Are Geriatrics-Focused Primary Care Clinics Better at Diagnosing Dementia Than Traditional Clinics? A Matched Cohort Study.

BACKGROUND: Dementia and mild cognitive impairment (MCI) are prevalent but underdiagnosed. OBJECTIVE: To compare new dementia/MCI diagnosis rates in geriatrics-focused primary care clinics and traditional primary care clinics. DESIGN: Secondary analysis of a prospective matched cohort study that spanned 2017-2021. PARTICIPANTS: Community-dwelling Veterans over 65 receiving primary care in a geriatrics-focused medical home (GeriPACT) or traditional primary care home (PACT) at one of 57 Veterans Affairs sites. We excluded individuals with a documented diagnosis of dementia or MCI in the year prior to enrollment. MAIN MEASURES: Diagnoses obtained from EHR. Cognitive status was assessed using modified Telephone Interview for Cognitive Status (mTICS) tool. KEY RESULTS: The 470 participants included in this analysis were predominantly white, non-Hispanic males with an average age of 80.3 years. 9.4% of participants received a diagnosis of dementia/MCI after 24 months: 11.5% in GeriPACT and 7.2% in PACT. Adjusted OR for dementia/MCI diagnosis based on GeriPACT exposure was 1.47 (95% CI 0.65-3.29). Low mTICS score (≤ 27) (OR 4.89, 95% CI 2.36-10.13) and marital status (married/partnered) (OR 1.89, CI 0.99-3.59) were independent predictors of dementia/MCI diagnosis. When stratified by cognitive status: diagnosis rates were 20.8% in GeriPACT and 16.7% in PACT among those who scored lower on the cognitive assessment (mTICS ≤ 27); 7.4% in GeriPACT and 3.6% in PACT among those who scored higher (mTICS > 27). The OR for new dementia/MCI diagnosis in GeriPACT was 1.19 (95% CI 0.49-2.91) among those with a low mTICS score and 1.85 (95% CI 0.70-4.88) among those with a higher mTICS score. CONCLUSIONS: Observed rates of new dementia/MCI diagnosis were higher in GeriPACT, but with considerable uncertainty around estimates. Geriatrics-focused primary care clinics may be a promising avenue for improving the detection of dementia in older adults, but further larger studies are needed to confirm this relationship.

Erythropoietin or darbepoetin for patients with cancer.

BACKGROUND: Anaemia associated with cancer and cancer therapy is an important clinical factor in the treatment of malignant diseases. Therapeutic alternatives are recombinant human erythropoietin (Epo), darbepoetin (Darbepo) and red blood cell transfusions. OBJECTIVES: The aim of this systematic review was to assess the effects of Epo or Darbepo to either prevent or treat anaemia in cancer patients. SEARCH STRATEGY: We searched the Central Register of Controlled Trials, MEDLINE and EMBASE and other data bases. Searches were done for the periods 01/1985 to 12/2001 for the first review and 1/2002 to 04/2005 for the update. We also contacted experts in the field and pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials on managing anaemia in cancer patients that compared the use of Epo/Darbepo (plus transfusion if needed) with observation until red blood cell transfusion was required. DATA COLLECTION AND ANALYSIS: Several reviewers independently assessed trial quality and extracted data. MAIN RESULTS: This update of the systematic review included a total of 57 trials with 9,353 patients. Of these, 27 trials with 3,287 adults were also included in the first Cochrane Review. Thirty trials with 6,066 patients were added during the update process. Use of Epo/Darbepo significantly reduced the relative risk of red blood cell transfusions (RR 0.64; 95% CI 0.60 to 0.68, 42 trials, n = 6,510). On average participants in the Epo/Darbepo group received one unit of blood less than the control group (WMD -1.05; 95% CI -1.32 to -0.78, 14 trials, n = 2,353). For participants with baseline haemoglobin below 12 g/dL haematological response was observed more often in participants receiving Epo/Darbepo (RR 3.43; 95% CI 3.07 to 3.84, 22 trials, n = 4,307). There was suggestive evidence that Epo/Darbepo may improve Quality of Life (QoL). The relative risk for thrombo embolic complications was increased in patients receiving Epo/Darbepo compared to controls (RR 1.67, 95% CI 1.35 to 2.06; 35 trials, n = 6,769). Uncertainties remain whether and how Epo/Darbepo effects tumour response (fixed effect RR 1.12; 95% CI 1.01 to 1.23, 13 trials, n = 2,833; random effects: RR 1.09; 95% CI 0.94 to 1.26) or overall survival (unadjusted and adjusted data: HR 1.08; 95% CI 0.99 to 1.18; 42 trials, n = 8,167). AUTHORS' CONCLUSIONS: There is consistent evidence that administration of Epo/Darbepo reduces the relative risk for blood transfusions and the number of units transfused in cancer patients. For patients with baseline haemoglobin below 12 g/dL (mild anaemia) there is strong evidence that Epo/Darbepo improves haematological response. There is suggestive evidence that Epo/Darbepo may improve QoL. However, there is strong evidence that Epo/Darbepo increases the relative risk for thrombo embolic complications. Whether and how Epo/Darbepo effects tumour response and overall survival remains uncertain.

Biochemical markers of central nervous system tumors measured in cerebrospinal fluid and their potential use in diagnosis and patient management: a review.

The concept of tumor markers was reviewed, and the potential uses of markers of central nervous system (CNS) tumors and methods for their evaluation were discussed. Markers examined included lactate dehydrogenase, aspartate aminotransferase, fructose-bisphosphate aldolase, the polyamines, desmosterol, and several other enzymatic, nonenzymatic, and immunologic markers. Data collated from the clinical studies surveyed showed isocitrate dehydrogenase, desmosterol, and the polyamines to have the greatest potential utility in the diagnosis of CNS tumors.

Epoetin treatment of anemia associated with cancer therapy: a systematic review and meta-analysis of controlled clinical trials.

Epoetin treatment offers an attractive but costly alternative to red blood cell transfusion for managing anemia associated with cancer therapy. The goal of this review is to facilitate more efficient use of epoetin by 1) quantifying the effects of epoetin on the likelihood of transfusion and on quality of life in patients with cancer treatment-related anemia and 2) evaluating whether outcomes are superior when epoetin treatment is initiated at higher hemoglobin thresholds. Two independent reviewers followed a prospective protocol for identifying studies. Outcomes data were combined with the use of a random-effects meta-analysis model. Double-blind, randomized, controlled trials that minimized patient exclusions were defined as higher quality for sensitivity analysis; randomized but unblinded trials and trials with excessive exclusions were included in the meta-analysis but were defined as lower quality. Twenty-two trials (n = 1927) met inclusion criteria, and 12 (n = 1390) could be combined for estimation of odds of transfusion. Epoetin decreased the percentage of patients transfused by 9%-45% in adults with mean baseline hemoglobin concentrations of 10 g/dL or less (seven trials; n = 1080), by 7%-47% in those with hemoglobin concentrations greater than 10 g/dL but less than 12 g/dL (seven trials; n = 431), and by 7%-39% in those with hemoglobin concentrations of 12 g/dL or higher (five trials; n = 308). In sensitivity analysis, the combined odds ratio for transfusion in epoetin-treated patients as compared with controls was 0.45 (95% confidence interval [CI] = 0.33 to 0.62) in higher quality studies and 0.14 (95% CI = 0.06 to 0.31) in lower quality studies. The number of patients needed to treat to prevent one transfusion is 4.4 for all studies, 5.2 for higher quality studies, and 2.6 for lower quality studies. Only studies with mean baseline hemoglobin concentrations of 10 g/dL or less reported statistically significant effects of epoetin treatment on quality of life; quality-of-life data were insufficient for meta-analysis. No studies addressed epoetin's effects on anemia-related symptoms. We conclude that epoetin reduces the odds of transfusion for cancer patients undergoing therapy. Evidence is insufficient to determine whether initiating epoetin earlier spares more patients from transfusion or results in better quality of life than waiting until hemoglobin concentrations decline to nearly 10 g/dL.

Effects of DL-alpha-methylornithine on proliferation and polyamine content of 9L rat brain tumor cells.

Treatment of 9L rat brain tumor cells with 10 mM DL-alpha-methylornithine (alpha MO) resulted in cytostasis when cells were plated in monolayer culture at an initial cell density of 5 x 10(5)/flask but not 1 x 10(6). Fifty mM caused cytostasis at both initial densities but more effectively at the lower one. Cytocidal effects measured by a colony-forming efficiency assay were observed at 100 mM but not at 75 mM or less. Both concentrations at both initial cell densities depleted intracellular putrescine content to less than 5% of control by 12 hr and spermidine content to less than 20% of control by 48 hr posttreatment. Intracellular spermine content increased between 1.5- and 2-fold with either concentration of alpha MO and at both densities. Flow cytometry revealed no differences in cell cycle distribution between controls and cells treated with 10 mM alpha MO. The cytostatic effect of 10 mM alpha MO on 9L cultures of lower initial density appeared to be a specific result of polyamine depletion since it was reversible by exogenous putrescine added 24 hr after treatment. The effect of 50 mM alpha MO was not reversible by exogenous putrescine or pyridoxal added simultaneously or 24 hr after treatment. Treatment of 9L cells with 50 mM DL-or L-ornithine caused growth inhibition equal to that produced by 50 mM alpha MO. The effect of 50 mM alpha MO is thus not attributable to polyamine depletion.

Comparisons between sensitive and resistant human tumor cell lines regarding effects of polyamine depletion on chloroethylnitrosourea efficacy.

We have reported that 2-difluoromethylornithine (DFMO)-induced polyamine (PA) depletion sensitized five chloroethylnitrosourea (CENU)-resistant, O6-alkylguanine repair-proficient (Mer+) human tumor cell lines to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), but failed to alter BCNU efficacy in a single CENU-sensitive, repair-deficient (Mer-) line. Further, alkaline elution assays of DNA interstrand cross-links (ISC) found no BCNU-induced ISC in either PA-depleted or control Mer+ cells, suggesting that targets other than ISC may be involved in the DFMO/BCNU drug interaction. To verify that DFMO-induced enhancement of BCNU action segregates with Mer phenotype, we tested three additional Mer- lines for effects of DFMO pretreatment on BCNU efficacy. We found no potentiation of BCNU by PA depletion in any of our human Mer- lines. We also used streptozotocin (STZ) to deplete the repair capacity of Mer+ cell lines, thus converting their BCNU sensitivity to near that of Mer- cells. Combined pretreatment with DFMO then STZ did enhance BCNU cell kill relative to STZ pretreatment alone. Exogenous putrescine restored BCNU sensitivity of (DFMO plus STZ)-pretreated cells to that of cells pretreated with STZ alone. Measurements of O6-alkylguanine DNA alkyltransferase activity verified that in at least one of the Mer+ lines (HT-29), STZ did deplete repair capacity to below detectable limits. These results suggest that in HT-29 cells, STZ and DFMO probably act via differing mechanisms to potentiate BCNU. Our observations also imply that targets for CENUs may differ between Mer+ and Mer- cells, with importance of ISC possibly limited to Mer- cells. Our data further suggest that PA depletion may potentiate CENUs only at targets critical in Mer+ cells. We also noted that 48-h treatments with DFMO markedly reduced clonogenicity of Mer- cells. Exogenous putrescine restored Mer- cell survival after DFMO to near that of controls. In contrast, Mer+ cells showed little, if any, effect of DFMO treatment on plating efficiency. These results suggest that PA depletion may be cytocidal to some Mer- cells.

Chemosensitization of cultured human carcinoma cells to 1,3-bis(2-chloroethyl)-1-nitrosourea by difluoromethylornithine-induced polyamine depletion.

We have investigated the effect of pretreatment with the ornithine decarboxylase inhibitor alpha-difluoromethylornithine (DFMO) on the cytocidal efficacy of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in a series of five cultured human adenocarcinoma cell lines. Plating efficiency assays were used to generate BCNU dose-response survival curves for DFMO-treated and control cells. The cell lines varied in their sensitivity to BCNU, with A-427 (lung) and HuTu-80 (duodenum) cells being most sensitive, HT-29 (colon) and ME-180 (cervix) most resistant, and MCF-7 (breast) showing intermediate sensitivity. For all five cell lines, a 48-h pretreatment with 5 mM DFMO reduced intracellular putrescine and spermidine content to less than 10% of control levels and decreased spermine content to between 60 and 70% of controls. This pretreatment resulted in a shift of the BCNU survival curves for each of the five cell lines downward and to the left, indicating that the cells were sensitized to the lethal effects of BCNU. Dose enhancement ratios for DFMO-induced chemosensitization ranged from 1.2 (HuTu-80 cells at the 1% survival level) to 1.9 (HT-29 cells at the 10% survival level). The cell lines most resistant to BCNU appeared to give the greatest degree of potentiation by DFMO pretreatment. For four of the five cell lines, addition of 50 to 100 microM exogenous putrescine to DFMO-pretreated cultures 12 to 24 h before BCNU addition reversed the chemosensitization. ME-180 cells were the sole exception. Exogenous putrescine did not increase the surviving fraction after BCNU of any cells not pretreated with DFMO. These results suggest that DFMO-induced chemosensitization to BCNU in the four cell lines other than ME-180 is a specific consequence of the inhibition of ornithine decarboxylase by DFMO and the resulting depletion of intracellular polyamine content.

Inhibitory action of alpha-difluoromethylornithine on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced rat urinary bladder carcinogenesis.

We previously have shown that urine components capable of stimulating ornithine decarboxylase activity of urothelium can enhance rat urinary bladder carcinogenesis, and that alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, suppresses carcinogen-initiated rat urinary bladder carcinogenesis. The present investigation was conducted to determine whether DFMO's suppressive effect is stage specific during carcinogenesis and whether the suppressive effect lasts with its continued use. Following initiation with 0.05% N-butyl-N-(4-hydroxybutyl)-nitrosamine in drinking water for 6 wk, male Fischer 344 rats initially weighing 125 to 150 g were randomly divided into two groups, the first receiving 0.2% DFMO in drinking water ad libitum and the second receiving tap water only. Groups of animals were killed at regular intervals until the completion of the experiment at 75 wk. The effect of DFMO was evaluated by monitoring the incidence of tumors, the mean number of tumors per rat, the mean volume of individual tumors, and the mean total tumor volume per rat. The results showed that continuous treatment with DFMO significantly reduced tumor formation until 60 wk (P less than 0.017). The effect was only of borderline significance (0.017 less than P less than 0.035) at 75 wk. Discontinuation of DFMO treatment at 40 wk resulted in the loss of protective effect in all comparisons except for the borderline effect on the tumor number and total tumor volume per rat. DFMO had no significant effect on the incidence or development of preneoplastic early lesions. Mucosal polyamine (spermidine and spermine) levels were reduced and correlated well with the reduction in tumor growth, suggesting that the reduction in tumor growth rate by DFMO may be due to its ability to reduce polyamine levels in urothelium. There were no side effects attributable to DFMO treatment. DFMO may be a useful chemopreventive agent to retard the recurrence of human superficial bladder cancer.

Comparison of DNA interstrand cross-linking and strand breakage by 1,3-bis(2-chloroethyl)-1-nitrosourea in polyamine-depleted and control human adenocarcinoma cells.

Recent evidence from our laboratory and from others suggested that pretreatment with alpha-difluoromethylornithine (DFMO) sensitizes some human and rodent tumor cell lines to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Many human tumor cells are resistant to chloroethylnitrosourea-induced DNA interstrand cross-linking and cell kill due to their high levels of the DNA repair protein O6-alkylguanine DNA alkyltransferase. We therefore investigated DFMO-mediated sensitization to BCNU in BCNU-sensitive and -resistant cells. Colony formation assays were used to compare BCNU cytotoxicity in DFMO-pretreated and control cultures of two colon tumor lines, HT-29 cells, which have high alkyltransferase levels and thus are BCNU-resistant, and BE cells, which are deficient in this repair capacity and thus are BCNU-sensitive. Polyamine depletion significantly enhanced BCNU cytotoxicity only for the repair-proficient HT-29 cell line. BE cells were 40-fold more sensitive to BCNU than were HT-29 cultures. However, in BE cells, no effect of polyamine depletion was found on cellular response to BCNU treatment at 72 h after DFMO treatment. Reverse-phase high-performance liquid chromatography assays of polyamine concentrations in cell extracts verified that DFMO produced comparable degrees of polyamine depletion for both cell lines. DNA alkaline elution analysis was used to monitor BCNU-induced formation of DNA single strand breaks, DNA interstrand cross-links, and DNA-protein cross-links. Equal concentrations of BCNU produced similar levels of strand breaks and DNA-protein cross-links in DFMO-pretreated and control cultures for both cell lines. These data suggest that DNA in polyamine-deficient HT-29 and BE cells is not more accessible to BCNU than is DNA in controls. No DNA interstrand cross-links were detected in either DFMO-pretreated or control HT-29 cells after BCNU treatment. Further, in BE cells which accumulate BCNU-induced DNA interstrand cross-links, no increase in the measureable levels of cross-links resulted from polyamine deficiency. Our observations suggest that mechanisms other than increased DNA interstrand cross-link formation may be mediating the enhanced efficacy of BCNU in polyamine-deficient HT-29 cell cultures. Our findings may also imply that cellular targets for BCNU other than DNA damage may be responsible for DFMO-induced chemosensitization in the repair-proficient cells.

Sensitization of 9L rat brain gliosarcoma cells to 1,3-bis(2-chloroethyl)-1-nitrosourea by alpha-difluoromethylornithine, an ornithine decarboxylase inhibitor.

alpha-Difluoromethylornithine, a known inhibitor of polyamine biosynthesis, significantly enhanced the cytotoxic effect of 1,3-bis(2-chloroethyl)-1-nitrosourea, a cell cycle-nonspecific agent, in 9L rat brain gliosarcoma cells in vitro. Administered as a single agent, alpha-difluoromethylornithine was not cytotoxic to 9L cells and, compared to untreated control cells, caused no perturbation of cell cycle kinetics. alpha-Difluoromethylornithine-induced depletion of intracellular polyamine levels appears to have caused the observed sensitization of 9L cells to 1,3-bis(2-chloroethyl)-1-nitrosourea. Restoration of intracellular polyamine levels by the addition of exogenous putrescine to treated 9L cells reversed this phenomenon.

Inhibition of carcinogenesis by alpha-difluoromethylornithine in heterotopically transplanted rat urinary bladders.

Inhibitory effects of alpha-difluoromethylornithine (DFMO) on urinary bladder carcinogenesis were examined using the heterotopically transplanted rat urinary bladder (HTB) model. Male Fischer rats with an HTB were arbitrarily divided into four groups. Group 1 rats received into the HTBs 0.25 mg of N-methyl-N-nitrosourea (MNU) once a week for 3 weeks, followed by instillation twice a week of 0.5 ml of 2% DFMO dissolved in normal rat urine. Group 2 rats received the same amount of MNU, followed by instillation of urine without DFMO. Group 3 rats received a single dose of 0.25 mg of MNU, followed by instillation twice a week of urine containing 2% DFMO. Group 4 rats were treated as those in Group 3 but without DFMO. At 8, 14, and 20 weeks after the last MNU administration, urothelial polyamine levels and [3H] thymidine incorporation by the urothelium of HTBs were determined in nine rats of Groups 1 and 2. The remaining animals of Groups 1 and 2 were killed 25 weeks after the beginning of MNU injection, while those of Groups 3 and 4, 30 weeks after the MNU treatment. The contents of 3 polyamines (putrescine, spermidine, and spermine) in urothelial cells were significantly lower in Group 1 as compared with Group 2. The incidences of carcinoma were significantly lower in the groups treated with DFMO (p less than 0.001, Group 1 versus Group 2; p less than 0.005, Group 3 versus Group 4). These observations indicate that administration of DFMO inhibits (or retards) bladder carcinogenesis in HTBs. A possible mechanism for this effect is suppression of polyamine biosynthesis and proliferation of bladder epithelial cells.

Altered cell cycle phase distributions in cultured human carcinoma cells partially depleted of polyamines by treatment with difluoromethylornithine.

We have studied the effects of partial polyamine depletion, induced by treatment with alpha-difluoromethylornithine (DFMO) on cell cycle phase distributions in five cultured human carcinoma cell lines. We used flow cytometry of cells stained with chromomycin-A3 and computer analysis to measure phase distributions of treated and control cultures. All five lines respond to 1-5 mM DFMO treatment with a total absence of measurable putrescine, a loss of greater than 90% of spermidine, and a 30-40% decline in spermine by 48 h after DFMO addition. The proliferation of all five lines is inhibited as well. Nonetheless, only four of the cell lines (HuTu-80, HT-29, MCF-7, and A-427) show a marked increase in the G1-phase fraction and decrease in the S-phase fraction as a consequence of DFMO treatment. Small, but significant, decreases in the G2-M populations of these cell lines also occurred after DFMO treatment. Exogenous putrescine (5-50 microM) reversed both the polyamine depletion and the perturbed phase distributions of DFMO-treated cultures but was without effect on phase distributions of cultures not treated with DFMO. The fifth cell line (ME-180) showed no effect of polyamine depletion on cell cycle phase distributions in DFMO-treated cultures and also no effect of exogenous putrescine on phase fractions of either control or DFMO-treated cells. These observations indicate that some human tumor cell lines are dependent upon adequate intracellular polyamine content for maintenance of cell cycle traverse. They also imply that human tumor cell lines are heterogeneous with regard to their cell cycle response to DFMO-induced polyamine deficiency.

Reduced cytocidal efficacy for adriamycin in cultured human carcinoma cells depleted of polyamines by difluoromethylornithine treatment.

We have studied the effect of pretreatment with difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor, on the cytocidal responses of four human adenocarcinoma cell lines to Adriamycin (ADR). The cell lines utilized included HuTu-80 (duodenum), HT-29 (colon), ME-180 (cervix), and A-427 (lung). A 48-h DFMO pretreatment reduced putrescine and spermidine content to less than 10 and less than 1% of control levels and decreased spermine to between 70 and 30% of controls. Plating efficiency assays were used to generate ADR dose-response survival curves for DFMO-treated and control cultures. The DFMO pretreatment significantly protected human adenocarcinoma cells from the lethal effects of ADR. Addition of exogenous putrescine to the DFMO-treated cultures 24 h before treatment with ADR restored their cytocidal response to ADR to near control levels. Putrescine had no effect on cell survival in cultures that were not pretreated with DFMO. These observations suggest that DFMO-induced protection from ADR may be a specific consequence of DFMO-induced inhibition of polyamine biosynthesis. Alternatively, since ADR efficacy varies directly with cellular growth rates and DFMO inhibits proliferation, the protection may have resulted from DFMO-induced growth inhibition. Comparison of ADR uptake in DFMO-pretreated and control cells showed that the protection did not result from decreased intracellular accumulation of ADR.

Inhibition of bone resorption by alpha-difluoromethylornithine may not be mediated by polyamine depletion.

We have examined the effect of alpha-difluoromethylornithine (DFMO) on bone polyamine content and parathyroid hormone (PTH)- and calcitriol-stimulated bone resorption in cultures of neonatal mouse calvaria. Polyamine content in bone homogenates was determined by reverse-phase paired-ion HPLC. Treatment with 5 mM DFMO for 48 h reduced putrescine from 0.4 nmol/bone to nondetectable levels, slightly decreased spermidine, and did not affect spermine. Bone resorption elicited by 48 h of treatment with PTH or calcitriol was inhibited by concentrations of DFMO greater than or equal to 5 mM added 48 h prior to hormone. This observation supported the concept that polyamines may play a role in bone resorption. However, other observations cast uncertainty on this conclusion. Measurement of calvarial polyamine content at 2 h intervals revealed no increase in endogenous polyamines for up to 10.5 h after calcitriol addition. Although addition of putrescine restored bone polyamine content, exogenous polyamines failed to reverse the inhibitory effects of DFMO on calcitriol-stimulated resorption. These results suggest that a mechanism other than depletion of polyamines could be contributing to the inhibitory effect of DFMO on resorption.

O2- and pneumonia-induced lung injury. II. Properties of pulmonary surfactant.

Pulmonary surfactant was isolated from the lavage fluids of animals during the course of exposure to 100% O2, 80% O2, 40% O2, or 80% O2 plus 10(8) Pseudomonas aeruginosa instilled intratracheally and analyzed for its phospholipid composition. After 4-5 days of exposure to 100% O2, disaturated phophatidylcholine (DSPC) decreased to 87% of control, whereas the ratio of phosphatidylglycerol to phosphatidylinositol (PG/PI) was 37% of control. Longer periods of ventilation with 100% O2 resulted in DSPC falling to less than 40% of control. The injury was not reversed by reducing the O2 to 50%; rather, a progressive deterioration ensued. Acute respiratory failure (ARF) induced by 5 days of bacterial infection was very similar to that seen after 5 days of exposure to 100% O2. Ventilation with 80% O2 for 6 days resulted in smaller changes in DSPC but with differences in PG/PI comparable to those seen with 100% O2 or infection. We conclude that the ability of the type II cell to synthesize surfactant of normal composition is significantly impaired in these models of ARF. The earliest index of biochemical modification is the substantial change in PG/PI, which may be predictive of early lung injury. Further exacerbation of the injury could result in the reduction of DSPC content, with subsequent changes in lung mechanics and gas exchange.

Effects of difluoromethylornithine on proliferation, polyamine content and plating efficiency of cultured human carcinoma cells.

We investigated the effects of an irreversible inhibitor of ornithine decarboxylase, difluoromethylornithine (DFMO), on the proliferation, polyamine content, and plating efficiency of five human adenocarcinoma cell lines in vitro. DFMO inhibited the growth of all five lines when added at concentrations between 0.1 and 5.0 mM. The cell lines varied in their sensitivity to DFMO-induced cytostasis, HuTu-80 being most sensitive and HT-29 being most resistant. These differences appeared to be related to the ability of DFMO to prevent continued production of putrescine in the treated cells. Exogenous putrescine (5-50 microM) reversed the growth inhibition for all five cell lines when added 48 h after DFMO treatment. The lowest concentration of exogenous putrescine (5 microM) only restored intracellular polyamine content of DFMO-treated cells to control levels for the first 24 h after its addition. After that time, spermidine content declined once again to that observed for cells treated with DFMO alone. The higher concentrations of exogenous putrescine restored the content of all three polyamines to control levels for as much as 3 days after its addition, but did not cause a greater increase in cell growth rates than did 5 microM putrescine. These data suggest that human adenocarcinoma cell proliferation is dependent on continued polyamine biosynthesis, but that the basal content of intracellular polyamines is greatly in excess of the minimum level required to support cell growth. In the 1.0-5.0 mM concentration range, DFMO treatment for 48 h caused a slight, but statistically significant, reduction in plating efficiency for three of our cell lines, and had no significant effect on the two others.

Effects of DFMO-induced polyamine depletion on human tumor cell sensitivity to antineoplastic DNA-crosslinking drugs.

We investigated the effect of pretreatment with difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor, on the cytocidal responses of four human adenocarcinoma cell lines to two alkylating and crosslinking agents: chlorambucil and N,N',N"-triethylenethiophosphoramide (thiotepa). The cell lines studied included HuTu-80 (duodenum), HT-29 (colon), ME-180 (cervix), and A-427 (lung). A 48- to 72-h pretreatment with DFMO reduced intracellular putrescine and spermidine contents to less than 10% and less than 1% of control levels. This treatment also caused a 30%-70% decline in spermine content. Survival of control and DFMO-pretreated cells after treatment with chlorambucil or thiotepa was measured by a plating efficiency assay. For three of the four lines studied, the DFMO-induced partial polyamine depletion significantly protected cells from the lethal effects of chlorambucil. In ME-180 cultures alone, DFMO pretreatment did not alter the cytocidal efficacy of chlorambucil. Addition of exogenous putrescine to cultures of HuTu-80, HT-29, or A-427 24 h after DFMO addition but 24 h before treatment with chlorambucil reversed the polyamine depletion and its protective effects on chlorambucil-induced cell kill. In contrast to the above observations, DFMO and partial polyamine depletion had no effect on cell survival after thiotepa treatment for any of the cell lines investigated.

Lipid metabolism in rabbits exposed to paraquat aerosol.

In order to examine the effects of paraquat on pulmonary lipid metabolism rabbits were exposed to double distilled water by aerosol, or 250 mg paraquat in double distilled water. One hour prior to sacrifice, a group of rabbits were injected with [2-14C]-acetate. The levels of phospholipids, fatty acids, cholesterol, and triglycerides were determined as were their 14C-contents in the lung, bronchoalveolar lavage fluid, serum, and liver. The serum of paraquat-exposed animals contained significantly increased levels of phospholipids, cholesterol, and triglycerides. Liver, lung, and bronchoalveolar lavage contained less than or equal to control levels of phospholipids, cholesterol, and triglycerides. Percent of palmitate in the hepatic fatty acid profile was slightly increased in liver but not in lung. The source of the increased lipids in the serum is unknown.

Maximal androgen blockade for advanced prostate cancer.

OBJECTIVES: This systematic review assessed the effect of maximal androgen blockade (MAB) on survival when compared to castration (medical or surgical) alone for patients with advanced prostate cancer. SEARCH STRATEGY: Randomized controlled trials were searched in general and specialized databases (MEDLINE, EMBASE, Cancerlit, Cochrane Library, VA Cochrane Prostate Disease register) and by reviewing bibliographies. SELECTION CRITERIA: All published randomized trials were eligible for inclusion provided they (1) randomized men with advanced prostate cancer to receive a non-steroidal anti-androgen (NSAA) medication in addition to castration (medical or surgical) or to castration alone, and (2) reported overall survival, progression-free survival, cancer-specific survival, and/or adverse events. Eligibility was assessed by two independent reviewers. DATA COLLECTION AND ANALYSIS: Information on patients, interventions, and outcomes were extracted by two independent reviewers using a standardized form. The main outcome measure for comparing effectiveness was overall survival at 1, 2, and 5 years. Secondary outcome measures included progression-free survival and cancer-specific survival. The relationship of specific NSAA on outcome was evaluated. Additionally, the incidence of adverse effects was measured. MAIN RESULTS: Twenty trials enrolling 6,320 patients were included. The pooled OR for overall survival was 1.03 (95% CI:0.85 to 1.25), 1.16 (95% CI:1.00 to 1.33), and 1.29 (95% CI:1.11 to 1.50) at 1, 2, and 5 years respectively. Overall survival was only significant at 5 years. The risk difference at 5 years was 0.048 (95% CI:0.02 to 0.077) and NNT at 5 years 20.8. Progression-free survival was improved only at 1 year follow-up (OR=1.38) and cancer-free survival was improved only at 5 years (OR=1.22). Adverse events occurred more frequently in those assigned to MAB and resulted in withdrawal in 10%. Quality of life was measured in only one study favored orchiectomy alone (less diarrhea and better emotional functioning in the first 6 months). REVIEWER'S CONCLUSIONS: MAB produces a modest overall and cancer-specific survival at 5 years but is associated with increased adverse events and reduced quality of life.

Erythropoietin for patients with malignant disease.

BACKGROUND: Anaemia associated with cancer and cancer therapy is an important clinical factor in the treatment of malignant diseases. Therapeutic alternatives are recombinant human erythropoietin (EPO) and red blood cell transfusions. OBJECTIVES: The aim of this systematic review was to assess the effect of erythropoietin to either prevent or treat anaemia in cancer patients. SEARCH STRATEGY: We searched the Central Register of Controlled Trials, MEDLINE (01/1985 to 12/2001), EMBASE (01/1985 to 12/2001), other databases and reference lists of articles. We also contacted experts in the field and pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials comparing the use of recombinant human erythropoietin (plus transfusion if needed) with red blood cell transfusions alone for the treatment or prevention of anaemia in cancer patients. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. All authors from included studies were contacted for additional information. MAIN RESULTS: Twenty seven trials with 3,287 adults were included. Use of erythropoietin significantly reduced the relative risk of red blood cell transfusions (RR 0.67; 95% CI 0.62 to 0.73, 25 trials, n = 3,069). On average participants in the erythropoietin group received one unit of blood less than the control group (WMD -1.00; 95% CI-1.31 to -0.70, 13 trials, n = 2,056). For participants with baseline haemoglobin below 10 g/dL haematological response was observed more often in participants receiving EPO (RR 3.60; 95% CI 3.07 to 4.23, 14 trials, n = 2,347). There was inconclusive evidence whether EPO improves tumour response (fixed effect RR 1.36; 95% CI 1.07 to 1.72, seven trials, n = 1,150; random effects: RR 1.21; 95% CI 0.92 to 1.59) and overall survival (adjusted data: HR 0.81; 95% CI 0.67 to 0.99; unadjusted data: HR 0.84; 95% CI 0.69 to 1.02, 19 trials, n = 2,865). There were no statistically significant adverse effects. Evidence was inconclusive with respect to quality of life and fatigue. REVIEWERS' CONCLUSIONS: There is consistent evidence that the administration of erythropoietin reduces the risk for blood transfusions and the number of units transfused in cancer patients. For patients with baseline haemoglobin below 10 g/dL there is strong evidence that erythropoietin improves haematological response. There is inconclusive evidence whether erythropoietin improves tumour response and overall survival. Research on side effects is inconclusive.