bluuebunny/crossref_metadata_2025 huggingface dataset:
Stimulation of Tumor Growth by Nutrition Support
Authors: Torosian Michael H.
Published: September 2009

Controversy exists regarding the use of nutrition support in the cancer patient. Although nutrition support can clearly improve host nutritional status and restore immunoconfidence, the efficacy of nutrition support to reduce morbidity and mortality associated with antineoplastic therapy is questionable. A potential concern with the use of nutrition support in the tumor‐bearing host is stimulation of primary tumor growth and metastasis. Numerous animal studies clearly demonstrate that oral and parenteral nutrition can significantly stimulate tumor cell proliferation and distant metastasis. Although cellular kinetic studies in humans have shown alterations after parenteral nutrition, objective measures of tumor growth, metastasis and tumor protein synthesis have not been affected by parenteral nutrition. This chapter summarizes the research and clinical work regarding the effect of nutrients on tumorigenesis, primary tumor growth, and metastasis in both animal and human tumors. (Journal of Parenteral and Enteral Nutrition16:72S‐75S)
Glutamine Facilitates Chemotherapy While Reducing Toxicity
Authors: Klimberg V. Suzanne , Nwokedi Emmanuel , Hutchins Laura F. , Pappas Alex A. , Lang Nicholas P. , Btoadwater J. Ralph , Read Raymond C. , Westbrook Kent C.
Published: September 2009

Dose intensification of chemotherapy is thought to increase survival. With recent advances in hemopoietic cell modulators such as granulocyte colony stimulating factor, the limiting toxicity of intensifying chemotherapeutic regimens has become the severity of the associated enterocolitis. In animal models, glutamine protects the host from methotrexate‐induced enterocolitis. This study evaluates the effects of a glutamine‐supplemented diet on the tumoricidal effectiveness of methotrexate. Sarcoma‐bearing Fisher 344 rats (n = 30) were pair‐fed an isocaloric elemental diet containing 1% glutamine or an isonitrogenous amount of glycine beginning on day 25 of the study. Rats from each group received two intraperitoneal injections of methotrexate (5 mg/kg) or saline on days 26 and 33 of the study. On day 40, rats were killed, tumor volume and weight were recorded, and tumor glutaminase activity and tumor morphometrics were measured. Blood was taken for arterial glutamine content, complete blood count, and blood culture. The gut was processed for glutaminase activity and synthesis phase of the deoxyribonucleic acid. In rats receiving methotrexate, the tumor volume loss was nearly doubled when glutamine was added to the diet. Significant differences in tumor glutaminase activity and morphometrics were not detected. The toxicity to the host was ameliorated. Significantly increased synthesis phase of deoxyribonucleic acid of the whole jejunum, decreased bacteremia, “sepsis,” and mortality were demonstrated. Glutamine supplementation enhances the tumoricidal effectiveness of methotrexate while reducing its morbidity and mortality in this sarcoma rat model. (Journal of Parenteral and Enteral Nutrition16:83S‐87S, 1992)
Nutrition in Advanced Cancer: Anorexia as an Outcome Variable and Target of Therapy
Authors: Tchekmedyian N. Simon , Halpert Cynthia , Ashley Judith , Heber David
Published: September 2009

The endpoints used as outcome variables in clinical cancer treatment trials, including nutrition intervention studies, should contain items that are meaningful to the patient. Variables to consider are appetite, food intake, physical performance, psychological and social functioning, response to cancer therapies, survival time, nutrition status, associated morbidity, and costs. Ideally, the design and conduct of nutrition trials should be carried out by a multidisciplinary team comprising medical oncologists, physician specialists in nutrition, dietitians, and social scientists. Anorexia has not been a focus of nutrition support trials in the past partly because of the lack of effective strategies to reverse it. Anorexia is one important cause of cancer starvation, and it also causes patient discomfort. This paper describes outcome variables that include patient derived subjective factors such as anorexia, and outlines new strategies to reverse anorexia. Pharmacologic strategies tested to reverse anorexia include corticosteroids, anabolic steroids, cyproheptadine, hydrazine sulfate, cannabinoids, and megestrol acetate. Of these, only the latter has been consistently well tolerated and effective, with significant improvements in appetite and food intake demonstrated in large‐scale, randomized, controlled trials involving more than 600 cancer patients. Dose‐response studies have demonstrated increasing efficacy with increasing doses of megestrol acetate from 160 to 800 mg/day. Doses in excess of 800 mg/day are not currently recommended. The mechanisms of action of megestrol acetate involve both behavioral and metabolic effects, and its impact on energy expenditure, appetite, body composition, endocrine function, and lipid metabolism is the subject of ongoing research. Such effects as well as new information on the role of various cytokines provide opportunities to test new therapies to renourish the cancer patient not by way of forced feeding, but by reversing the systemic effects of malignancies that impair renutrition. (Journal of Parenteral and Enteral Nutrition16:885–925, 1992)
Home Parenteral Nutrition in Patients With a Cancer Diagnosis
Authors: Howard Lyn
Published: September 2009

The clinical outcome for 1362 patients with active cancer managed on home parenteral nutrition (HPN) is compared with that of 122 patients with radiation enteritis (“cured” cancer) and 416 patients with Crohn's disease. This longitudinal clinical information was reported to the North American Home Parenteral and Enteral Nutrition Registry (Oley Foundation/A.S.P.E.N. joint project) between 1985 and 1989. The data shows that the number of active cancer patients on this therapy is increasing 13% per year. The annual survival rate is 25% for patients with active cancer, as compared with 88% for patients with radiation enteritis and 95% for patients with Crohn's disease. Although 50% of all active cancer patients starting HPN are dead within 6 to 9 months, the prognosis is somewhat better in children, and 20% of these active cancer patients appear to do well, returning to full oral nutrition and experiencing complete rehabilitation. These are presumed to be patients with a potentially curable cancer requiring super‐aggressive treatment, which causes temporary severe gastrointestinal dysfunction. Adult active cancer patients have the same rehospitalization rate for HPN complications (once per year) as radiation enteritis and Crohn's disease patients. However, their rehospitalization rate for non‐HPN complications is four times higher. This article reviews the factors that may explain the growth of HPN in active cancer patients and discusses some of the unanswered clinical questions that urgently need to be addressed to more effectively determine the appropriateness or inappropriateness of HPN management in the active cancer setting. (Journal of Parenteral and Enteral Nutrition16:93S‐99S, 1992)
Management of Acute Diarrhea in Infants
Authors: Rhoads Marc
Published: September 2009

In 1999, children seen in the emergency room of a developed country for watery diarrhea and dehydration will most likely receive an intravenous infusion of fluid, followed by instructions to give oral rehydration solution (ORS) and clear liquids for a day, followed by half‐strength lactose‐free formula. In fact, the majority of these children could best be managed with supervised ORS followed by early (within 4–6 h) refeeding of their normal diet, based on large numbers of clinical trials and a meta‐analysis. In the next decade, effective therapy in addition to glucose‐containing oral rehydration solutions should be available which should reduce diarrheal volume and duration of purging. These include amino acid‐supplemented “Super ORSs,” ORS with soluble fibers, liquid zinc, and probiotic milks containing bacteria which boost the immune response and reduce stool number. In addition, children wealthy enough to be able to afford the new tetravalent vaccine will be largely protected from dehydrating rotavirus diarrhea, the most common cause of dehydration in infants. (Journal of Parenteral and Enteral Nutrition23:S18‐S19, 1999)
A Clinical Study of the Effectiveness of Oral Glutamine Supplementation During Total Parenteral Nutrition: Influence on Mesenteric Mononuclear Cells
Authors: Aosasa Suefumi , Mochizuki Hidetaka , Yamamoto Tetsuhisa , Ono Satoshi , Ichikura Takashi
Published: September 2009

Bacterial translocation (BT) is a well‐known insult during total parenteral nutrition (TPN) and a high incidence of morbidity has been reported in septic patients receiving TPN. Inflammatory cytokines were shown to play an important role in the pathogenesis of critical complications following sepsis. Previous studies have indicated that supplementation of TPN with glutamine is effective in preventing BT in animals, but its effectiveness in humans is unclear. The aim of this study was to determine the effectiveness of oral glutamine supplementation to patients receiving TPN in suppressing cytokine production of mesenteric blood mononuclear cells (M‐MNC). Fifteen colorectal cancer patients were divided into 3 groups according to preoperative nutrition management. (1) TPN group: TPN with conventional glutamine‐free amino acid solution. (2) Gln group: TPN with oral glutamine supplementation of 30 g/d. (3) Control group: oral intake of normal food. M‐MNC were obtained immediately after laparotomy and tumor necrosis factor‐alpha (TNF‐α) and interleukin‐10 (IL‐10) production of M‐MNC was evaluated with or without lipopolysaccharide (LPS) stimulation. TNF‐α and IL‐10 production by LPS‐stimulated M‐MNC was increased in the TPN group and suppressed in the Gln group. In conclusion, oral glutamine supplementation to patients with TPN was shown to be effective for the prevention of M‐MNC activation to avoid excessive production of cytokines. (Journal of Parenteral and Enteral Nutrition23:S41‐S44, 1999)
Glutamine Supplementation in Low‐Birth‐Weight Infants: Mechanisms of Action
Authors: Neu Josef , DeMarco Vincent , Weiss Michael
Published: September 2009

Very low‐birth‐weight infants have minimal endogenous nutritional reserves and are at high risk for stresses that induce further breakdown of these diminished reserves. They frequently receive very little glutamine because enteral feedings are often delayed and glutamine is not included in parenteral nutrition. Here we describe studies of glutamine supplementation in very low‐birth‐weight infants and discuss potential mechanisms for the beneficial effects. (Journal of Parenteral and Enteral Nutrition23:S49‐S51, 1999)
Interleukin‐11: Its Biology and Prospects for Clinical Use
Authors: Grosfeld Jay L. , Xunxiang Du  , Williams David A.
Published: September 2009

IL‐11 is a multifunctional cytokine that has pleiotropic effects on a variety of tissue including the bone marrow and intestinal mucosa. IL‐11 is useful in elevating the platelet count in cancer patients with chemotherapy‐induced thrombocytopenia and has a cytoprotective effect on the bowel mucosa in a variety of causes of gut damage and a trophic effect on the villi after massive bowel resection. (Journal of Parenteral and Enteral Nutrition 23:S67‐S69, 1999)
Nucleotides and Intestine
Authors: Tsujinaka Toshimasa , Kishibuchi Masamori , Iijima Shohei , Yano Masahiko , Monden Morito
Published: September 2009

Background: Dietary nucleotides play an important role in the growth and development of the intestine. Parenteral supplementation of nucleic acids may be necessary to maintain the mucosal proliferation and barrier functions during parenteral nutrition (PN). Methods: Male Wistar rats were divided into 3 groups: FED (food ad libitum with saline infusion); PN (a standard PN solution); and OG (OG‐6, a mixture of nucleotide and nucleosides, in addition to the PN solution). The mucosal wet weight, protein, and DNA contents, villous height and crypt depth, electronmicroscopic examination of the intercellular junctions, proliferating activity of the mucosal cells, mucosal permeability, bacterial translocation, and mucosal cathepsin activities were examined. Results: The wet weight, protein, and DNA contents of the jejunal mucosa were significantly increased in the OG group, compared with those in the PN group. The morphometric examination revealed a significant increase in the villous height but not in the crypt depth in the OG group. The widths of both the tight and intermediate junctions were narrower in the OG group than those in the PN group. The activity of diamine oxidase was increased in the OG group, compared with that in the PN group. The ratio of proliferating cell nuclear antigen positive cells and the index of bromodeoxy uridine labeling index in the OG group were as high as in the FED group, and significantly higher than those in the PN group. The portal concentration of fluorescein isothiocyanate‐dextran 70,000 after intragastric loading was significantly higher in the PN group than that in OG group. Likewise, the rate of urinary lactulose excretion after intragastric loading was higher in the PN group. The positive rate of bacteria cultured in mesenteric lymph nodes was higher in the PN group than in the OG group although the difference was not significant. The activities of mucosal cathepsins (B, H, and L), markers for phagocytic degradation of extrinsic substances and organisms, were higher in the PN group than those in the OG and FED groups. Conclusions: Parenteral supplementation of nucleic acids supports the mucosal cell proliferation and functions. (Journal of Parenteral and Enteral Nutrition23:S74‐S77, 1999)
Colonic Digestion and Absorption of Energy From Carbohydrates and Medium‐Chain Fat in Small Bowel Failure
Authors: Jeppesen Palle Bekker , Mortensen Per Brøbech
Published: September 2009

Gut function and the degree of intestinal insufficiency or failure in short bowel patients can be quantified with respect to wet weight and energy absorption by the use of balance studies. This enables the physician to distinguish patients with extreme intestinal failure inconsistent with the restoration of intestinal autonomy by dietary manipulation from short bowel patients with borderline gut failure in whom dietary manipulations may result in the weaning from parenteral support. A high‐carbohydrate, low long‐chain fat diet and a diet where long‐chain fat has been replaced by medium‐chain triglycerides increase absorption of energy in patients with small bowel failure, provided that they have a preserved colon in continuity. This is due to the ability of the colonic flora to ferment carbohydrates malabsorbed in the small bowel to the short‐chain fatty acids (SCFAs). These SCFAs are easily absorbed across the colonic mucosa resulting in a salvage of carbohydrate energy that otherwise would have been lost in feces. In contrast, long‐chain fatty acids are not absorbed by the colon, and long‐chain fat malabsorbed in the small bowel of short bowel patients are not retained in the large bowel. Recent work has indicated that the water soluble medium‐chain fatty acids are effectively absorbed in the large bowel similar to the SCFAs. This may explain an almost complete absorption of medium‐chain triglycerides in short bowel patients, even in patients with virtually no absorption of long‐chain fat, and why this only occurs in patients with a colon in continuity. Manipulation of the dietary fat:carbohydrate ratio is much less efficacious in short bowel patients with no colonic function, and the use of medium‐chain triglycerides has no proven effect on overall energy absorption from short bowel patients without a large bowel in continuity. Hence, the colon has increasingly important digestive functions as small bowel failure proceeds, not only when it comes to absorption of water and sodium, but also of energy from carbohydrates and medium‐chain fat. (Journal of Parenteral and Enteral Nutrition23:S101‐S105, 1999)
Epidermal Growth Factor and the Short Bowel Syndrome
Authors: Thompson Jon S.
Published: September 2009

Because epidermal growth factor (EGF) has multiple effects on the intestinal epithelium and endogenous EGF plays an important role in maintaining normal intestinal structure and the response to injury, EGF should be important in the intestinal adaptive response to resection. The accumulated data in the literature support a role for endogenous EGF in the intestinal adaptive response. Endogenous EGF is increased in saliva and diminished in urine after intestinal resection. This suggests increased tissue utilization of endogenous EGF during adaptation. Intestinal EGF receptor activity is increased after resection. Intestinal adaptation is impaired in animals with defective EGF receptors. Thus EGF receptor activity also is important during adaptation. The results of experimental studies suggest that EGF administered at the time of resection enhances the intestinal adaptive response. Both structural and functional adaptation are augmented. The route, dose, and timing of EGF administration are important factors. EGF has additive effects with glutamine and growth hormone on adaptation. Several observations from these reports have relevance to the potential clinical application of EGF therapy: (1) EGF should be given soon after resection; (2) early transient administration may lead to a substantial effect on adaptation; (3) both systemic and enteral therapy may be effective; (4) luminal nutrients are important but not essential in mediating EGF‐stimulated adaptation; and (5) combined therapy with other nutrients and growth factors may have merit. In conclusion, endogenous EGF plays an important role in intestinal adaptation. Furthermore, experimental results suggest the potential clinical usefulness of EGF to stimulate intestinal adaptation after massive intestinal resection. There is currently no evidence to support the use of EGF in patients with well‐adapted short bowel syndrome. (Journal of Parenteral and Enteral Nutrition23:S113‐S116,1999)
Cartilagenous and Osseous Metaplasia in the Heart of an Albino Rat
Authors: Sharma Rajeshwar N.
Published: September 2009

Cartilagenous and osseous metaplasia were observed in the heart of a 370-day-old male Charles River-CD rat. The papillary muscle, chordae tendineae, subendocardium, and myocardium of the left ventricle were affected, and the lesions resembled in most instances an endochondral bone formation with primitive bone marrow. A few emboli of cartilage surrounded by fibrous tissue were also observed in the lumen of the left ventricle. Severe cardiomyopathies were noted, and these were associated with the metaplastic changes.
A Semiquantitative Method to Evaluate Drug-Induced Juvenile Arthropathy in the Canine
Authors: Gough Alec W. , De LaIglesia Felix A.
Published: September 2009

In order to evaluate the arthropathogenic properties of some antibacterial agents, groups of juvenile Beagle dogs received orally either 500 mg/kg of oxolinic acid, 100 mg/kg of oxolinic acid or 500 mg/kg of pipemidic acid. Arthropathic lesions were characterized by articular cartilage vesiculations and erosions which developed in the treated groups. The severity of cartilage damage was graded in each articular surface and an arthropathic index for each group was calculated from these severity scores. The results concerning the evaluation of lesion incidence and severity demonstrated that the toxic effect of oxolinic acid on articular cartilage was dose dependent and that pipemidic acid had a greater arthropathic potential than oxolinic acid.
Studies on the validity of urinary enzyme assay in the diagnosis of drug-induced renal lesions in rats
Authors: Watanabe M. , Nomura G. , Hirata M. , Imai K. , Koizumi H.
Published: September 2009

The validity of urinary enzyme assays in the diagnosis of renal lesions was studied in rats for evaluation in comparison with other tests such as urinalysis and serum biochemical assay. Tubular damages of slight or severe degree were induced by daily intramuscular administration of 500 mg/kg or 1,000 mg/kg of kanamycin (KM) for 7 and 6 days respectively. Glomerular lesions were induced subcutaneous injection of 30 mg/kg of puromycin (PM) for 6 days. The enzymes, assayed daily before and after the onset of administration, were lactic dehydrogenase (LDH), aspartate aminotransferase (GOT), alkaline phosphatase (AI-P), acid phosphatase (Ac-P), leucin aminopeptidase (LAP) and γ-glutamyl transpeptidase (γ-GT). The distribution of these enzymic activities in the kidneys was histochemically examined. Assays of LDH and GOT on the kidney tissue homogenate were also conducted. Histological alterations of the kidneys were examined in the rats sacrificed after termination of administration.

Significant elevation of the LDH and GOT urine levels were observed within 24 hours in rats treated with 500 mg/kg of KM with the high enzyme levels being maintained throughout the administration period, while the other enzymes remained within pretreatment levels or were only slightly elevated. Serum urea nitrogen (BUN) and creatinine levels remained unchanged with no abnormality being found in the urinalysis of this group. In the group treated with 1,000 mg/ kg of KM, concomitant rising of all urine enzyme levels was observed, with elevation of the LDH and GOT levels being extreme while the BUN and serum creatinine levels rose only at the termination of the administration period. The BUN level rose earlier than did most of the urinary enzymes in puromycin-treated rats.

Depletion of LDH activity was histochemically demonstrated in the kidneys where no histological alteration was observable, while the activities of AI-P, γ-GT, and LAP showed no distinct changes until the tabular destruction became severe. Upon termination of both KM and PM administration, the depletion of LDH and GOT activities was noted in a kidney homogenate assay for the enzymes.

These results clearly showed that among the enzymes studied, the LDH and GOT urine levels are the most sensitive indicators for detecting proximal tubular lesions induced by KM. It was further demonstrated that the urinary enzyme assay in combination with serum BUN measurement is an effective examination for distinguishing tubular from glomerular lesions.
Susceptibility of Specific Mouse Liver Lobes to Liver Neoplasms Induced with Benzidine Dihydrochloride
Authors: Frith C. H. , Baetcke K. P. , Nelson C. J. , Schieferstein G.
Published: September 2009

The incidence of liver tumors induced in mice with benzidine dihydrochloride was highest in the left lateral lobe, intermediate in the right lateral and central lobes and lowest in the caudate lobe. The distribution of liver tumors was related to lobe volume and weight.
Primary Tumors of the Spleen in Guinea Pigs
Authors: Hoch-Ligeti Cornelia , Congdon Charles C. , Deringer Margaret K. , Stewart Harold L.
Published: September 2009

A classification and morphologic description of primary splenic tumors of guinea pigs is presented for the first time. Twenty glomerate vascular tumors, 15 sinusoidal hemangioendotheliomas, 4 hemangiosarcomas, 2 chondromatous and 5 lipomatous tumors with or without fibrous or vascular components were encountered in the spleen of male and female guinea pigs of 2 inbred strains and one noninbred stock. Foci of cellular arrangements distinctive for splenic tissues were observed in every tumor. In 2 additional guinea pigs, hemangiosarcomas were found disseminated in the spleen, liver, lung and kidney; since the splenic origin of these tumors was uncertain, they were not included in this group of primary splenic tumors.

At all levels used, whole body irradiation with X-or gamma rays increased the rate of occurrence and the number of splenic tumors. A significantly greater number of splenic tumors developed in the irradiated than in the untreated inbred guinea pigs after the age of 30 months. In the irradiated noninbred guinea pigs significantly fewer splenic tumors occurred than in the guinea pigs of the inbred strains.
Rapid Tracheal Infusion Method for Routine Lung Fixation Using Rat and Guinea Pig
Authors: Buckingham Kent W. , Wyder William E.
Published: September 2009

A rapid tracheal infusion method for lung fixation was performed. An infusion time of 1 minute, at 20 cm to 30 cm constant infusion height, allowed reproducible inflation and fixation of lung samples for subsequent histologic processing. The resulting microscopic sections of lung were superior in quality to lungs fixed by standard immersion methods, and were comparable in quality to lungs fixed using longer infusion times.
Primary Tumors and Adenomatosis Of The Lung In Untreated and In Irradiated Guineá Pigs
Authors: Hoch-Ligeti Cornelia , Congdon Charles C. , Deringer Margaret K. , Strandberg John D. , Sass Bernard , Stewart Harold L.
Published: September 2009

The morphology of alveologenic tumor, hemangiosarcoma, lymphangioma, intrabronchial papilloma and adenomatosis observed in the lung of guinea pigs is described. Electron micrographs revealed alveologenic tumor to consist of Type II pneumocytes and the lesion of adenomatosis to consist of distended alveoli lined with ciliated bronchial type epithelial cells.

A relationship between the dose of gamma or X-ray irradiation received and the frequency of guinea pigs with lung tumors could not be established. In guinea pigs, which survived over 20 months, the frequency of alveologenic tumors in the inbred strains was 23/107 in irradiated and 11/79 in untreated guinea pigs; this difference was statistically not significant. The frequency of tumor bearing inbred males (11/60) was significantly lower than of tumor bearing noninbred males (23/65). In the irradiated guinea pigs alveologenic tumors occurred earlier and tumor nodules in the lung were more numerous than in the untreated guinea pigs.

Primary hemangiosarcoma involved the lung of one untreated and one irradiated strain 2 guinea pig. A single lymphangioma was found in an untreated inbred guinea pig. Intrabronchial papillomas were observed twice in irradiated and once in untreated guinea pigs.

Adenomatosis was present in the lung of 2 untreated inbred and 5 irradiated noninbred guinea pigs.
Precursor Lesions and Pathogenesis of Spontaneous Mammary Tumors in Mice
Authors: Sass Bernard , Vlahakis George , Heston Walter E.
Published: September 2009

A histologic study was done on the spontaneously occuring precursor and neoplastic lesions of mammary gland in inbred and hybrid female mice.

Hyperplastic alveolar nodules (HAN) are small groups of non-encapsulated mammary acini lined by a single layer of low cubodial epithelial cells. The stroma of HAN often contain macrophages laden with ceroid pigment, which imparts to them a yellow color. Microfoci of carcinoma may be found within HAN, and adenoacanthomas may arise within acini in which there is chronic inflammation. Plaques are pregnancy-dependent lesions which occur in three albino mouse strains: DD, GRS, and RIII. These plaques are disc-shaped, are circumscribed or unencapsulated, have a central myxomatous core, and have acini which exhibit radial symmetry. Plaques can give rise to adenocarcinomas type P, type B (papillary and cystic) and also to the unusual and distinctive pale cell carcinoma. The spontaneous tumors described in this paper are mammary gland adenocarcinomas with sebaceous cell nests, tumors which are papillomas and contain basal epithelial elements and acini derived from mammary, sebaceous glands, or hair follicles.
An Analysis of the Carcinogenesis Testing Experience of the National Cancer Institute
Authors: DVM G. H. Hottendorf , Pachter I. J.
Published: September 2009

Tabulations of the results of the initial approximately 200 NCI carcinogenesis bioassays conducted in mice and rats were published recently. However, no analysis of the results were provided. Such an analysis is the subject of this report.

Ninety eight NCI bioassays were positive for carcinogenicity. Only three bioassays (<2%) were negative in both species and the ratio of positive to negative bioassays was 33:1. The remaining 47% of the bioassays were considered to be suggestive or inconclusive and it is inappropriate to refer to the total positive rate as 50%. The liver was the predominant tumor site and the only tumors produced in either rodent species in 19% of the positive bioassays were in the livers of mice. The high ratio of positive to negative results and the use of the mouse liver as a discriminating target organ raise serious concerns about the carcinogenesis protocol and in the methods of evaluating the results. Several recommendations are offered which may be useful in the current reexamination of bioassay procedures.
Naturally Occurring Chemodectoma in Rats
Authors: Bhandari J. C.
Published: September 2009

Two naturally occurring cases of chemodectoma, one in a 10-week-old albino male rat and another in a 2-year-old albino female rat, are reported. They appear to be the first reported cases of chemodectoma in rats although one case of aortic body tumor was reported previously in an albino rat.
Biological markers of preneoplastic foci and neoplastic nodules in rodent liver
Authors: Bannasch Peter , Moore Malcolm A. , Klimek Fritz , Zerban Heide
Published: September 2009

Foci of altered hepatocytes are regularly observed early during hepatocarcinogenesis in rodents. The abnormal hepatocytes may show a number of different phenotypes as characterized by various cytomorphological and cytochemical markers. The first appearance and the further development of the abnormal cell populations depend on the dose of the carcinogen given and on the duration of the carcinogenic treatment. According to cytochemical, morphometric and autoradiographic findings in rats receiving low doses (2–10% of the LD 50/kg bw/day) of hepatocarcinogens for limited periods (“stop” experiments), glycogenotic (clear or acidophilic) hepatocytes indicate the first step of the neoplastic cell transformation which can be detected by these methods at present. The glycogenotic cells undergo a characteristic metamorphosis and give rise to basophilic tumor cells poor in glycogen, but rich in ribosomes. Under extreme experimental conditions, such as a single or repeated application of higher doses of one or several chemical carcinogens a puzzling picture emerges which is “reversible” to a large extent after withdrawal of the respective compounds. This observation points to a phenotypic instability of the cellular changes induced in certain experimental systems. Foci of altered hepatocytes persisting after withdrawal of the carcinogenic compounds are considered preneoplastic lesions. They may transform into neoplastic nodules which are also persistent and share a number of cytomorphological and cytochemical markers with the focal lesions. The persistent nodules progress to hepatocarcinomas after lag periods of weeks or months. However, the foci may also progress to hepatocarcinomas without passing a nodular intermediate stage. The development of both neoplastic nodules and carcinomas from the preneoplastic glycogen storage foci can proceed independent of further administration of carcinogen. The sequence of cellular changes during hepatocarcinogenesis derived from the experimental results in rodents is strongly supported by observations in humans, especially by the increasing reports on the appearance of hepatic tumors in patients who suffer from inborn hepatic glycogenosis.
Ultrastructure of altered hepatocytes induced by diethylnitrosamine (DENA)
Authors: Zaki F. George
Published: September 2009

Administration of diethylnitrosamine I.P. at dose level of 2 mg/kg five days a week to young Sprague-Dawley rats induced foci of altered hepatocytes entirely devoid of glucose-6-phosphatase and adenosine triphosphatase activity. Several weeks later, these foci developed hepatocellular carcinoma mostly of the trabecular type.

Although these “preneoplastic” altered cells appeared as normal hepatocytes when examined in HE-sections, they were found to exhibit sites of dedifferentiation with ultrastructural features of hepatoma cells. Early morphological changes indicative of neoplastic transformation took place first as excessive storage of glycogen then as marked alterations at the surface membranes of such cells. Striking increase in coated pinocytotic vesicles appeared along the apposing cell membranes associated with loss of sinusoidal microvilli, protrusion of cytoplasmic blebs in the intercellular spaces, reduction or loss of desmosomes and obliteration of bile canaliculi. Subsequent changes were seen as dilation and disruption of the rough endoplasmic reticulum (RER), dispersal of ribosomes, proliferation and clustering of the smooth endoplasmic reticulum (SER), predominance of annulate lamellae, depletion of glycogen, enlargement of the Golgi cisterns and segregation of nucleolar elements.

After 20 weeks, rats given DENA at a dose level of 25 mg/kg twice a week developed pronounced cirrhotic nodules in addition to multiple hepatocellular carcinoma. In contrast to the neoplastic nodules, the cirrhotic ones retained normal activity of glucose-6-phosphatase and adenosine triphosphatase and exhibited ultrastructural features typical of normal hepatocytes.
Interpretation of Rodent Hepatocellular Proliferative Alterations and Hepatocellular Tumors in Chemical Safety Assessment,
Authors: Maronpot R. R. , Boorman G. A.
Published: September 2009

Benign and malignant liver tumors have been frequently observed in National Cancer Institute/National Toxicology Program rodent carcinogenesis bioassays using Fischer 344 rats and B6C3F1 mice. A multilayered pathology review process enhances consistency and accuracy of the histologic diagnoses. All data, including statistically analyzed tumor prevalences, are ultimately reviewed by a multidisciplinary team of scientists for judgment regarding the carcinogenicity of the chemical. Rationale for interpretation of hepatocellular alterations is illustrated with results from the recently completed NCI/NTP bioassays of di(2-ethylhexyl)phthalate, C.I. Disperse Yellow 3, C.I. Solvent Yellow 14, and pentachloroethane.
Choline Deficiency, Partial Hepatectomy, and Liver Tumors in Rats and Mice
Authors: Newberne Paul M. , Camargo Joao Lauro V. de , Clark Anthony J.
Published: September 2009

Choline deficiency (CD) increases susceptability of (he rat liver to a number of hepatocellular carcinogens with a wide diversity of structure and potency. While severe CD results in micronodular cirrhosis and enhanced tumor induction, even a mild deficiency, without cirrhosis is sufficient to result in the increased carcinogenic response. The effects of CD are in part mediated via modulation of microsomal and, possibly, cytosolic enzymes responsible for activation/deactivation of carcinogens.

The B6C3F1 hybrid mouse is remarkably sensitive to initiation/promotion of liver tumors by many substances or conditions. Choline deficiency or partial hepatectomy alone, or in concert, markedly enhances liver tumor induction in the absence of any known carcinogen. These data indicate that the liver of this strain of mouse is “initiated” at or shortly after birth and can be promoted by non-carcinogenic substances or conditions.
Proliferative liver lesions and sex steroids in rats
Authors: Schuppler J. , Schulte-Hermann R. , Timmermann-Trosiener I. , Günzel P.
Published: September 2009

In standard two year tumorigenicity studies some gestagens, alone or in combination with an estrogen have been shown to produce proliferative liver lesions (PLL) in rats. Estrogens in general have not produced PLLs; for ethinyl estradiol the situation is equivocal.

The steroids which increase the incidence of PLLs have not been shown to have the characteristics usually associated with classical hepatocarcinogens such as diethylnitrosamine (e.g. negative mutagenicity and cytoxicity, failure to bind covalently to DNA). Therefore, another mechanism must be assumed. A possible explanation is given by the ability demonstrated for a few steroids (mestranol alone or in combination with norethindrone, ethinylestradiol) to promote preneoplastic islands induced by diethylnitrosamine, resulting in an increase in tumor incidence over rats given only the carcinogen. Spontaneous preneoplastic islands in rats occur in various incidence in different strains and we have recently shown that their reaction to steroids—enhanced proliferation—is the same as the effect on preneoplastic islands produced by classical carcinogens. Sex steroids also enhance the growth or normal hepatocytes. It, therefore, seems reasonable to assume that sex steroids produce PLLs by acting on spontaneous preneoplastic lesions and not by the mechanisms usually associated with classical carcinogens.

Extrapolating the incidence of PLLs in rats to a risk in humans may be highly misleading because of different pharmacokinetic patterns. Even in rats treated orally for two years with sex steroids dosed as multiples of the human contraceptive dose, resorption and biovailability may vary by a factor of 10 or more. It is, therefore, inappropriate to state that one sex steroid is more active in the production of PLLs than another, unless the data from pharmacokinetic studies are taken into account.

Available evidence shows that sex steroids act as tumor promotors and enhance the growth of normal hepatocytes. It is extremely doubtful whether a sex steroid producing PLLs in the rat after two years of oral treatment can be classified as an initiating tumorigen for the rat. Substantial risk for humans cannot be inferred, because of the high incidence of spontaneous preneoplastic lesions in rats, and because of the very high sensitivity of the rat liver to a variety of chemically unrelated compounds including sex steroids.
Human Liver Neoplasia and Steroid Exposure
Authors: Barrows George H. , Mays E. Truman , Christopherson William M.
Published: September 2009

This study examines experience with over 250 liver tumors in young women. Most were oral contraceptive related. There were two distinct benign liver tumor types: focal nodular hyperplasia and liver cell adenoma. Six benign liver tumors were examined for estrogen receptors. They did not contain significant quantities of estrogen receptor, supporting experimental studies of an epigenetic origin. Multiple tumors occurred in about 20% of cases but did not change the favorable prognosis associated with benign tumors. The most significant source of morbidity and mortality was spontaneous hemorrhage or rupture. Twenty-three women in this series had hepatocellular carcinoma and the majority of these were associated with prolonged steroid usage. These malignant liver tumors occurred in young females without cirrhosis or other factors known to be associated with hepatic malignancy. Unlike “hepatocellular carcinomas” reported in males taking anabolic androgenic steroids, the tumors in females had a high rate of metastasis to a variety of organs. The risk of liver tumors in oral contraceptive users remains unknown, but must be very small since an estimated 150 million women worldwide and 40 million in the U.S.A. have used oral contraceptives.
Chemically Induced Hepatocellular Proliferative Changes in the Rat Without Evidence of Neoplastic Transformation,
Authors: Sparano B. M. , Brecher M. P. , Gordon G. , Iatropoulos M. J. , King C. D. , Gallo P.
Published: September 2009

The hypothesis that hepatocellular proliferative changes give rise to autonomous, neoplastic lesions in rodents was tested in this study in which hepatoproliferative lesions induced in rats by feeding an experimental psychoactive drug, cyproximide, were examined at various times during the course of a 24 month study. A total of 610 male and female rats (Charles River Laboratories COBS®CD®(SD)BR, Wilmington, Mass.) were distributed into three groups. Each of two treatment groups contained 230 rats given 0.1% or 0.4% of cyproximide in the diet. One hundred and fifty rats were given a drug-free diet and served as controls. Five males and five females from each group were sacrificed for postmortem examination after 6, 12 and 20 months of drug diet feeding after which remaining rats were retained for recovery (nontreatment) periods of 18, 12 and 4 months, respectively. An additional 25 males and 25 females from each dose level were treated for 24 months and then sacrificed along with all surviving recovery and control rats. The results of this study demonstrated that the incidence of proliferative lesions was greater in the liver of treated rats (especially females) than in control rats; however, the incidence of hepatocellular neoplasms was the same in treated and control rats.
The Use of In vivo Hepatic Initiation-Promotion Systems in Understanding the Hepatocarcinogenesis of Technical Grade Dinitrotoluene.
Authors: Popp James A. , Leonard Thomas B.
Published: September 2009

A 2 year bioassay sponsored by the Chemical Industry Institute of Toxicology demonstrated the potent hepatocarcinogenicity of technical grade dinitrotoluene (DNT) which contains 76% 2,4-DNT, 18% 2,6-DNT and less than 3% of each 2,3; 2,5; 3,4 and 3,5-DNT isomers. In contrast, a 2 year bioassay of 2,4-DNT sponsored by the National Cancer Institute did not result in the appearance of hepatic neoplasms above the spontaneous incidence. Using previously described in vivo hepatic initiation-promotion systems, an evaluation of the initiating and promoting activity of individual DNT isomers was undertaken to provide an understanding for the differences between the two bioassays. Weak hepatocyte initiating activity was identified in technical grade DNT and purified 2,6-DNT. In contrast, 2,3; 2,4; 2,5; 3,4 and 3,5 isomers had no detectable initiating activity. When fed following a diethylnitrosamine initiating regimen, technical grade DNT, purified 2,4 and 2,6-DNT isomers had demonstrable promoting activity. Therefore, the hepatic neoplasms resulting from technical grade DNT feeding apparently resulted from the initiating activity of 2,6-DNT followed by the promoting effect of both the 2,4 and 2,6-DNT isomers. The lack of hepatic neoplasms following chronic feeding of 2,4-DNT was apparently due to the lack of hepatic initiating activity.
The Biology of Carcinogen-Induced Hepatocyte Nodules and Related Liver Lesions in the Rats
Authors: Farber Emmanuel
Published: September 2009

The only known sequence of tissue changes seen during liver cancer development involves microscopic foci or islands of altered hepatocytes, hepatocyte nodules, a subset of these nodules, the persistent nodules, nodules in nodules and ultimately hepatocellular carcinoma. The nodules show an array of architectural, fine ultrastructural, vascular, biochemical and physiological properties characteristic of this new population of hepatocytes. Despite their origin following initiation with a chemical carcinogen, the vast majority (98–99%) of nodules undergo a complex process of remodeling or redifferentiation to normal looking mature liver. A very small minority persist, continue to grow slowly and ultimately may act as a site of origin for new later precancerous nodules and metastasizing hepatocellular carcinoma. The basis for the different behaviour patterns, remodelling of the majority and persistence of the minority is not understood. Even though the vast majority of nodules do undergo remodelling and “disappear”, it would be unwise at this time to ignore this key role of nodules in general in cancer development.
Hypolipidemics Carcinogenicity and Extrapolation of Experimental Results for Human Safety Assessments
Authors: de la Iglesia Felix A. , Farber Emmanuel
Published: September 2009

Dyslipoproteinemias represent a group of disorders closely related to alterations of cholesterol and triglycerides. The alterations of these lipids are considered important risk factors in coronary heart disease and indicate the need for clinically effective and safe drugs.

Hypolipidemic agent therapy, however, does not appear without risk since the administration of these agents is by necessity, on a long-term basis. In the conduct of animal safety studies with some hypolipidemics, hyperplastic nodules or tumors developed in the liver of rodents. Data from the literature seem to indicate that the tumor response in rodents varies with the type of hypolipidemic drug administered. This paper summarizes the studies with the new lipid-regulating agent gemfibrozil. Aside from conventional long-term studies in rodents, the ultrastructural aspects of the liver were analyzed in several species and genotoxicity assays and short-term tests for hepatocarcinogenicity were conducted. Thus, it was possible to obtain an overview of these biological phenomena in order to allow for safety extrapolations. The biological behavior of these liver nodules showed that gemfibrozil and clofibrate-induced hepatocytes had not undergone malignant transformation. Further, the phenomenon of peroxisome proliferation, a characteristic event that follows hypolipidemic administration in rodents, was not confirmed in primate or human liver. Peroxisome proliferation has been linked to the process of hepatocarcinogenesis in rodents, although genotoxicity assays were negative and initiation/promotion tests failed to elicit tumors or nodules in a system where hepatocarcinogens manifest their activity.

Thus, hypolipidemics such as gemfibrozil or clofibrate may possess low tumorigenic potential with low risk due to the lack of correlation between these tests. Nevertheless, these agents are indicated for specific lipoprotein phenotype alteration with the resulting clinical benefits.
Chemically Induced Hepatocellular Proliferative Changes in the Rat Without Evidence of Neoplastic Transformation
Authors: Sparano B. M. , Brecher M. P. , Gordon G. , Iatropoulos M. J. , King C. D. , Gallo P.
Published: September 2009

The hypothesis that hepatocellular proliferative changes give rise to autonomous, neoplastic lesions in rodents was tested in this study in which hepatoproliferative lesions induced in rats by feeding an experimental psychoactive drug, cyproximide, were examined at various times during the course of a 24 month study. A total of 610 male and female rats (Charles River Laboratories COBS®CD®(SD)BR, Wilmington, Mass.) were distributed into three groups. Each of two treatment groups contained 230 rats given 0.1% or 0.4% of cyproximide in the diet. One hundred and fifty rats were given a drug-free diet and served as controls. Five males and five females from each group were sacrificed for postmortem examination after 6, 12 and 20 months of drug diet feeding after which remaining rats were retained for recovery (nontreatment) periods of 18, 12 and 4 months, respectively. An additional 25 males and 25 females from each dose level were treated for 24 months and then sacrificed along with all surviving recovery and control rats. The results of this study demonstrated that the incidence of proliferative lesions was greater in the liver of treated rats (especially females) than in control rats; however, the incidence of hepatocellular neoplasms was the same in treated and control rats.
Occurrence of Myeloid Bodies in Rats Following Two-Year Administration of Imipramine Hydrochloride
Authors: Spaet Robert H. , Sullivan David J. , Diener Robert M.
Published: September 2009

Sprague-Dawley CD rats received daily oral doses (45 mg/kg) of the cationic amphiphilic tricyclic antidepressant imipramine HCI (Tofranil®) for up to two years. Representative specimens of liver, lung, spleen, mesenteric lymph node, retina and dorsal root ganglion were examined for myeloid bodies (MB). The extent that MB affected a given cell or group of cells was qualitatively determined. Myeloid bodies were observed in a variety of cell types after one year of administration to treated rats. They were less common after a subsequent three month recovery period. Fewer MB were observed in rats treated for one year than were previously reported in short term studies. Fewer MB were seen after two years of treatment than after one year although the same organs were affected. Thus, MB appear to decrease in number with increasing time of compound administration. This may result from a more efficient metabolism of the drug or because of decreased levels of phospholipid in aged rats.