Safety, Tolerability and Pharmacokinetics of Icapamespib, a Selective Epichaperome Inhibitor, in Healthy Adults.

BACKGROUND: Neurodegenerative diseases are devastating conditions that most commonly affect individuals 65 years and older. Currently there are no effective treatments or cures for neurodegenerative diseases, and therapeutics that selectively target the underlying causes of these diseases are needed. Epichaperomes play a major role in the maintenance and progression of neuronal pathology. Inhibiting epichaperomes induces degradation of disease associated proteins and is a promising therapeutic approach to treat neurodegenerative diseases, in particular Alzheimer's Disease and amyotrophic lateral sclerosis. OBJECTIVES: This Phase 1 clinical study evaluated the safety, tolerability, pharmacokinetics, and bioavailability of icapamespib, a purine scaffold inhibitor of epichaperomes that is specific to epichaperomes, in healthy subjects. DESIGN: Double-blind, placebo-controlled dose escalating single ascending dose and multiple ascending doses and an unblinded two-period cross-over bioavailability study design. SETTING: Single site in the United States. PARTICIPANTS: Healthy men or women of 18 to 60 years of age, inclusive, for Part 1 (single ascending dose), ≥ 60 years of age for Part 2 (multiple ascending dose), or 18 to 49 years of age for Part 3 (bioavailability). TREATMENT: In the single ascending dose group, oral single doses (10, 20, and 30 mg icapamespib or placebo) were administered to healthy non-elderly subjects. In the multiple ascending dose group, multiple doses (20 and 30 mg icapamespib once daily for 7 days or placebo) were administered to healthy elderly subjects. In the bioavailability group, the bioavailability of once daily oral icapamespib solution and tablet was assessed in healthy non elderly subjects. MEASUREMENTS: Safety was evaluated based on assessments of treatment-emergent adverse events, physical examinations, clinical laboratory tests (hematology, clinical chemistry, and urinalysis), vital signs, and 12-lead electrocardiograms. Icapamespib concentration was evaluated in plasma and cerebrospinal fluid, the latter in Part 2 (multiple ascending dose) only. RESULTS: Forty-eight subjects in total were randomized and assessed for tolerability, pharmacokinetics, and bioavailability parameters as follows: 24 subjects in Part 1 (single ascending dose) with PU-AD 10 mg (n = 6), 20 mg (n = 6), 30 mg (n = 6), and placebo (n = 6); 16 subjects in Part 2 (multiple ascending dose) with icapamespib 20 mg (n = 6), 30 mg (n = 6), and placebo (n = 4); and 8 subjects in Part 3 (bioavailability) crossed-over between icapamespib 30 mg (tablet) and icapamespib 30 mg (oral solution). Single doses of icapamespib up to 30 mg and multiple doses of icapamespib up to 30 mg for 7 days were generally safe and well tolerated in healthy non-elderly and elderly subjects. Treatment-emergent adverse events were mild, with headache being the most common treatment-emergent adverse event. Mean icapamespib exposure (area under the curve) was dose-proportional over the dose range tested. The median time to maximum observed plasma concentration ranged from 1.00 to 2.00 h across single ascending dose, multiple ascending dose, and bioavailability groups; icapamespib exposure was 50% higher in elderly subjects compared with non-elderly subjects but was well tolerated. CONCLUSIONS: The study provides clinical evidence of the safety of icapamespib in healthy non elderly and elderly subjects and supports the advancement of icapamespib to Phase 2 evaluation in Alzheimer's Disease and other neurodegenerative diseases.

Patients undergoing colorectal surgery at a Veterans Affairs Hospital do not experience racial disparity in length of stay either before or after implementing an enhanced recovery pathway.

BACKGROUND: Enhanced Recovery Pathways (ERP) have been shown to reduce racial disparities following surgery. The objective of this study is to determine whether ERP implementation mitigates racial disparities at a Veterans Affairs Hospital. METHODS: A retrospective cohort study was conducted using data obtained from the Veterans Affairs Surgical Quality Improvement Program. All patients undergoing elective colorectal surgery following ERP implementation were included. Current procedural terminology (CPT) codes were used to identify patients who underwent similar procedures prior to ERP implementation. RESULTS: Our study included 417 patients (314 pre-ERP vs. 103 ERP), 97.1% of which were male, with an average age of 62.32 (interquartile range (IQR): 25-90). ERP patients overall had a significantly shorter post-operative length of stay (pLOS) vs. pre-ERP patients (median 4 days (IQR: 3-6.5) vs. 6 days (IQR: 4-9) days (p < 0.001)). Within the pre-ERP group, median pLOS for both races was 6 days (IQR: 4-6; p < 0.976) and both groups experienced a decrease in median pLOS (4 vs. 6 days; p < 0.009 and p < 0.001) following ERP implementation. CONCLUSIONS: Racial disparities did not exist in patients undergoing elective surgery at a single VA Medical Center. Implementation of an ERP significantly reduced pLOS for black and white patients.

Longitudinal Functional Magnetic Resonance Spectroscopy Study in Subjects with Mild Cognitive Impairment and Alzheimer's Disease.

BACKGROUND: Longitudinal changes of brain metabolites during a functional stimulation are unknown in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) subjects. OBJECTIVE: This study was to evaluate the longitudinal changes of brain metabolites using proton magnetic resonance spectroscopy (1H MRS) in response to treatment during a memory task in the subjects of cognitive normal (CN), aMCI, and AD. METHODS: We acquired functional magnetic resonance spectroscopy (fMRS) data from 28 CN elderly, 16 aMCI and 12 AD subjects during a face-name association task. We measured fMRS metabolite ratios over 24 months in the 8-month apart, determined the temporal changes of the metabolites, and evaluated the differences among the three groups under the three different conditions (base, novel, repeat). RESULTS: The results of comparisons for the three subject groups and the three-time points showed that tNAA/tCho and tCr/tCho were statistically significant among the three subject groups in any of the three conditions. The dynamic temporal change measurements for the metabolites for each condition showed that Glx/tCho and Glu/tCho levels at the third visit increased significantly compared with in the first visit in the novel condition in the AD group. CONCLUSION: We found declines in tNAA/tCho and tCr/tCho in the aMCI and AD subjects with increasing disease severity, being highest in CN and lowest in AD. The Glx/tCho level increased temporally in the AD subjects after they took an acetylcholine esterase inhibitor. Therefore, Glx may be suitable to demonstrate functional recovery after treatment.

Primary care networks and team effectiveness: the case of a large-scale quality improvement disparity reduction program.

Documentation of primary care teams' involvement in disparity reduction efforts exists, yet little is known about how teams interact or perceive their effectiveness. We investigated how the social network and structural ties among primary-care-clinic team members relate to their perceived team effectiveness (TE), in a large-scale disparity reduction intervention in Israel's largest insurer and provider of services. A mixed-method design of Social Network Analysis and qualitative data collection was employed. 108 interviews with medical, nursing, and administrative teams of 26 clinics and their respective managerial units were performed and information on the organizational ties, analyzing density and centrality, collected. Pearson correlations examined association between network measures and perceived TE. Clinics with strong intra-clinic density and high clinic-subregional-management density were positively correlated with perceived TE. Clinic in-degree centrality was also positively associated with perceived TE. Qualitative analyses support these findings with teamwork emerging as a factor which can impede or facilitate teams' ability to design and implement disparity reduction interventions. The study demonstrates that in an organization-wide disparity reduction initiative, cohesive intra-network structure and close relations with mid-level management increase the likelihood that teams perceive themselves as possessing the skills and resources needed to lead and implement disparity reduction efforts. List of abbreviations Team Effectiveness (TE); Clalit Health Services (Clalit); Social Network Analysis (SNA); Quality Improvement (QI); National Health Care Collaborative (NHPC); Tampa Bay Community Cancer Network (TBCCN).

Effect of residual feed intake on hypothalamic gene expression and meat quality in Angus-sired cattle grown during the hot season.

The relationship between heat stress, meat quality, and residual feed intake (RFI) is unknown in growing steers. To address this issue, high RFI (HRFI) and low RFI (LRFI) individuals were compared by assessing RFI in 48 Angus-sired steers during a 70-d feeding trial conducted during July through September to identify steers with calculated RFI at least 2 SD apart. The association of RFI with indices of meat quality and expression of genes within hypothalamic and adipose tissue was then determined in LRFI and HRFI steers. While on test, feed intake was recorded daily with BW and hip heights recorded every 14 d. Ultrasound measurements of rib eye area (REA) and backfat (BF) were recorded initially and before harvest. Carcass and growth data were analyzed using a mixed model with RFI level (LRFI and HRFI) as the independent variable. The least square means for RFI were -1.2 and 0.99 kg DMI/d, respectively, for the LRFI and HRFI cohorts (P < 0.0001). Dry matter intake was higher for the HRFI individuals versus the LRFI steers (P < 0.0001) while on-test gain was not different (P < 0.95). Marbling score was greater in LRFI than HRFI steers (P < 0.05). However, there were no differences in REA (P < 0.53), BF (P < 0.65), yield grade (P < 0.24), or objective Hunter color measures between LRFI and HRFI steers indicating there was no consistent relationship between RFI and indices of meat quality. Hypothalamic neuropeptide Y (NPY), agouti related protein (AGRP), relaxin-3 (RLN3), melanocortin 3 receptor, and relaxin/insulin-like family peptide receptor 1 (RXFP1) mRNA were expressed 280, 185, 202, 183, and 163% greater, respectively (P < 0.01), while proopiomelanocortin (POMC) mRNA was expressed 42% lower in LRFI than HRFI animals (P < 0.05). Hypothalamic GnRH mRNA expression was 67% lower while gonadotropin inhibiting hormone (GnIH) mRNA was 209% higher in LRFI than HRFI animals (P < 0.01). Pituitary expression of FSHß and LHß correlated to hypothalamic GnRH levels (P < 0.05) indicating changes in gene expression within the hypothalamus had functional consequences. Leptin mRNA expression levels were not different between adipose tissue of LRFI or HRFI steers (P < 0.84). These data indicate that animals with superior RFI evaluated during warm conditions have higher expression of orexigenic neuropeptide genes independent of the expression of adipose-derived leptin. Furthermore, the gonadotropin axis may also influence feed efficiency under these conditions.

Residual feed intake studies in Angus-sired cattle reveal a potential role for hypothalamic gene expression in regulating feed efficiency.

Mechanisms underlying variation in residual feed intake (RFI), a heritable feed efficiency measure, are poorly understood while the relationship between RFI and meat quality is uncertain. To address these issues, 2 divergent cohorts consisting of High (HRFI) and Low (LRFI) RFI individuals were created by assessing RFI in 48 Angus-sired steers during a 70 d feeding trial to identify steers with divergent RFI. The association of RFI with indices of meat quality and expression of genes within hypothalamic and adipose tissue was then determined in LRFI and HRFI steers. While on test, feed intake was recorded daily with BW and hip heights recorded at 14 d intervals. Ultrasound measurements of rib eye area (REA) and backfat (BF) were recorded initially and before harvest. Carcass and growth data were analyzed using a mixed model with RFI level (LRFI, HRFI) as the independent variable. The least-square means (lsmeans) for RFI were -1.25 and 1.51 for the LRFI and HRFI cohorts (P < .0001). Dry matter intake was higher for the HRFI individuals versus the LRFI steers (P < .0001) while on test BW gain was not different between the 2 groups (P < 0.73). There were no differences detected in marbling score (P < 0.93), BF (P < 0.61), REA (P < 0.15), yield grade (P < 0.85) or objective Hunter color measures between LRFI and HRFI steers indicating that there was no relationship between RFI and meat quality. Neuropeptide-Y (NPY), relaxin-3 (RLN3), melanocortin 4 receptor (MC4R), and GnRH mRNA expression was 64%, 59%, 58%, 86% lower (P < 0.05), respectively, while gonadotropin inhibiting hormone (GnIH) and pro-opiomelanocortin (POMC) mRNA expression was 198% and 350% higher (P < 0.01) in the arcuate nucleus of LRFI steers. Expression of agouti-related protein (AGRP), relaxin/insulin-like family peptide receptor 1 (RXFP1), and melanocortin 3 receptor mRNA was similar between LRFI and HRFI animals. Pituitary expression of FSHß (P < 0.03) and LHß (P < 0.01) was correlated to hypothalamic GnRH levels suggesting that changes in gene expression within the arcuate nucleus had functional consequences. Leptin mRNA expression was 245% higher in the adipose tissue of LRFI steers consistent with lower levels of NPY and higher expression of POMC in their hypothalami. These data support the hypothesis that differences in hypothalamic neuropeptide gene expression underlie variation in feed efficiency in steers while the gonadotropin axis may also influence feed efficiency.

Metabolic profiling of biofilm bacteria known to cause microbial influenced corrosion.

This study builds upon previous research that demonstrated the simplicity of obtaining metabolite profiles of bacteria in urban water networks, by using the metabolic profile of bacteria extracted from a reticulation pipe biofilm, which is known to cause microbial influenced corrosion (MIC). The extracellular metabolites of the isolated bacteria, and those bacteria in consortium, were analysed in isolation, and after exposure to low levels of copper. Applying chemometric analytical methodologies to the metabolomic data, we were able to better understand the profile of the isolated biofilm bacteria, which were differentiated according to their activity and copper exposure. It was found that the metabolic activity of the isolated bacteria and the bacteria in consortium varied according to the bacterium's ability to metabolise copper. This demonstrates the power of metabolomic techniques for the discrimination of water reticulation biofilms comprising similar bacteria in consortium, but undergoing different physico-chemical activities, such as corrosion and corrosion inhibition.

Grain feeding coordinately alters expression patterns of transcription factor and metabolic genes in subcutaneous adipose tissue of crossbred heifers.

The ability to improve meat quality and production efficiency in cattle is limited by an inability to enhance marbling and simultaneously limit undesirable adipose tissue accretion. The objective of this study was to examine expression of regulatory genes in subcutaneous (SCF) adipose tissue of heifers in response to increasing days on feed (DOF) and finishing strategy. Crossbred heifers (n = 24) were allotted as follows: Group 1 = 0 d, Group 2 = 99 d on winter annual ryegrass (grass; Lolium multiflorum Lam.), Group 3 = 218 g on grass, Group 4 = 99 d on grass followed by 119 d on grain. Adipose tissue samples were collected at time of harvest and frozen. Carcass characteristics were measured 24 h postharvest. As expected, HCW (P < 0.0001), ribeye area (REA; P < 0.0002), backfat (BF; P < 0.0001), KPH (P < 0.0001), and marbling score (P < 0.0009) increased with DOF though frame score was not different (P < 0.95). Average daily gain decreased with DOF (P < 0.0001). Yield grade increased (P < 0.0014) but cook loss percentage decreased (P < 0.001) with DOF without changes in 24-h pH (P < 0.31). Interestingly, Warner-Bratzler shear force (WBS) was decreased with DOF (P < 0.0089). Meanwhile, BF (P < 0.01) and KPH (P < 0.05) were greater, whereas marbling values trended greater in grain versus grass-finished heifers. Neither ADG (P < 0.89), HCW (P < 0.26), frame score (P < 0.85), nor REA (P < 0.38) were different between these groups. Grain finishing increased yield grade (P < 0.001) but did not affect 24-h pH (P < 0.88), cook loss percentage (P < 0.98), or WBS (P < 0.44) compared with grass-finished heifers. The expression of PPARγ, bone morphogenic protein 2 (BMP2), and SMAD family member 1 (SMAD1) mRNA was upregulated in response to DOF and grain finishing, whereas sterol regulatory element binding protein 1c (SREBP-1c), sonic hedgehog (SHH), chicken ovalbumin protein transcription factor 1 (COUP-TF1), chicken ovalbumin protein transcription factor 2 (COUP-TF2), and preadipocyte factor-1 (PREF-1) mRNA was decreased in response to DOF and grain finishing. These changes were associated with increased expression of lipoprotein lipase (LPL), stearoyl-coenzyme A desaturase (SCD), and fatty acid synthase (FAS) mRNA. In summary, increasing DOF was associated with improved meat quality whereas gene expression studies suggest several novel genes are associated with subcutaneous adipose tissue development in growing and finishing cattle.

Application of metabolomics to understanding biofilms in water distribution systems: a pilot study.

Biofilms formed in pipes are known to contribute to waterborne diseases, accelerate corrosion and cause aesthetic taste and odour issues within the potable water supply network. This paper describes a pilot study, undertaken to assess the potential of using metabolomics to monitor bacterial activity in biofilms of an urban water network. Using samples from a water mains flushing programme, it was found that a profile of intracellular and extracellular metabolites associated with microbial activity could be obtained by analysing samples using gas chromatography mass spectrometry. Chemometric analysis of the chromatograms in conjunction with data from the mass spectrometer showed that it is possible to differentiate between biofilms from different pipe materials and planktonic bacteria. This research demonstrates that metabolomics has the potential for investigating biofilms and other microbial activity within water networks, and could provide a means for enhancing monitoring programmes, understanding the source of water quality complaints, and optimising water network management strategies.

Epidemiological differences between adenocarcinoma of the oesophagus and adenocarcinoma of the gastric cardia in the USA.

BACKGROUND AND AIMS: It has been suggested that gastric cardia adenocarcinoma (GCA) is a distinct entity from oesophageal adenocarcinoma (OA). We examined several epidemiological features of GCA and OA in the USA to elucidate differences/similarities between these malignancies. METHODS: Using the database of Surveillance, Epidemiology, and End Results (SEER) program, we examined incidence rates for temporal changes, and ethnic and age distributions, and performed birth cohort analyses for cases with morphologically and histologically confirmed OA or GCA. RESULTS: The age adjusted incidence rates of OA rose progressively, reaching 1.8 per 100 000 (95% confidence interval 1.7-1.9) during 1987-1991 and 2.5 per 100 000 (2.3-2.6) during 1992-1996. In 1992-1996, Whites were affected five times more than Blacks, and men eight times more than women. A significant increase in incidence occurred among younger persons aged 45-65 years. Irrespective of age, OA was characterised by higher incidence rates among more recent birth cohorts: a 40% increase in incidence for each five year increase in the date of birth--a "birth cohort effect". On the other hand, the incidence rates of GCA reached their highest level of 3.3 per 100 000 (3.2-3.4) in 1987-1991 and subsequently declined during 1992-1996 to 3.1 per 100 000 (3.0-3.3). Whites were affected twice more than blacks and men five times more than women. Most patients with GCA were older than 60 years with no increase among younger persons and no birth cohort effect (p=0.99). CONCLUSION: Several significant epidemiological differences exist between OA and GCA. These differences suggest that these two malignancies are separate entities with different risk factors.

Population-based study of microinvasive adenocarcinoma of the uterine cervix.

OBJECTIVE: To analyze lymph node status and survival rates of women with microinvasive cervical adenocarcinoma (International Federation of Gynecology and Obstetrics stages IA(1) and IA(2)). METHODS: The Surveillance, Epidemiology, and End Results (SEER) Public-Use Database was used to identify cases of microinvasive cervical adenocarcinoma diagnosed between 1988 and 1997. Variables analyzed included stage, extent of surgery, lymph node status, radiation therapy, and age. Statistics included analysis of trends, analysis of variance, log-rank test, one-sided binomial confidence interval estimation, and power analysis. RESULTS: Among 301 reported cases, 131 had stage IA(1) and 170 IA(2) disease. Simple hysterectomies were done in 54 women with IA(1) and 64 with IA(2) disease and radical hysterectomies were done in 50 and 83 women, respectively. Only one of 140 women who had lymphadenectomy had a single positive lymph node. There were four tumor-related deaths (one with IA(1), and three with IA(2) disease). There were no deaths among 96 women (47, IA(1); 49, IA(2)) treated by simple hysterectomy alone. The mean follow-up was 46.5 months (range 1--119). The censored survival rate was 98.7% overall (99.2% IA(1), 98.2% IA(2)). Power analysis estimated that 720 patients would be required in each group to detect a 2% difference in survival. Using one-sided 95% confidence interval estimations, the risk-adverse events rate for IA(1) was no more than 3.57%, and 4.50% for IA(2) disease. CONCLUSION: Prognosis is excellent for microinvasive adenocarcinoma of the uterine cervix. In 96 cases (31.9%), simple hysterectomy alone proved adequate.

Trends in Gleason score for prostate cancer diagnosed between 1983 and 1993.

PURPOSE: During the 1980s and 1990s the number, incidence rate and proportion of moderately differentiated prostate cancer cases ascertained by population based cancer registries increased substantially. The increase is thought to have resulted from the widespread use of prostate specific antigen (PSA) for screening because it occurred coincidentally with the introduction of PSA for early detection of prostate cancer. We investigate this increase in a population based study. MATERIALS AND METHODS: To report the trends in tumor grade we conducted a blinded, standardized pathological study and reviewed medial records of a stratified random sample of cases diagnosed before and after the introduction of PSA (1983 to 1984 and 1992 to 1993). Archival tumor biopsy specimens or transurethral resection of the prostate specimens were reviewed for the diagnosis of cancer and assignment of Gleason score. Medical records were reviewed to determine the method of prostate cancer detection for each case. RESULTS: We found a small but statistically insignificant shift in the distribution of Gleason scores assigned after review of biopsy or transurethral resection specimens. The proportion of Gleason score 2, 3 and 4 tumors decreased, and the proportion of 7, 8, 9 and 10 tumors as a group did not change. The shifts in Gleason score resulted in a slight statistically nonsignificant increase in mean Gleason score. There was a significant shift in the method of detection from predominately incidental detection in the earlier period to predominately screen detection in the later period. Because the proportion of screen detected tumors increased and they had a significantly higher mean Gleason score than incidentally detected tumors within each interval, the overall mean Gleason score increased. CONCLUSIONS: After a standardized pathological review a small shift in the distribution of Gleason scores occurred resulting in a small increase in mean Gleason score between 1983 and 1984, and 1992 and 1993. There was little change in the proportion of Gleason score 7, 8, 9 and 10 tumors between the 2 periods.

Trends in survival of patients with hepatocellular carcinoma between 1977 and 1996 in the United States.

The recent increase in the incidence of hepatocellular cancer in the United States is thought to underlie the rising mortality of this malignancy. However, it remains unknown whether survival of patients with hepatocellular carcinoma (HCC) has changed during the same time period. Using the SEER database (Surveillance, Epidemiology, and End Results) of the National Cancer Institute, we examined the temporal changes and determinants of survival among patients with histologically proven HCC over a 20-year period. Between 1977 and 1996, 7,389 patients diagnosed with HCC were followed in the survival database of SEER. The overall 1-year relative survival rate increased from 14% (95% confidence intervals (CI): 12-16) during 1977-1981 to 23% (95% CI: 21-24) during 1992 to 1996. Between the same two time periods, less improvement was seen in the 5-year survival rates, which increased from 2% (95% CI: 1-3) to only 5% (95% CI: 4-7). The median survival increased slightly from 0.57 years during 1977 to 1981 to 0.64 years during 1992 to 1996. In general, there were no significant differences in survival between men and women or between ethnic groups. During 1987 to 1991, a small fraction (0.8%) of patients underwent radical surgery; these patients had 1-year survival of 59% (95% CI: 35-83%), and 5-year survival of 35% (95% CI: 12-58%). Similar rates were seen during 1992-1996. In conclusion, a small improvement in survival of patients with HCC was seen between 1977 and 1996. Most of this apparent benefit is restricted to the first year following cancer diagnosis, raising the possibility of lead-time bias. There were no significant differences related to gender or ethnicity.

Patterns of mammography use among Hispanic, American Indian, and non-Hispanic White women in New Mexico, 1994-1997.

For screening efforts to maximally reduce mortality in the general population, a large proportion of women need to utilize mammography routinely. To investigate utilization of mammography in a community setting, the authors used population-based data collected by the New Mexico Mammography Project for residents of the Albuquerque, New Mexico, metropolitan area for the period 1994-1997. The authors computed screening rates and the proportion of women who routinely use mammography. The utilization of mammography was low. Only 50% of the women aged 50-74 years were screened each year. Less than one third of women aged 40-49 years or 75 years and older were screened annually. The percentage of women who routinely used mammography on an annual or biennial basis was low in all age groups, especially among Hispanics and American Indians. Women aged 50-74 years had the highest percentage of routine annual mammography use, ranging from 30% in non-Hispanic Whites to 20% in Hispanics. Current utilization of mammography in community-based screening efforts is unlikely to achieve a potential 30% reduction in breast cancer mortality. Interventions are needed to increase the routine use of mammography.

The rising incidence of adenocarcinoma relative to squamous cell carcinoma of the uterine cervix in the United States--a 24-year population-based study.

OBJECTIVE: The aim of this study was to compare the age-adjusted incidence and survival for invasive adenocarcinoma and squamous cell carcinoma of the uterine cervix using population-based data. METHODS: The SEER database was used to identify all cases of cervical cancer registered between 1973 and 1996. Stage was defined as localized, regional, or distant. Age-adjusted incidence rates were analyzed statistically using the Jonchkeere-Terpstra exact test for trends. Relative and observed survival rates, respectively, were compared using z tests and log-rank tests. RESULTS: The age-adjusted incidence rates per 100,000 for all invasive cervical cancers decreased by 36.9% over 24 years [12.35 (1973-1977) vs 7.79 (1993-1996)]. Similarly, the age-adjusted incidence rates for squamous cell carcinoma declined by 41.9% [9.45 (1973-1977) vs 5.49 (1993-1996)]. In contrast, the age-adjusted incidence rates for adenocarcinoma increased by 29.1% [1.34 (1973-1977) vs 1.73 (1993-1996)]. The proportion of adenocarcinoma increased 107.4% relative to all cervical cancer, 95.2% relative to squamous cell carcinoma, and 49.3% relative to the population of women at risk [10. 8% vs 22.4% (P < 0.001), 12.4% vs 24.0% (P < 0.001), and 1.40 vs 2. 09 per 100,000 women (P < 0.001), respectively]. Observed survival rates for adenocarcinoma vs squamous cell carcinoma were poorer for regional (P = 0.04), but not localized or distant disease. CONCLUSIONS: Over the past 24 years, the incidence of all cervical cancer and squamous cell carcinoma has continued to decline. However, the proportion of adenocarcinoma relative to squamous cell carcinoma and to all cervical cancers has doubled, and the rate of adenocarcinoma per population at risk has also increased. These results suggest that current screening practices in the United States are insufficient to detect a significant proportion of adenocarcinoma precursor lesions.

Primary mediastinal malignancies in children: report of 22 patients and comparison to 197 adults.

PURPOSE: Examine a contemporary series of patients with primary pediatric malignant mediastinal tumors and determine epidemiology, histology, treatment, and survival. Patients and Methods. All malignancies diagnosed between January 1, 1973 and December 31, 1995 were analyzed. RESULTS: Twenty-two patients, age 18 years or less, with pediatric primary mediastinal malignancies were identified from a database of 110,284 patients with primary malignancies. During the same period, 197 adult patients with primary mediastinal malignancies were identified. Fifty-nine percent of the pediatric patients were male. Median age was 11 years. Lymphoma was present in 55%, neurogenic malignancies in 23%, malignant germ cell tumors in 18%, and sarcoma in 5%. Neurogenic tumors presented in infants and lymphomas and germ cell tumors presented in teens (p = 0.005). In treated children, surgery was used more often in neurogenic tumors and germ cell tumors than in lymphomas (p = 0.002). Five-year survival was 74% for lymphomas, 67% for neurogenic tumors, 25% for germ cell tumors, and 61% overall (p = 0.23). Compared to adults, children had more neurogenic tumors (p < 0.001) and fewer thymomas (p = 0.0499). There were no significant differences in staging or survival between children and adults. CONCLUSIONS: Pediatric mediastinal malignancies occurred with a frequency of 1/5,013 patients with malignant tumors. Lymphoma, neurogenic tumors, and germ cell tumors predominated. Compared to adults, children had more neurogenic tumors and fewer thymomas. Within the pediatric group, differences were found in age of presentation between histologic groups. These differences between adults and children, and between infants and teens, should be considered when evaluating a patient suspected of having mediastinal malignancy.

Patient and tumor characteristics of colon cancers with microsatellite instability: a population-based study.

Molecular screening for microsatellite instability (MSI) in colon cancers has been proposed to identify individuals with hereditary nonpolyposis colorectal cancer. To date, most reports of MSI in colorectal cancer have been based on studies of clinical case series or high-risk families. We examined the proportion of incident colon cancers in the general population that exhibit MSI by patient and tumor characteristics. We interviewed 201 colon cancer cases ascertained by the New Mexico Tumor Registry in the metropolitan Albuquerque area for demographic information, lifestyle factors, medical history, and family cancer history. Paired normal and tumor tissue specimens were obtained for each case. Three microsatellite markers were used; instability was defined as observed alteration at two or more loci. Overall, 37 of 201 (18%) colon cancers exhibited instability. MSI was more common among cases >70 years (26%) and most common among cases >80 years (38%). MSI was significantly associated with tumors in the proximal colon and with later stage and poor differentiation among cases >70 years. MSI was not associated with a history of polyps. Family history of colorectal cancer was associated with MSI only among cases <50 years. When all factors were analyzed jointly in a regression model, proximal subsite and poor differentiation remained significantly associated with MSI. One patient, whose tumor exhibited MSI, fulfilled the Amsterdam Criteria for hereditary nonpolyposis colorectal cancer. Our study provides a population-based estimate of MSI in colon tumors and a representative estimate of the proportion of colorectal cancer patients in the general population who consent to be interviewed for family cancer history and to have biological samples analyzed.

Biologic characteristics of interval and screen-detected breast cancers.

BACKGROUND: Interval breast cancer is defined as a cancer that is detected within 12 months after a negative mammogram. The failure of mammography to detect breast cancer depends on testing procedures, radiologist interpretation, patient characteristics, and tumor properties. Although errors by radiologists explain some interval cancers, another explanation is that the tumor is rapidly growing and was too small to be detected on the last mammogram. To determine whether markers of tumor growth rate are associated with risk of an interval cancer, we conducted a population-based study with the use of data collected statewide by the New Mexico Mammography Project. METHODS: Among women who received a mammographic examination from 1991 throughout 1993, we ascertained records of all patients with breast cancer diagnosed within 12 months of a negative screening mammographic examination (interval cancers) and corresponding tumor samples, when available. We selected an age- and ethnicity-matched comparison group of control patients with screen-detected breast cancers diagnosed during the same period. In tumor samples, p53, bcl-2, and Ki-67 were examined immunologically and the apoptotic index was assessed histologically. We used logistic regression to determine whether interval cancers were associated with selected demographic, radiologic, and biologic characteristics. RESULTS: It is more likely that mammography did not detect tumors with a high proportion of proliferating cells (>20%) than tumors with a low proportion of proliferating cells (<5%) (odds ratio [OR] = 4.09; 95% confidence interval [CI] = 1.14-14.65). The OR for mammographic failure was 2.96 (95% CI = 1.07-8.20) among cancers that expressed p53 compared with cancers that did not. Interval cancers also had fewer apoptotic cells. Approximately 75% of interval cancers appear to have tumors with 5% proliferating cells or more. Younger women had a higher proportion of rapidly proliferating and aggressive cancers. CONCLUSION: Rapidly growing and aggressive tumors account for a substantial proportion of mammographic failure to detect breast cancer, especially among younger women, who have a high proportion of aggressive cancers.

Uranium mining and lung cancer among Navajo men in New Mexico and Arizona, 1969 to 1993.

Navajo men who were underground miners have excess risk of lung cancer. To further characterize the long-term consequences of uranium mining in this high-risk population, we examined lung cancer incidence among Navajo men residing in New Mexico and Arizona from 1969 to 1993 and conducted a population-based case-control study to estimate the risk of lung cancer for Navajo uranium miners. Uranium mining contributed substantially to lung cancer among Navajo men over the 25-year period following the end of mining for the Navajo Nation. Sixty-three (67%) of the 94-incident lung cancers among Navajo men occurred in former uranium miners. The relative risk for a history of mining was 28.6 (95% confidence interval, 13.2-61.7). Smoking did not account for the strong relationship between lung cancer and uranium mining. The Navajo experience with uranium mining is a unique example of exposure in a single occupation accounting for the majority of lung cancers in an entire population.