Association between anaesthetic technique and unplanned admission to intensive care after thoracic lung resection surgery: the second Association of Cardiothoracic Anaesthesia and Critical Care (ACTACC) National Audit.

Unplanned intensive care admission is a devastating complication of lung resection and is associated with significantly increased mortality. We carried out a two-year retrospective national multicentre cohort study to investigate the influence of anaesthetic and analgesic technique on the need for unplanned postoperative intensive care admission. All patients undergoing lung resection surgery in 16 thoracic surgical centres in the UK in the calendar years 2013 and 2014 were included. We defined critical care admission as the unplanned need for either tracheal intubation and mechanical ventilation or renal replacement therapy, and sought an association between mode of anaesthesia (total intravenous anaesthesia vs. volatile) and analgesic technique (epidural vs. paravertebral) and need for intensive care admission. A total of 253 out of 11,208 patients undergoing lung resection in the study period had an unplanned admission to intensive care in the postoperative period, giving an incidence of intensive care unit admission of 2.3% (95%CI 2.0-2.6%). Patients who had an unplanned admission to intensive care unit had a higher mortality (29.00% vs. 0.03%, p < 0.001), and hospital length of stay was increased (26 vs. 6 days, p < 0.001). Across univariate, complete case and multiple imputation (multivariate) models, there was a strong and significant effect of both anaesthetic and analgesic technique on the need for intensive care admission. Patients receiving total intravenous anaesthesia (OR 0.50 (95%CI 0.34-0.70)), and patients receiving epidural analgesia (OR 0.56 (95%CI 0.41-0.78)) were less likely to have an unplanned admission to intensive care after thoracic surgery. This large retrospective study suggests a significant effect of both anaesthetic and analgesic technique on outcome in patients undergoing lung resection. We must emphasise that the observed association does not directly imply causation, and suggest that well-conducted, large-scale randomised controlled trials are required to address these fundamental questions.

Patient-Report Satisfaction and Health-Related Quality of Life in TiLOOP® Bra-Assisted or Implant-Based Breast Reconstruction Alone.

INTRODUCTION: Implant-based breast reconstructions (IBBR) using alternatives to acellular dermal matrixes are increasing. Data on complications are limited, and information concerning health-related quality of life (HR-QoL) following the use of these synthetic meshes do not exist. METHODS: Between January 2006 and January 2013, patients undergoing immediate or delayed-immediate IBBR with or without titanium covered polypropylene mesh (TiLOOP® Bra) were investigated. HR-QoL was assessed using the validated self-reporting BREAST-Q questionnaire. Patient demographics and complications were evaluated retrospectively. Stepwise regression backward elimination analysis was performed to identify influential factors on each BREAST-Q domain. RESULTS: Of the 90 women, 42 had IBBR alone and 48 in combination with TiLOOP® Bra. The mean follow-up was 18 months in the TiLOOP® Bra and 17.5 months in the implant alone group (p = 0.827). The overall complication rate was 21.1 %, with 14.6 % in the TiLOOP® Bra and in 28.6 % in the implant alone group (p = 0.105). Capsular contraction rate was 4.4 % in the TiLOOP® Bra and 16.7 % in the implant alone group (p = 0.052). The analysis of the HR-QoL showed no significant differences between the groups. Surgeries prior to IBBR had a positive influence on HR-QoL. TiLOOP® Bra was associated with a negative effect on "satisfaction with breast" (ß = -5.72; p < 0.001), as it was no longer observed for "satisfaction with outcome" and other domains.

Short duration of lamivudine for the prevention of hepatitis B virus transmission in pregnancy: lack of potency and selection of resistance mutations.

This study sought to assess the antiviral efficacy of lamivudine (LMV) administered during third trimester to reduce maternal viraemia and to identify the emergence of LMV resistance. A prospective observational analysis was performed on 26 mothers with high viral load (>107 IU/mL). Twenty-one women received LMV (treated group) for an average of 53 days (range 22-88 days), and the remaining five formed the untreated control group. Serum samples from two time points were used to measure HBV DNA levels and antiviral drug resistance. The LMV-treated women achieved a median HBV DNA reduction of 2.6-log10 IU/mL. Although end-of-treatment (EOT) HBV DNA in four (18%) LMV-treated women remained at >10(7) IU/mL (± 0.5 log IU/mL), no mother-to-baby transmission was observed. In contrast, a baby from the untreated mother was HBsAg positive at 9 months postpartum. Four technologies were used for drug resistance testing. Only ultra-deep pyrosequencing (UDPS) was sufficiently sensitive to detect minor viral variants down to <1%. UDPS showed that LMV therapy resulted in increased viral quasispecies diversity and positive selection of HBV variants with reverse transcriptase amino acid substitutions at sites associated with primary LMV resistance (rtM204I/V and rtA181T) in four (19%) women. These viral variants were detected mostly at low frequencies (0.63-5.92%) at EOT, but one LMV-treated mother had an rtA181T variant that increased from 2.2% pretherapy to 25.59% at EOT. This mother was also infected with the vaccine escape variant (sG145R), which was inhibited by LMV treatment. LMV therapy during late pregnancy only reduced maternal viraemia moderately, and drug-resistant viral variants emerged.

Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study.

AIMS/HYPOTHESIS: The primary aim of this completed multicentre randomised, parallel, double-blind placebo-controlled study was to elucidate the mechanisms of glucose-lowering with colesevelam and secondarily to investigate its effects on lipid metabolism (hepatic de novo lipogenesis, cholesterol and bile acid synthesis). METHODS: Participants with type 2 diabetes (HbA(1c) 6.7-10.0% [50-86 mmol/mol], fasting glucose <16.7 mmol/l, fasting triacylglycerols <3.9 mmol/l and LDL-cholesterol >1.55 mmol/l) treated with diet and exercise, sulfonylurea, metformin or a combination thereof, were randomised by a central coordinator to either 3.75 g/day colesevelam (n = 30) or placebo (n = 30) for 12 weeks at three clinical sites in the USA. The primary measure was the change from baseline in glucose kinetics with colesevelam compared to placebo treatment. Fasting and postprandial glucose, lipid and bile acid pathways were measured at baseline and post-treatment using stable isotope techniques. Plasma glucose, insulin, total glucagon-like peptide-1 (GLP-1), total glucose-dependent insulinotropic polypeptide (GIP), glucagon and fibroblast growth factor-19 (FGF-19) concentrations were measured during the fasting state and following a meal tolerance test. Data was collected by people blinded to treatment. RESULTS: Compared with placebo, colesevelam improved HbA(1c) (mean change from baseline of 0.3 [SD 1.1]% for placebo [n = 28] and -0.3 [1.1]% for colesevelam [n = 26]), glucose concentrations, fasting plasma glucose clearance and glycolytic disposal of oral glucose. Colesevelam did not affect gluconeogenesis or appearance rate (absorption) of oral glucose. Fasting endogenous glucose production and glycogenolysis significantly increased with placebo but were unchanged with colesevelam (treatment effect did not reach statistical significance). Compared with placebo, colesevelam increased total GLP-1 and GIP concentrations and improved HOMA-beta cell function while insulin, glucagon and HOMA-insulin resistance were unchanged. Colesevelam increased cholesterol and bile acid synthesis and decreased FGF-19 concentrations. However, no effect was seen on fractional hepatic de novo lipogenesis. CONCLUSIONS/INTERPRETATION: Colesevelam, a non-absorbed bile acid sequestrant, increased circulating incretins and improved tissue glucose metabolism in both the fasting and postprandial states in a manner different from other approved oral agents. TRIAL REGISTRATION: ClinicalTrials.gov NCT00596427 FUNDING: The study was funded by Daiichi Sankyo.

Prostate cancer treatment and the relationship of androgen deprivation therapy to cognitive function.

Prostate cancer is the second most common form of cancer in men. For advanced, high risk prostate cancer, androgen deprivation therapy (ADT) is the preferred treatment and can induce remission, but resistance to ADT brings biochemical recurrence and progression of cancer. ADT brings adverse effects such as erectile dysfunction, decreased libido, and diminished physical strength. It is estimated that between 25 and 50% of men on ADT manifest some form of cognitive dysfunction that may be self-reported or reported by a family member. There is concern that impaired cognitive function with ADT is due to loss of testosterone support. Testosterone and its metabolites are known to possess neuroprotective properties. While a direct causal relationship between ADT and cognitive decline in prostate cancer patients has not been established, this review describes the controversy surrounding the possible connection between ADT and neurocognitive deterioration. The cellular and molecular mechanisms believed to underlie the protection of neuronal integrity by androgens are discussed. Results from animal models and human clinical studies are presented. Finally, we call attention to lifestyle modifications that may minimize cognitive issues in prostate cancer patients.

First report of an imported case of haemorrhagic fever with renal syndrome in South Africa.

Haemorrhagic fever with renal syndrome (HFRS) is caused by hantavirus infection. Hantaviruses are not endemic to South Africa, and we report the first detection of an imported case of HFRS in the country. The case involved a traveller from Croatia who presented to a Johannesburg hospital with an acute febrile illness with renal dysfunction. The patient reported visiting rurally located horse stables in Croatia before falling ill, and that a worker in the stables with similar illness was diagnosed with HFRS. Given the exposure history and clinical findings of the case, a clinical diagnosis of HFRS was made and confirmed by laboratory testing.

Optical materials.

Optical technologies are becoming increasingly important in areas that were traditionally the domain of electronics. This trend is likely to continue into the foreseeable future with optics and electronics being integral, mutually compatible components of systems for consumer markets, industry, and defense. The basis of this progress is the development of materials that have the required purity, physical properties, and optical quality; glass fibers for optical transmission, semiconductors for lasers and detectors, and nonlinear materials for optical switching are examples. In this article, some of the materials of choice for a variety of applications are described and the frontiers of materials research for new areas of opportunity are discussed. Particular emphasis is placed on optical materials for the transmission and processing of information.

Materials for optical information processing.

The goal for optical information processing is to use the unique characteristics of light which are not readily achieved with electronic devices, namely, ultrahigh speed (picoseconds), a high degree of parallelism (image processing), and conductor-free interconnection. The requirements of the nonlinear materials to perform such functions, using all-optical interactions, are discussed and the limitations of the nonlinear mechanisms are outlined.

A beta 3 integrin mutation abolishes ligand binding and alters divalent cation-dependent conformation.

The ligand-binding function of integrin adhesion receptors depends on divalent cations. A mutant alpha IIb beta 3 integrin (platelet gpIIb/IIIa) that lacks ligand recognition shows immunologic evidence of a perturbed interaction with divalent cations. This was found to be caused by a G----T mutation that resulted in an Asp119----Tyr119 substitution in the beta 3 subunit. This residue is proximal to bound ligand and is in a conserved region among integrins that are enriched in oxygenated residues. The spacing of these residues aligns with the calcium-binding residues in EF hand proteins, suggesting interaction with receptor-bound divalent cation as a mechanism of ligand binding common to all integrins.

[Renal cell carcinoma diagnosis and prognosis within the context of the WHO classification 2016]. / Histopathologische Diagnose und Prognose des Nierenzellkarzinoms im Kontext der WHO-Klassifikation 2016.

BACKGROUND: Histological classification of renal cell carcinoma (RCC) has become more and more important for clinical management, but relatively few is known regarding the swiftness with which the 2016 World Health Organization (WHO) classification of RCC was adopted in the daily routine diagnostics. AIM: To retrospectively review the histological diagnosis of RCC within the context of 2016 WHO classification followed by survival analysis. MATERIAL AND METHODS: Retrospective register based analysis of RCC diagnosis between 1998 and 2017 and survival analysis. RESULTS: 1440 RCC cases were registered between 1998 and 1917. According to 2016 WHO classification, 77.7% clear cell RCC and 22.3% non-clear cell RCC were diagnosed. A total of 37 rare subtypes were recorded, among those 1% MiT family translocation RCC, 0.35% acquired cystic disease-associated RCC, 0.35% multilocular cystic renal neoplasm of low malignant potential, 0.35% collecting duct carcinoma, 0.3% mucinous tubular and spindle cell carcinoma, 0.1% clear cell papillary RCC and 0.1% RCC with (angio)leiomyomatous stroma. Cox regression analysis showed significant different overall survival and progression-free survival between the histological subtypes. DISCUSSION: The complexity of the 2016 WHO classification of RCC put high demands on histopathological diagnostics. At University Medicine Center Rostock morphological distinct RCC entities have been mostly diagnosed by conventional means via hematoxillin and eosin stained slides, but beyond immunohistochemistry additionally molecular techniques were established. The histologic subtyping of RCC according to 2016 WHO classification has prognostic significance and might have predictive significance for unique therapeutic approaches.

Cost of neutropenic complications of chemotherapy.

BACKGROUND: Cost of neutropenic complications of myelosuppressive chemotherapy has been reported to be substantial. Prior research, however, has focused on initial hospitalization only and has failed to account for follow-on care. PATIENTS AND METHODS: Using a US health-care claims database, all adult cancer patients who received a course of chemotherapy were identified. For each such patient, each unique cycle of chemotherapy within the course and each occurrence of neutropenic complications within these cycles were characterized. Patients developing neutropenic complications in a given cycle (neutropenia patients), starting with the first, were matched (1:1) to those who did not develop neutropenic complications in that cycle (comparison patients), and health-care costs (i.e. expenditures) were tallied for each matched pair. RESULTS: Neutropenia patients (n = 373) and comparison patients were similar in terms of baseline characteristics. Costs of neutropenia-related care were $12,397 (95% confidence interval $10,274-$14,754) higher for neutropenia versus comparison patients [$14,407 ($12,357-$16,743) versus $2010 ($1490-$2553)]. Among neutropenia patients, mean cost of initial hospitalization for neutropenic complications was $7813 ($6537-$9379); cost of all subsequent neutropenia-related care averaged $6594 ($5217-$8272). CONCLUSIONS: Neutropenic complications of myelosuppressive chemotherapy are costly. Prior research focusing on initial hospitalization only may have underestimated the cost of these complications by as much as 40%.

Prostate cancer treatment and the relationship of androgen deprivation therapy to cognitive function

Prostate cancer is the second most common form of cancer in men. For advanced, high risk prostate cancer, androgen deprivation therapy (ADT) is the preferred treatment and can induce remission, but resistance to ADT brings biochemical recurrence and progression of cancer. ADT brings adverse effects such as erectile dysfunction, decreased libido, and diminished physical strength. It is estimated that between 25 and 50% of men on ADT manifest some form of cognitive dysfunction that may be self-reported or reported by a family member. There is concern that impaired cognitive function with ADT is due to loss of testosterone support. Testosterone and its metabolites are known to possess neuroprotective properties. While a direct causal relationship between ADT and cognitive decline in prostate cancer patients has not been established, this review describes the controversy surrounding the possible connection between ADT and neurocognitive deterioration. The cellular and molecular mechanisms believed to underlie the protection of neuronal integrity by androgens are discussed. Results from animal models and human clinical studies are presented. Finally, we call attention to lifestyle modifications that may minimize cognitive issues in prostate cancer patients.

Rising incidence of breast cancer: relationship to stage and receptor status.

We used the population-based tumor registry of Kaiser Permanente in the United States (Portland, OR) to analyze breast cancer incidence from 1960 to 1985. Overall, incidence rose 45% during this period. The largest increases occurred in women 60 years of age or older (74%) and in those 45-59 (36%). The rate in women aged 20-44 has remained essentially unchanged. Localized and regional disease showed similar increases. Review of medical records revealed that only a small portion of this increase was likely to result from increased screening activities. From the increased availability of receptor assays in a large proportion of cases since the mid-1970s, we observed that incidence of estrogen receptor-negative cancers rose 22%-27% between the mid-1970s and the mid-1980s. In contrast, incidence of estrogen receptor-positive tumors increased an average of 131% in the same period, perhaps implicating hormonal factors in the rising incidence of breast cancer.

Conjugated estrogens and breast cancer risk in women.

The relationship between conjugated estrogen(s) (CE) and breast cancer was investigated by the examination of the records of 345 women with newly diagnosed breast cancer and 611 healthy controls belonging to a prepaid health plan. Use of CE was associated with a 40% elevation in risk [relative risk (RR) = 1.4; 95% confidence interval-1.0-2.0]. The RR was 1.3 for menopausal women with intact ovaries and 1.5 for those with ovaries removed. There was statistically significant evidence of a dose-response relationship with the three measures of dose evaluated. RR's rose to about twofold for women with 10 or more CE prescriptions noted in their charts, for those with 5 years or more between their first and last prescription, and for those with a usual daily dose of 1.25 mg or more. The RR associated with having ever used CE and with long-term use was highest among those women with a family history of breast cancer. These data support the hypothesis that long-term use of CE is associated with increased breast cancer risk.

Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01.

Data are presented from 1,166 patients with Dukes B and C carcinoma of the colon who were entered into the National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol C-01 between November 1977 and February 1983. Patients were randomized to one of three therapeutic categories: 1) no further treatment following curative resection (394 patients); 2) postoperative chemotherapy consisting of 5-fluorouracil, semustine, and vincristine (379 patients); or 3) postoperative BCG (393 patients). The average time on study was 77.3 months. A comparison between patients receiving postoperative adjuvant chemotherapy and those treated with surgery alone indicated that there was an overall improvement in disease-free survival (P = .02) and survival (P = .05) in favor of the chemotherapy-treated group. At 5 years of follow-up, patients treated with surgery alone were at 1.29 times the risk of developing a treatment failure and at 1.31 times the likelihood of dying as were similar patients treated with combination adjuvant chemotherapy. Comparison of the BCG-treated group with the group treated with surgery alone indicated that there was no statistically significant difference in disease-free survival (P = .09). There was, however, a survival advantage in favor of the BCG-treated group (P = .03). At 5 years of follow-up, patients randomized to the surgery-alone arm were at 1.28 times the risk of dying as were similar patients treated with BCG. Further investigation disclosed that this survival advantage in favor of BCG was a result of a diminution in deaths that were non-cancer related. When analyses were conducted on which events not related to cancer recurrence were eliminated, the survival difference between the BCG and control groups became nonsignificant (P = .40); the cumulative odds at 5 years decreased from 1.28 to 1.10. The findings from this study are the first from a randomized prospective clinical trial to demonstrate that a significant disease-free survival and survival benefit can be achieved with postoperative adjuvant chemotherapy in patients with Dukes B and C carcinoma of the colon who have undergone curative resection.

Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia.

BACKGROUND: Experimental studies have provided strong evidence that human papillomavirus (HPV) is the long-sought venereal cause of cervical neoplasia, but the epidemiologic evidence has been inconsistent. PURPOSE: Given improvements in HPV testing that have revealed a strong link between sexual activity history and cervical HPV infection, we conducted a large case-control study of HPV and cervical intraepithelial neoplasia (CIN) to evaluate whether sexual behavior and the other established risk factors for CIN influence risk primarily via HPV infection. METHODS: We studied 500 women with CIN and 500 control subjects receiving cytologic screening at Kaiser Permanente, a large prepaid health plan, in Portland, Ore. The established epidemiologic risk factors for CIN were assessed by telephone interview. We performed HPV testing of cervicovaginal lavage specimens by gene amplification using polymerase chain reaction with a consensus primer to target the L1 gene region of HPV. Unconditional logistic regression analysis was used to estimate relative risk of CIN and to adjust the epidemiologic associations for HPV test results to demonstrate whether the associations were mediated by HPV. RESULTS: The case subjects demonstrated the typical epidemiologic profile of CIN: They had more sex partners, more cigarette smoking, earlier ages at first sexual intercourse, and lower socioeconomic status. Statistical adjustment for HPV infection substantially reduced the size of each of these case-control differences. Seventy-six percent of cases could be attributed to HPV infection; the results of cytologic review suggested that the true percentage was even higher. Once HPV infection was taken into account, an association of parity with risk of CIN was observed in both HPV-negative and HPV-positive women. CONCLUSION: The data show that the great majority of all grades of CIN can be attributed to HPV infection, particularly with the cancer-associated types of HPV. IMPLICATIONS: In light of this conclusion, the investigation of the natural history of HPV has preventive as well as etiologic importance.

Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial.

BACKGROUND: Evidence has accumulated from observational studies that people eating more fruits and vegetables, which are rich in beta-carotene (a violet to yellow plant pigment that acts as an antioxidant and can be converted to vitamin A by enzymes in the intestinal wall and liver) and retinol (an alcohol chemical form of vitamin A), and people having higher serum beta-carotene concentrations had lower rates of lung cancer. The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate (vitamin A) taken daily against placebo in 18314 men and women at high risk of developing lung cancer. The CARET intervention was stopped 21 months early because of clear evidence of no benefit and substantial evidence of possible harm; there were 28% more lung cancers and 17% more deaths in the active intervention group (active = the daily combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate). Promptly after the January 18, 1996, announcement that the CARET active intervention had been stopped, we published preliminary findings from CARET regarding cancer, heart disease, and total mortality. PURPOSE: We present for the first time results based on the pre-specified analytic method, details about risk factors for lung cancer, and analyses of subgroups and of factors that possibly influence response to the intervention. METHODS: CARET was a randomized, double-blinded, placebo-controlled chemoprevention trial, initiated with a pilot phase and then expanded 10-fold at six study centers. Cigarette smoking history and status and alcohol intake were assessed through participant self-report. Serum was collected from the participants at base line and periodically after randomization and was analyzed for beta-carotene concentration. An Endpoints Review Committee evaluated endpoint reports, including pathologic review of tissue specimens. The primary analysis is a stratified logrank test for intervention arm differences in lung cancer incidence, with weighting linearly to hypothesized full effect at 24 months after randomization. Relative risks (RRs) were estimated by use of Cox regression models; tests were performed for quantitative and qualitative interactions between the intervention and smoking status or alcohol intake. O'Brien-Fleming boundaries were used for stopping criteria at interim analyses. Statistical significance was set at the .05 alpha value, and all P values were derived from two-sided statistical tests. RESULTS: According to CARET's pre-specified analysis, there was an RR of 1.36 (95% confidence interval [CI] = 1.07-1.73; P = .01) for weighted lung cancer incidence for the active intervention group compared with the placebo group, and RR = 1.59 (95% CI = 1.13-2.23; P = .01) for weighted lung cancer mortality. All subgroups, except former smokers, had a point estimate of RR of 1.10 or greater for lung cancer. There are suggestions of associations of the excess lung cancer incidence with the highest quartile of alcohol intake (RR = 1.99; 95% CI = 1.28-3.09; test for heterogeneity of RR among quartiles of alcohol intake has P = .01, unadjusted for multiple comparisons) and with large-cell histology (RR = 1.89; 95% CI = 1.09-3.26; test for heterogeneity among histologic categories has P = .35), but not with base-line serum beta-carotene concentrations. CONCLUSIONS: CARET participants receiving the combination of beta-carotene and vitamin A had no chemopreventive benefit and had excess lung cancer incidence and mortality. The results are highly consistent with those found for beta-carotene in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study in 29133 male smokers in Finland.

Detection of human papillomavirus DNA in cytologically normal women and subsequent cervical squamous intraepithelial lesions.

BACKGROUND: Human papillomavirus (HPV) infection has been strongly associated with cervical carcinoma and its cytologic precursors, squamous intraepithelial lesions (SIL). We investigated the risk of SIL prospectively following polymerase chain reaction (PCR)-based DNA testing for a wide range of genital HPV types in a cohort of initially cytologically normal women, to clarify the role of HPV in the etiology of SIL. METHODS: Starting in April 1989, 17,654 women who were receiving routine cytologic screening at Kaiser Permanente (Portland, OR) were followed for the development of incident SIL. During follow-up, 380 incident case patients and 1037 matched control subjects were eligible for this nested case-control study. Cervical lavages collected at enrollment and, later, at the time of case diagnosis (or the corresponding time for selection of control subjects) were tested for HPV DNA using a PCR-based method. The data were analyzed as contingency tables with two-sided P values or, for multivariable analyses, using odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: In comparison with initially HPV-negative women, women who tested positive for HPV DNA at enrollment were 3.8 times (95% CI = 2.6-5.5) more likely to have low-grade SIL subsequently diagnosed for the first time during follow-up and 12.7 times more likely (95% CI = 6.2-25.9) to develop high-grade SIL. At the time of diagnosis, the cross-sectional association of HPV DNA and SIL was extremely strong (OR = 44.4 and 95% CI = 24.2-81.5 for low-grade SIL and OR = 67.1 and 95% CI = 19.3-233.7 for high-grade SIL). HPV16 was the virus type most predictive of SIL, even low-grade SIL. CONCLUSIONS: These findings are consistent with the hypothesis that HPV infection is the primary cause of cervical neoplasia. Furthermore, they support HPV vaccine research to prevent cervical cancer and efforts to develop HPV DNA diagnostic tests.

The beta-carotene and retinol efficacy trial (CARET) for chemoprevention of lung cancer in high risk populations: smokers and asbestos-exposed workers.

CARET is a multicenter, two-armed, double-masked randomized chemoprevention trial in Seattle, Portland, San Francisco, Baltimore, Connecticut, and Irvine, to test whether oral administration of beta-carotene (30 mg/day) plus retinyl palmitate (25,000 IU/day) can decrease the incidence of lung cancer in high risk populations, namely, heavy smokers and asbestos-exposed workers. The intervention combines the antioxidant action of beta-carotene and the tumor suppressor mechanism of vitamin A. As of April 30, 1993, CARET had randomized 1,845 participants in the 1985-1988 pilot phase plus 13,260 "efficacy" participants since 1989; of these, 4,000 are asbestos-exposed males and 11,105 are smokers and former smokers (44% female). Accrual is complete everywhere except Irvine, which was the last center added (1991), and the safety profile of the regimen to date has been excellent. With 14,420 smokers, 4,010 asbestos-exposed participants, and 114,100 person-years through February 1998, we expect CARET to be capable of detecting a 23% reduction in lung cancer incidence in the two populations combined and 27, 49, 32, and 35% reductions in the smokers, female smokers, male smokers, and asbestos-exposed subgroups, respectively. CARET is highly complementary to the alpha-tocopherol-beta-carotene study in Finland and the Harvard Physicians Health Study (beta-carotene alone) in the National Cancer Institute portfolio of major cancer chemoprevention trials.