Epigenomic alterations define lethal CIMP-positive ependymomas of infancy.

Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.

Data resources for the identification and interpretation of actionable mutations by clinicians.

Following initial characterization of the reference human genome, initiatives have evolved worldwide to identify genomic aberrations in cancer with the aim of deriving diagnostic, prognostic and predictive information. However, the functional and clinical relevance of many somatic variants in cancer are presently unknown and there is no consensus definition of 'actionability' for genomic aberrancies. Therefore, while robust detection of a variety of genetic aberrations in clinical specimens remains a technical hurdle, the greater challenge lies in the interpretation of these alterations. Critical evaluation of genomic variation in cancer requires the integration of available clinical and preclinical evidence related to their frequencies, functions and roles as therapeutic targets. Many publicly accessible data resources have compiled such evidence to facilitate the understanding of genomic results and ultimately translating results to clinical action. Information for these data resources is derived from various sources including large population genomic datasets, curation of published literature, and data sharing by the scientific community. Currently, there is no widely accepted guidance to definitively assess and integrate the diagnostic, prognostic and predictive information of somatic variants using these knowledge databases. This review will describe data resources pertinent to the identification and interpretation of actionable genomic aberrations by clinicians, and highlight relevant issues in the clinical application of tumor molecular profiling results.

Tailoring precursors for deposition: synthesis, structure, and thermal studies of cyclopentadienylcopper(i) isocyanide complexes.

We report here the synthesis and characterization of a family of copper(I) metal precursors based around cyclopentadienyl and isocyanide ligands. The molecular structures of several cyclopentadienylcopper(I) isocyanide complexes have been unambiguously determined by single-crystal X-ray diffraction analysis. Thermogravimetric analysis of the complexes highlighted the isopropyl isocyanide complex [(η(5)-C5H5)Cu(CN(i)Pr)] (2a) and the tert-butyl isocyanide complex [(η(5)-C5H5)Cu(CN(t)Bu)] (2b) as possible copper metal chemical vapor deposition (CVD) precursors. Further modification of the precursors with variation of the substituents on the cyclopentadienyl ligand system (varying between H, Me, Et, and (i)Pr) has allowed the affect that these changes would have on features such as stability, volatility, and decomposition to be investigated. As part of this study, the vapor pressures of the complexes 2b, [(η(5)-MeC5H4)Cu(CN(t)Bu)] (3b), [(η(5)-EtC5H4)Cu(CN(t)Bu)] (4b), and [(η(5)-(i)PrC5H4)Cu(CN(t)Bu)] (5b) over a 40-65 °C temperature range have been determined. Low-pressure chemical vapor deposition (LP-CVD) was employed using precursors 2a and 2b to synthesize thin films of metallic copper on silicon, gold, and platinum substrates under a H2 atmosphere. Analysis of the thin films deposited onto both silicon and gold substrates at substrate temperatures of 180 and 300 °C by scanning electron microscopy and atomic force microscopy reveals temperature-dependent growth features: Films grown at 300 °C are continuous and pinhole-free, whereas films grown at 180 °C consist of highly crystalline nanoparticles. In contrast, deposition onto platinum substrates at 180 °C shows a high degree of surface coverage with the formation of high-density, continuous, and pinhole-free thin films. Powder X-ray diffraction and X-ray photoelectron spectroscopy (XPS) both show the films to be high-purity metallic copper.

Biallelic EPCAM deletions induce tissue-specific DNA repair deficiency and cancer predisposition.

We report a case of Mismatch Repair Deficiency (MMRD) caused by germline homozygous EPCAM deletion leading to tissue-specific loss of MSH2. Through the use of patient-derived cells and organoid technologies, we performed stepwise in vitro differentiation of colonic and brain organoids from reprogrammed EPCAMdel iPSC derived from patient fibroblasts. Differentiation of iPSC to epithelial-colonic organoids exhibited continuous increased EPCAM expression and hypermethylation of the MSH2 promoter. This was associated with loss of MSH2 expression, increased mutational burden, MMRD signatures and MS-indel accumulation, the hallmarks of MMRD. In contrast, maturation into brain organoids and examination of blood and fibroblasts failed to show similar processes, preserving MMR proficiency. The combined use of iPSC, organoid technologies and functional genomics analyses highlights the potential of cutting-edge cellular and molecular analysis techniques to define processes controlling tumorigenesis and uncovers a new paradigm of tissue-specific MMRD, which affects the clinical management of these patients.

Novel mRNA isoforms and mutations of uridine monophosphate synthetase and 5-fluorouracil resistance in colorectal cancer.

The drug fluorouracil (5-FU) is a widely used antimetabolite chemotherapy in the treatment of colorectal cancer. The gene uridine monophosphate synthetase (UMPS) is thought to be primarily responsible for conversion of 5-FU to active anticancer metabolites in tumor cells. Mutation or aberrant expression of UMPS may contribute to 5-FU resistance during treatment. We undertook a characterization of UMPS mRNA isoform expression and sequence variation in 5-FU-resistant cell lines and drug-naive or -exposed primary and metastatic tumors. We observed reciprocal differential expression of two UMPS isoforms in a colorectal cancer cell line with acquired 5-FU resistance relative to the 5-FU-sensitive cell line from which it was derived. A novel isoform arising as a consequence of exon skipping was increased in abundance in resistant cells. The underlying mechanism responsible for this shift in isoform expression was determined to be a heterozygous splice site mutation acquired in the resistant cell line. We developed sequencing and expression assays to specifically detect alternative UMPS isoforms and used these to determine that UMPS was recurrently disrupted by mutations and aberrant splicing in additional 5-FU-resistant colorectal cancer cell lines and colorectal tumors. The observed mutations, aberrant splicing and downregulation of UMPS represent novel mechanisms for acquired 5-FU resistance in colorectal cancer.

A systematic approach to assessing the clinical significance of genetic variants.

Molecular genetic testing informs diagnosis, prognosis, and risk assessment for patients and their family members. Recent advances in low-cost, high-throughput DNA sequencing and computing technologies have enabled the rapid expansion of genetic test content, resulting in dramatically increased numbers of DNA variants identified per test. To address this challenge, our laboratory has developed a systematic approach to thorough and efficient assessments of variants for pathogenicity determination. We first search for existing data in publications and databases including internal, collaborative and public resources. We then perform full evidence-based assessments through statistical analyses of observations in the general population and disease cohorts, evaluation of experimental data from in vivo or in vitro studies, and computational predictions of potential impacts of each variant. Finally, we weigh all evidence to reach an overall conclusion on the potential for each variant to be disease causing. In this report, we highlight the principles of variant assessment, address the caveats and pitfalls, and provide examples to illustrate the process. By sharing our experience and providing a framework for variant assessment, including access to a freely available customizable tool, we hope to help move towards standardized and consistent approaches to variant assessment.

The differential effects of statins on the risk of developing pancreatic cancer: a case-control study in two centres in the United Kingdom.

INTRODUCTION: There are plausible biological mechanisms for how statins may prevent pancreatic cancer, although the evidence from epidemiological studies in the general population is conflicting. This study aims to clarify whether statins exert their effects in specific sub-groups, namely, gender, smoking status and diabetes. METHODS: A matched case-control study was conducted in patients diagnosed with pancreatic cancer, and a group of dermatology patients of similar ages and gender, diagnosed with basal cell carcinoma. Participants' medical records were reviewed for information on statin use prior to diagnosis. Odds ratios and 95 % CIs for the development of pancreatic cancer were estimated using conditional logistic regression. Subgroup analysis was performed in men, women, smokers and those with type 2 diabetes. RESULTS: Two hundred fifty-two cases (median age 71 years, range 48-73 years, 51 % women) and 504 controls were identified, of which 23 % of cases were regular statin users versus 21 % of controls. In the general study population there was no association between pancreatic cancer and regular statin use (OR 0.82, 95 % CI 0.53-1.23, p = 0.33). However, in male smokers, regular statin use was associated with significantly reduced odds of pancreatic cancer compared to male smokers not prescribed a statin (OR 0.11, 95 % CI 0.01-0.96, p = 0.05). In patients with type 2 diabetes statins use was not associated with reduced odds (OR 0.92, 95 % CI 0.35-2.45, p = 0.80), with no gender effects. CONCLUSIONS: In male smokers, statins may reduce the odds of pancreatic cancer. Statin use should be measured in aetiological studies of pancreatic cancer but analysed in specific sub-groups. Future work should investigate statins as chemopreventative agents in this high risk sub-group.

Addition of short-term androgen deprivation therapy to dose-escalated radiation therapy improves failure-free survival for select men with intermediate-risk prostate cancer.

BACKGROUND: Dose-escalated (DE) radiation therapy (RT) and androgen deprivation therapy (ADT) improve prostate cancer outcomes over standard-dose RT. The benefit of adding ADT to DE-RT for men with intermediate-risk prostate cancer (IR-PrCa) is uncertain. PATIENTS AND METHODS: We identified 636 men treated for IR-PrCa with DE-RT (>75Gy). The adult comorbidity evaluation-27 index classifed comorbidity. Kaplan-Meier and log-rank tests compared failure-free survival (FFS) with and without ADT. RESULTS: Forty-five percent received DE-RT and 55% DE-RT with ADT (median 6 months). On Cox proportional hazard regression that adjusted for comorbidity and tumor characteristics, ADT improved FFS (adjusted hazard ratio 0.36; P = 0.004). Recursive partitioning analysis of men without ADT classified Gleason 4 + 3 = 7 or ≥50% positive cores as unfavorable disease. The addition of ADT to DE-RT improved 5-year FFS for men with unfavorable disease (81.6% versus 92.9%; P = 0.009) but did not improve FFS for men with favorable disease (96.3% versus 97.4%; P = 0.874). When stratified by comorbidity, ADT improved FFS for men with unfavorable disease and no or mild comorbidity (P = 0.006) but did not improve FFS for men with unfavorable disease and moderate or severe comorbidity (P = 0.380). CONCLUSION: The addition of ADT to DE-RT improves FFS for men with unfavorable IR-PrCa, especially those with no or minimal comorbidity.

Nitrogen management is essential to prevent tropical oil palm plantations from causing ground-level ozone pollution.

More than half the world's rainforest has been lost to agriculture since the Industrial Revolution. Among the most widespread tropical crops is oil palm (Elaeis guineensis): global production now exceeds 35 million tonnes per year. In Malaysia, for example, 13% of land area is now oil palm plantation, compared with 1% in 1974. There are enormous pressures to increase palm oil production for food, domestic products, and, especially, biofuels. Greater use of palm oil for biofuel production is predicated on the assumption that palm oil is an "environmentally friendly" fuel feedstock. Here we show, using measurements and models, that oil palm plantations in Malaysia directly emit more oxides of nitrogen and volatile organic compounds than rainforest. These compounds lead to the production of ground-level ozone (O(3)), an air pollutant that damages human health, plants, and materials, reduces crop productivity, and has effects on the Earth's climate. Our measurements show that, at present, O(3) concentrations do not differ significantly over rainforest and adjacent oil palm plantation landscapes. However, our model calculations predict that if concentrations of oxides of nitrogen in Borneo are allowed to reach those currently seen over rural North America and Europe, ground-level O(3) concentrations will reach 100 parts per billion (10(9)) volume (ppbv) and exceed levels known to be harmful to human health. Our study provides an early warning of the urgent need to develop policies that manage nitrogen emissions if the detrimental effects of palm oil production on air quality and climate are to be avoided.

Impact of whole genome amplification on analysis of copy number variants.

Large-scale copy number variants (CNVs) have recently been recognized to play a role in human genome variation and disease. Approaches for analysis of CNVs in small samples such as microdissected tissues can be confounded by limited amounts of material. To facilitate analyses of such samples, whole genome amplification (WGA) techniques were developed. In this study, we explored the impact of Phi29 multiple-strand displacement amplification on detection of CNVs using oligonucleotide arrays. We extracted DNA from fresh frozen lymph node samples and used this for amplification and analysis on the Affymetrix Mapping 500k SNP array platform. We demonstrated that the WGA procedure introduces hundreds of potentially confounding CNV artifacts that can obscure detection of bona fide variants. Our analysis indicates that many artifacts are reproducible, and may correlate with proximity to chromosome ends and GC content. Pair-wise comparison of amplified products considerably reduced the number of apparent artifacts and partially restored the ability to detect real CNVs. Our results suggest WGA material may be appropriate for copy number analysis when amplified samples are compared to similarly amplified samples and that only the CNVs with the greatest significance values detected by such comparisons are likely to be representative of the unamplified samples.

A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of NRXN1alpha.

The authors report a patient with mild mental retardation, autistic features, multiple vertebral malformations, and an unusual facial appearance who carries a de novo submicroscopic deletion of chromosome 2p16.3. The patient's deletion is approximately 320 kb in size and includes only the part of the NRXN1 gene that codes for the neurexin1alpha promoter and initial coding exons. The more downstream neurexin1beta promoter and the region surrounding it are intact. Neurexin1beta has been associated with autism in several recent studies, but this is the first reported patient with loss of only neurexin1alpha and not of neurexin1beta. These findings suggest that neurexin1alpha function in correct dosage is necessary for normal neurological development.

OCTANE (Ontario-wide Cancer Targeted Nucleic Acid Evaluation): a platform for intraprovincial, national, and international clinical data-sharing.

Cancer is a genetic disease resulting from germline or somatic genetic aberrations. Rapid progress in the field of genomics in recent years is allowing for increased characterization and understanding of the various forms of the disease. The Ontario-wide Cancer Targeted Nucleic Acid Evaluation (octane) clinical trial, open at cancer centres across Ontario, aims to increase access to genomic sequencing of tumours and to facilitate the collection of clinical data related to enrolled patients and their clinical outcomes. The study is designed to assess the clinical utility of next-generation sequencing (ngs) in cancer patient care, including enhancement of treatment options available to patients. A core aim of the study is to encourage collaboration between cancer hospitals within Ontario while also increasing international collaboration in terms of sharing the newly generated data. The single-payer provincial health care system in Ontario provides a unique opportunity to develop a province-wide registry of ngs testing and a repository of genomically characterized, clinically annotated samples. It also provides an important opportunity to use province-wide real-world data to evaluate outcomes and the cost of ngs for patients with advanced cancer. The octane study is attempting to translate knowledge to help deliver precision oncology in a Canadian environment. In this article, we discuss the background to the study and its implementation, current status, and future directions.

Enzyme histochemical phenotypes in primary hepatocellular carcinomas.

A marked heterogeneity of enzyme histochemical phenotypes was demonstrated in 48 primary hepatocellular carcinomas induced by feeding 2-acetylaminofluorene to rats. All eight possible combinations of three abnormal traits, gain of gamma-glutamyl transpeptidase activity, loss of adenosine-5'-triphosphatase activity, and loss of glucose-6-phosphatase activity, were represented among the hepatocellular carcinomas. The four combinations in which two or three traits occurred together were seen in 85% of the carcinomas, while those categories with a normal phenotype or containing only single marker changes contained the few remaining neoplasms. As expected, the carcinomas all showed greatly increased and variable [3H]thymidine labeling indices; however, neither the rates of cell replication or the degrees of differentiation of the carcinomas appeared to correlate in any meaningful way with the patterns of phenotypic diversity. The distribution of histochemical phenotypes in the carcinomas differs greatly from that reported for enzyme-altered hyperplastic islands induced by carcinogens, but the significance of the difference is not apparent at the present time.

Ovariectomy accelerates the growth of microscopic hepatocellular neoplasms in the mouse: possible association with whole body growth and fat deposition.

Ovariectomy (ovex) shortens the latency for development of hepatocellular neoplasms in mice, but the mechanism by which this occurs is not known. In the present study, B6C3F1 mice were given single i.p. injections of diethylnitrosamine (5 mg/kg) when they were 15 days old and either ovexed or sham operated 7 weeks later. Groups of 6 to 8 mice were killed after an additional 8, 14, 20, and 26 weeks. Four ovexed and four sham-operated mice were also killed after 56 weeks. By 8 weeks after surgery, the fractional volume of microscopic liver neoplasms in the ovexed mice was 4.3 times greater than in the shams and ablation had caused a 27% greater gain in body weight. During the following 18 weeks, tumor burdens were 3.9 to 10.6 times greater in ovexed than in the sham-operated mice and the rates of weight gain were similar in the two groups. Stereological analysis indicated that ovexed animals had more tumors than sham-operated animals, 575 versus 234/liver at 8 weeks and 952 versus 724/liver at 14 weeks after surgery. The ovex-induced increase in the number of neoplasms was spread throughout most of the size classes at both times; however, the impact on tumor burden of a small number of large tumors was only apparent at 14 weeks, when 8% of them accounted for more than two thirds of the aggregate tumor volume. The effect of the early emergence of these more rapidly growing tumors was also obvious at 1 year, when the livers of ovexed mice were more than twice the size of the shams (5.1 versus 1.8 g) and they contained 4 times as many tumors larger than 1 cm in diameter than the shams (2 versus 0.5/mouse). Since these very large tumors were invariably, at least partially, composed of trabecular hepatocellular carcinoma, ovariectomy appears to have also fostered tumor progression. The time course of ovex-stimulated weight gain and the manner in which it affected body composition were also analyzed. Eight days following ovex, the rate of weight gain abruptly increased. The acceleration persisted for only 14 days, after which it leveled off at body weights that were 24% higher than in sham-operated mice. The difference in weights resulted from 2.5 times more fat and 10% more protein in the carcasses of ovexed than sham-operated mice. This study identifies an early 8-week period in which hormonal changes resulting from ovex maximally stimulate the growth of liver tumors.(ABSTRACT TRUNCATED AT 400 WORDS)

Morphology and anatomic localization of renal microneoplasms and proximal tubule dysplasias induced by four different estrogens in the hamster.

Estrogens are known to induce tumors in high frequency in orchiectomized Syrian golden hamsters, but the histogenesis of the tumors is controversial. In order to identify the earliest precursors of the tumors, animals were implanted with pellets of four different estrogens, sacrificed at times ranging up to 6.4 months, and the various neoplastic and nonneoplastic lesions were characterized. Infiltrating cancers were identified in 80% of animals exposed to diethylstilbestrol, 17 beta-estradiol, and hexestrol for periods of 5.3-6.4 months; however hamsters exposed to ethinyl estradiol for comparable times did not develop any tumors. Proximal tubule dysplasia, identified as focal collections of abnormal-appearing cells with increased [3H]thymidine-labeling indices (eight times higher than nondysplastic cells), was the only nonmalignant change that, for every agent, either preceded or accompanied the development of cancer. The dysplastic lesions were further subdivided into two types when it became apparent that they and carcinoma in situ, another lesion in the proximal tubules, might be part of a continuum of tumor progression that results in infiltrating cancer. Another dysplastic variant, classified as florid dysplasia because of its extensive involvement of tubules, showed well-differentiated features; it was seen only in the ethinyl estradiol-treated hamsters. In a quantitative study of the anatomic localization of dysplasias and microcancers (less than 0.5 mm in diameter) induced by diethylstilbestrol, both lesions showed highest incidence in the deep renal parenchyma. The dysplasias were at least eight times more prevalent in the proximal tubules of the innermost 10% of the cortex and subjacent medulla than in the rest of the cortex. We conclude that proximal tubule dysplasias developing in the deep renal parenchyma are the most likely precursors of the estrogen-induced cancers.

Growth kinetics of microscopic hepatocellular neoplasms in carcinogen-resistant and carcinogen-responsive strains of mice.

The initiation and growth of microscopic hepatocellular neoplasms in C57BL/6 mice, considered relatively resistant to hepatocarcinogenesis, was compared with that of the more responsive C3H and B6C3F1 (C57BL/6 x C3H) strains. Tumors were induced by giving male mice injections of diethylnitrosamine when they were 15 days old. During the first 18 weeks postinjection, the growth rates of neoplasms in the three strains were almost identical (doubling time of 2.1 to 2.5 weeks). However, after that time, only the growth rates of the C57BL/6 neoplasms slowed; between 30 and 42 weeks the doubling time had increased to 13 weeks. In addition, at all sacrifice times the number of neoplasms in the C3H strain was at least 2.5 times higher than in the C57BL/6 and B6C3F1 strains. These results suggest that the genetic determinant(s) for inhibited tumor growth (expressed only in C57BL/6 mice) are recessive to those for unimpeded tumor growth (expressed in C3H and B6C3F1 mice), while the determinant(s) for large numbers of tumors (expressed only in C3H mice) are recessive to those for small numbers of tumors (expressed in C57BL/6 and B6C3F1 mice). In addition to the interstrain differences in tumor growth, two other types of tumor growth heterogeneity were identified. First, in each of the three strains, the largest tumors were found to grow faster than the smaller tumors. This suggests that the very broad range in tumor size that is seen in this model results from the long-term differences in the growth rates of individual neoplasms. Second, we found that in microscopic hepatic neoplasms in B6C3F1 mice, the thymidine labeling indices were 2.3 times greater in the outer 50-microns shell (2 cells thick) than in the next deeper 50-micron layer cells. This suggests that even in these minute neoplasms, gradients in blood-borne oxygen, nutrients, or growth factors are responsible for heterogeneous growth.

Partial "feedback control" of beta-hydroxy-beta-methylglutaryl coenzyme A reductase activity in primary hepatocellular carcinomas.

The activity of beta-hydroxy-beta-methylglutaryl coenzyme A reductase, the rate-controlling enzyme of cholesterol synthesis, was studied in normal livers and in 64 primary hepatocellular carcinomas from rats fed a basal diet or a diet containing either 2% cholestyramine or 5% cholesterol. The average enzyme activity in hepatocellular carcinomas from rats fed the basal diet was more than twice that in normal liver. Dietary cholesterol caused a reduction in activity to one-ninth of the normal hepatic enzyme activity, whereas cholestyramine feeding resulted in a 7-fold increase above the basal level. The data tended to confirm the previously documented observation that "diet-induced feedback inhibition" of cholesterol synthesis is not expressed in hepatomas, since the enzyme activity was reduced only slightly in cancers from rats fed cholesterol. However, the activities from cancers of cholestyramine-fed rats were 2.7 times greater than those from cholesterol-fed rats. Thus, a degree of control was clearly demonstrable, although it represented only 4% of that seen in normal liver. To our knowledge this is the first report of at least partial "feedback control" of beta-hydroxy-beta-methylglutaryl coenzyme A reductase activity in hepatocellular carcinomas grown in vivo.

Presence of alpha-fetoprotein-positive cells in hepatocellular foci and microcarcinomas induced by single injections of diethylnitrosamine in infant mice.

Single injections of diethylnitrosamine (5 and 50 micrograms/g body weight) in male C57BL/6J X C3HeB/FeJ F1 mice when they were 15 days old resulted in the induction of RNA-rich hepatocellular foci and nodules that contained alpha-fetoprotein (AFP)-positive hepatocytes after 20 and 28 weeks. The focal lesions were composed of 1- to 2-cell-thick plates of hepatocytes or closely packed clusters of cells, but they did not show the histological patterns that are diagnostic of trabecular hepatocellular carcinoma. AFP-positive hepatocytes were found in almost one-fourth (14 of 60) of the foci and nodules in a serially sectioned block of liver from a mouse given one injection of 50 micrograms/g body weight diethylnitrosamine and killed at 28 weeks. In general, the presence or absence of AFP-positive cells correlated with the size of the foci and nodules. All six nodules with diameters greater than 1.5 mm contained AFP-positive cells, while all 12 foci smaller than 0.24 mm in diameter were negative for AFP. However, among the 42 foci that were intermediate in size, there were 8 AFP-positive foci, the sizes of which appeared rather randomly distributed among the negative foci. Reactive changes in hepatocytes could be ruled out as a cause of the induction of AFP because the foci first appeared many weeks after the administration of diethylnitrosamine in these mice. Since bile ductules or oval cells, which occasionally appeared in these foci, were lacking entirely in AFP and since ductules are absent from the early-appearing and smallest foci, we believe that in this model the AFP-positive foci arise only from hepatocytes. The presence of AFP in the focal lesions and in tumor thrombi that extended from them into hepatic vein branches supports the hypothesis that some foci undergo progression to invasive microcarcinomas and that these in turn are precursors of late-appearing (after 1 year) metastasizing trabecular hepatocellular carcinomas.

Prostatic localization of spontaneous early invasive carcinoma in Lobund-Wistar rats.

Animal models of human prostate cancer are very limited in number but are of obvious importance to develop. Dr. Morris Pollard (M. Pollard, J. Natl. Cancer Inst., 51: 1235-1241, 1973) has reported that Lobund-Wistar rats develop spontaneous metastatic prostatic cancer when they become old (approximately 25% incidence after 25 months). A chemically induced form of the disease has also been described in Lobund-Wistar rats. However, recent reports suggest that most of the chemically induced adenocarcinomas are not prostatic in origin, with most arising in the seminal vesicle, and thereby raise questions about the origin of the spontaneous cancers. We herein report cancer spontaneously arising in the lateral lobes of the prostates in Lobund-Wistar rats. One of 8 rats killed at 16 months of age showed prostatic carcinoma in situ. Two of 39 rats killed at 20 months displayed early invasive adenocarcinomas with no signs of metastases. Because sectioning of the prostates in this study was limited to face sections from a single block for each rat, it is highly probable that the true incidence of dysplasias and carcinomas is underestimated by these data. Dysplastic or neoplastic changes were not seen in either the seminal vesicles or other portions of the prostatic complex. The nuclei of adenocarcinoma cells showed less labeling with antibody to the androgen hormone receptor than did normal cells. These data strongly support the validity of the Pollard model of spontaneous prostate cancer in Lobund-Wistar rats.

Dietary intervention at middle age: caloric restriction but not dehydroepiandrosterone sulfate increases lifespan and lifetime cancer incidence in mice.

Dietary manipulations to prevent cancer and other diseases of aging have drawn broad public and scientific attention. One indicator of this interest is that dehydroepiandrosterone (DHEA) supplements are widely consumed by those who hope that this hormone may keep them "younger longer." However, key data to support this belief are lacking. For example, the influence of DHEA treatment on spontaneous cancer and life span in healthy, long-lived strains of mice or rats is unknown. This is in contrast to the situation for caloric restriction (CR), which is known to oppose cancer development and increase maximum life span in rodents. To address this issue, we assigned 300 middle age (12-month-old) male C57BL/6 mice to one of four groups (n = 75 for each group) and evaluated them for longevity and spontaneous disease patterns. Two groups were fed a normal diet (ND), and two others were fed a calorie-restricted diet (RD). One ND group and one RD group were also given 25 microg/ml DHEA sulfate (DHEAS) in their drinking water. Although urine samples from DHEAS-treated mice contained 10-fold more DHEA and DHEAS than did samples from unsupplemented mice, DHEAS administration did not affect body weight, life span, or cancer patterns. The RD lowered body weight by 26% and increased maximum life span by approximately 15%. The incidence of the most prevalent cancer, plasma cell neoplasm, was higher in RD mice (66%) than in ND mice (41%). Thus, DHEAS, as administered here, influenced neither cancer nor longevity at two caloric intakes. In contrast, CR from middle age increased longevity, the age at which tumor-bearing mice died, and the percentage of mice dying with cancers, suggesting that CR may retard promotion and/or progression of existing lymphoid cancers.