by the appearance of extracellularly localized TGF-beta 1 in the basal layers. A dose rate of 16 micrograms/wk for 4 wk was unable to induce the same response. In contrast, after 20 weekly topical applications of 16 or 64 micrograms of BAP, an increase in TGF-beta 1 mRNA concentration and the appearance of extracellularly localized protein in the epidermis were observed. These changes in TGF-beta 1 expression were paralleled by changes in epidermal morphology. A similar group of animals treated with 4 micrograms of BAP/wk for 20 wk did not respond differently from untreated controls. Papillomas resulting from treatment with 16 or 64 micrograms of BAP/wk for 28 wk stained for intracellularly localized TGF-beta 1 predominantly in the differentiating and nondividing layers. Papillomas stained for extracellularly localized TGF-beta 1 solely in the less differentiated and dividing cells. These results suggest that tumorigenesis by BAP involves the induction of cumulative changes in epidermal TGF-beta 1 mRNA and protein concentrations as well as alterations in skin morphology associated with a tumor-promotion process.

Stimulation of TGF-beta 1 mRNA concentration in mouse skin treated with benzo[a]pyrene.

Topical application of benzo[a]pyrene (B[a]P) at dose rates of 32 or 64 micrograms/week to the dorsal skin of female Swiss (ICR) mice resulted in a marked and rapid increase in concentration of RNA for transforming growth factor beta 1 (TGF-beta 1) in epidermis. Two RNA species 1.9 and 2.5 kb, detected by a mouse TGF-beta 1 cDNA probe, were coordinately expressed. The concentration of these species appeared to be maximal 6-12 h after application, and returned to control levels after 48 h. A second, less intense maximum was observed 72-96 h after treatment. Similar effects were observed in CD-1 and HRS (both hr/hr and hr/+) mice, which are also sensitive to B[a[] tumorigenesis. In comparison with 32 and 64 micrograms/week a dose rate of 16 micrograms/week was essentially without activity in increasing TGF-beta 1 RNA concentration. All three dose rates induced an increase in epidermal RNA for ornithine decarboxylase, however, and with kinetics similar to those observed with the potent tumor-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate. The results obtained support other findings made in this laboratory, that at high dose rates above 16 micrograms tumorigenesis by B[a]P involves a strong tumor-promoting component. The latter further appears to be mediated by increased TGF-beta 1 expression.

BCG treatment of Crohn's disease.

Among 53 patients with documented Crohn's disease, 30% manifested a defect in delayed hypersensitivity demonstrated by negative DNCB skin tests and significant (p less than 0.01) T-lymphocyte hyporeactivity. A double-blind controlled trial was conducted to evaluate oral Bacillus Calmette-Guerin (BCG) therapy in nine of these patients with Crohn's disease and deficient cellular immunity. All patients had a Crohn's Disease Activity Index (CDAI) greater than 150 (at least moderate activity) upon randomization to BCG (five patients) or placebo (four patients) treatment for six to 12 months. No significicant differences between BCG and placebo treatment were found in the CDAI, laboratory tests and gastrointestinal roentgenograms. We conclude that the disturbance in cell-mediated immunity in patients with Crohn's disease probably is a manifestation of the disease rather than an etiological factor and that immunostimulation with oral BCG is not effective therapy.

Gallstone dissolution by chenodeoxycholic acid and phenobarbital.

Gallstone dissolution and biliary lipids were determined and compared in patients receiving either chenodeoxycholic acid (CDC), or CDC and phenobarbital (PB) for 11/2 to 2 years. Among patients with radiolucent gallstones, dissolution occurred in 53% of those receiving CDC alone and in only 25% of those receiving both CDC and PB. No dissolution occurred in 13 other patients with calcified gallstones. Patients with dissolution had a significantly greater molar percentage of CDC and a significantly lower saturation index in bile than those without dissolution. Diarrhea and transiently abnormal liver function tests were the most frequently observed side-effects but only diarrhea necessitated a reduction of the CDC dose. Gallstones recurred following dissolution in one of six patients followed for six months after discontinuation of CDC. In conclusion, PB did not enhance CDC-induced desaturation of bile or gallstone dissolution.