Protocol Outlines for Parts 1 and 2 of the Prospective Endoscopy III Study for the Early Detection of Colorectal Cancer: Validation of a Concept Based on Blood Biomarkers.

BACKGROUND: Programs for population screening of colorectal cancer (CRC) have been implemented in several countries with fecal immunochemical testing (FIT) as the preferred platform. However, the major obstacle for a feces-based testing method is the limited compliance that reduces the clinical sensitivity for detection of participants with non-symptomatic CRC. Therefore, research approaches have been initiated to develop screening concepts based on biomarkers in blood. Preliminary results show that protein, genetic, epigenetic, and metabolomic components may be valuable in blood-based screening concepts, particularly when combinations of the various components appear to lead to significant improvements. OBJECTIVES: The protocol described in this paper focuses on the validation of concepts based on biomarkers in blood in a major population screened by FIT. METHODS: In Part 1, participants will be identified and included through the Danish CRC Screening Program comprising initial FIT and subsequent colonoscopy to those with a positive result. Blood samples will be collected from 8000 FIT-positive participants, who are offered subsequent colonoscopy. Findings and interventions at colonoscopy together with personal data including co-morbidity will be recorded. Blood samples and data will also be collected from 6000 arbitrarily chosen participants with negative FIT. In Part 2, blood samples and data will be collected from 30,000 FIT-negative participants three times within 4 years. The blood samples will be analyzed using various in-house and commercially available manual and automated analysis platforms. RESULTS: We anticipate Part 1 to terminate late August 2016 and Part 2 to terminate late September 2022. The results from Parts 1 and 2 will be presented within 12 to 18 months from termination. CONCLUSIONS: The purpose of this study is to improve the efficacy of identifying participants with neoplastic bowel lesions, to identify false negative participants, to identify participants at risk of interval neoplastic lesions, to improve the compliance in screening sessions, and to establish guidelines for out-patient follow-up of at-risk participants based on combinations of blood-based biomarkers.

Hyaluronic Acid Assays: Turbidimetric or Enzyme-Based Immune Assay? A Method Comparison Study.

BACKGROUD: Hyaluronic acid (HA) is proposed as a marker of functional liver capacity. The aim of the present study was to compare a new turbidimetric assay for measuring HA with the current standard method. METHODS: HA was measured by a particle-enhanced turbidimetric immunoassay (PETIA) and enzyme-linked immunosorbent assay (ELISA) in a 40-sample dilution series and 39 intensive care unit (ICU) patients. Agreement was assessed with Bland-Altman's method. RESULTS: In the ICU patients, the median HA concentration was 159.0 ng/ml (interquartile range (IQR) 117.5-362.5 ng/ml) with ELISA and 157.5 ng/ml (IQR 92.5-359.6 ng/ml) with PETIA. The mean difference was 12.88 ng/ml (95% CI, -4.3 to 30.1 ng/ml, P = 0.14) and the 95% limits of agreement were -91.17 to 116.9 ng/ml. In the dilution series, the mean difference was -59.26 ng/ml (95% CI, -74.68 to 43.84 ng/ml, P < 0.0001) and the 95% limits of agreement were 35.23 to -153.8 ng/ml. CONCLUSION: We found random variation between the PETIA and ELISA test that could affect performance in a clinical context, but only to a lesser extent in a research context. The new clinical biochemistry assay for HA determination will allow for large studies of the clinical utility of HA.

D-lactate is a valid biomarker of intestinal ischemia induced by abdominal compartment syndrome.

BACKGROUND: Intra-abdominal hypertension (IAH) often leads to abdominal compartment syndrome, which is followed by intestinal ischemia and associated with a high mortality. The diagnosis of abdominal compartment syndrome is difficult, and no valid biochemical markers are available. We conducted an experimental study on pigs to determine if D-lactate could be a useful biochemical marker of intestinal ischemia. MATERIALS AND METHODS: A total of eight pigs (intervention group) underwent insufflation of carbon dioxide in the abdominal cavity to induce IAH and were compared with that of eight pigs (sham group) without IAH. Blood samples were taken from the portal and jugular veins at 0, 60, 120, 180, and 240 min after insufflation of carbon dioxide, and concentrations of D-lactate and L-lactate in the two groups were compared using an unpaired t-test. RESULTS: The concentrations of D-lactate were increased in portal blood after 180 min of IAH (P = 0.036) and jugular blood after 240 min of IAH (P = 0.028) in the intervention group compared with those in the sham group. A similar tendency was found for L-lactate levels after 180 min of IAH (P = 0.032 and P = 0.017 for portal and jugular blood samples, respectively). Examination of the intestines revealed both macroscopic and microscopic signs of ischemia in all but one animal in the intervention group and only in one sham-pig. CONCLUSIONS: Our findings suggest that D-lactate could be a useful biochemical marker of intestinal ischemia induced by IAH.

The influence of the gastrointestinal tract and the liver on cystatin C serum concentrations.

OBJECTIVE: The purpose of this study in humans was to examine the influence of the gastrointestinal tract and liver on the serum concentrations of cystatin C. METHODS: Eighteen healthy volunteers and 28 patients suspected of having chronic intestinal ischemia underwent catheterization of the abdominal aorta and the central hepatic vein. Blood samples were taken simultaneously from the abdominal aorta and the central hepatic vein 60, 90 and 120 minutes after the start of the investigation. After the first blood sample, a standard liquid meal was ingested. Measurement of splanchnic blood flow was performed using the Fick principle with constant infusion of (99m)Tc-Bridatec. Angiography was performed at the end of the investigation. RESULTS: The splanchnic blood flow increased significantly postprandially in the healthy volunteers and in the patients with normal angiography by 0.613-0.698 L/min and increased non- significantly in the patients with abnormal angiography (n = 5) by 0.135 L/min on average. ANOVA and the Bonferroni's multiple comparison test showed no significant difference between the means of cystatin C, creatinine or urea in the samples taken 60, 90 and 120 minutes after the start of the investigation in the abdominal aorta and the hepatic vein in the healthy volunteers or in the patients suspected of chronic intestinal ischemia with normal angiography. CONCLUSION: There was no indication of hepatic elimination of cystatin C, creatinine or urea. The serum concentrations of cystatin C, creatinine and urea in the central hepatic vein and the abdominal aorta were independent of the splanchnic blood flow.

The natural history of liver regeneration in rats: description of an animal model for liver regeneration studies.

BACKGROUND: Rodent models have been used to evaluate aspects of liver regeneration. The aim of the present study was to investigate the natural history of liver regeneration in healthy rats. METHODS: A 70% partial hepatectomy was performed in 64 rats. The animals were randomised into 8 groups and evaluated on postoperative days one to eight. Hepatocyte proliferation was evaluated by immunohistochemistry using unbiased stereological principles. RESULTS: The mean rat body weight was 238 g (211-287). The mean weight of the resected liver was 6.3 g (5.2-7.3) and the estimated mean total liver weight was 8.9 g (7.4-10.4). Both liver weight analysis and regeneration rate showed an ascending curve, with a maximum slope on postoperative days 1-4, reaching a steady state on days 5-8. Hepatocyte proliferation (positive Ki-67 cell profiles pr. mm(2)) was high (250 cell profiles/mm(2)) on postoperative days 1-3 and tapered off on day 5. CONCLUSION: Seventy percent partial hepatectomy in healthy rats induces a rapid regenerative response and PODs 2, 4 and 8 seems optimal for assessing hepatic growth in future studies.

Detecting reduced renal function in children: comparison of GFR-models and serum markers.

BACKGROUND: The aim of this study was to compare the ability of renal indicators [serum creatinine (SCr), cystatin C (SCysC)] and glomerular filtration rate (GFR)-models to discriminate normal and reduced renal function. As a single cut-off level will always lead to false classifications, we propose using two cut-off levels, dividing renal function into normal or reduced, with an intermediate "gray zone" of indeterminable results. METHODS: Glomerular filtration rate was measured by plasma clearance of (51)Cr-EDTA (13.7-147.4 mL/min/1.73 m(2)) in 119 children (age range 2.3-14.9 years). Reduced renal function was defined as a GFR of <82 mL/min/1.73 m(2). SCr, SCysC, age-normalized creatinine (SCr-ratio), and eight published GFR-models were compared for their ability to correctly classify renal function as normal or reduced. Cut-off levels were determined so as to give 99 % certainty outside the gray zone. RESULTS: The multivariable GFR-models by Schwartz et al. (J Am Soc Nephrol 2009; 20:629-637) and Zappitelli et al. (Am J Kidney Dis 2006; 48:221-230) and two models by Andersen et al. [Am J Kidney Dis 2012; 59(1):50-57: body cell mass (BCM)-model and Weight-model] performed significantly better than all other variables (P < 0.01), with the BCM-model performing the best (P < 0.05). The SCr-based Schwartz formula and SCr-ratio both performed better than SCr and SCysC. CONCLUSIONS: Among the 119 children enrolled in this study and the renal indicators tested, the BCM-model had the best diagnostic performance in terms of screening for normal or reduced renal function, and the SCr-ratio was a superior diagnostic tool to both SCr and SCysC.

L- and D-lactate as biomarkers of arterial-induced intestinal ischemia: an experimental study in pigs.

BACKGROUND: Intestinal ischemia is difficult to diagnose, and search for new biomarkers has led to interest in D-lactate, which arises from bacterial fermentation in the gastrointestinal tract. METHODS: The superior mesenteric artery was clamped in eight pigs for 6 h to induce ischemia of the intestine. Eight sham-operated pigs served as controls. Systemic and portal plasma D- and L-lactate were sampled in 1 h intervals. L-LDH was inactivated prior to D-lactate measurement by addition of NaOH. RESULTS: In systemic vein samples, we found a significant mean difference in the change of D-lactate from baseline to 6 h between the sham and intervention group (.007 ± .011 mmol/l vs. .030 ± .013 mmol/l, respectively) (P = .020). Both systemic and portal circulation levels of plasma L-lactate increased significantly between the two groups within an hour. The mean difference for L-lactate were -.020 ± .215 mmol/l and 1.440 ± 1.454 mmol/l in the sham and intervention group, respectively (P = .009). CONCLUSION: L-lactate was found to be a marker of arterial-induced intestinal ischemia in both the systemic and portal circulation. There was no significant elevation of D-lactate at either site during the 6 h of ischemia.

Comparison of bone and renal effects in HIV-infected adults switching to abacavir or tenofovir based therapy in a randomized trial.

INTRODUCTION: Our objective was to compare the bone and renal effects among HIV-infected patients randomized to abacavir or tenofovir-based combination anti-retroviral therapy. METHODS: In an open-label randomized trial, HIV-infected patients were randomized to switch from zidovudine/lamivudine (AZT/3TC) to abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC). We measured bone mass density (BMD) and bone turnover biomarkers (osteocalcin, osteocalcin, procollagen type 1 N-terminal propeptide (P1NP), alkaline phosphatase, type I collagen cross-linked C-telopeptide (CTx), and osteoprotegerin). We assessed renal function by estimated creatinine clearance, plasma cystatin C, and urinary levels of creatinine, albumin, cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL). The changes from baseline in BMD and renal and bone biomarkers were compared across study arms. RESULTS: Of 40 included patients, 35 completed 48 weeks of randomized therapy and follow up. BMD was measured in 33, 26, and 27 patients at baseline, week 24, and week 48, respectively. In TDF/FTC-treated patients we observed significant reductions from baseline in hip and lumbar spine BMD at week 24 (-1.8% and -2.5%) and week 48 (-2.1% and -2.1%), whereas BMD was stable in patients in the ABC/3TC arm. The changes from baseline in BMD were significantly different between study arms. All bone turnover biomarkers except osteoprotegerin increased in the TDF/FTC arm compared with the ABC/3TC arm, but early changes did not predict subsequent loss of BMD. Renal function parameters were similar between study arms although a small increase in NGAL was detected among TDF-treated patients. CONCLUSION: Switching to TDF/FTC-based therapy led to decreases in BMD and increases in bone turnover markers compared with ABC/3TC-based treatment. No major difference in renal function was observed. TRIAL REGISTRATION: Clinicaltrials.gov NCT00647244.

GFR prediction from cystatin C and creatinine in children: effect of including body cell mass.

BACKGROUND: Aiming to develop a more accurate cystatin C-based model for estimation of glomerular filtration rate (GFR) in children, we hypothesized that inclusion of body cell mass (BCM) would increase the accuracy of the GFR estimate in comparison to a well-established GFR reference method. STUDY DESIGN: Diagnostic test accuracy study. SETTINGS & PARTICIPANTS: 119 children (mean age, 8.8; range, 2.3-14.9 years) referred for GFR measurement by chromium 51 ethylenediaminetetraacetic acid ((51)Cr-EDTA) clearance (mean GFR, 98; range, 13.7-147.4 mL/min/1.73 m(2)). INDEX TEST: GFR estimations by the 2 prediction models resulting from theoretical considerations corroborated by forward stepwise variable selection: GFR (mL/min) = 0.542 × (BCM/SCysC)(0.40) × (height × BSA/SCr)(0.65) and GFR (mL/min) = 0.426 × (weight/SCysC)(0.39) × (height × BSA/SCr)(0.64), where SCysC is serum cystatin C level, BSA is body surface area, and SCr is serum creatinine level. The accuracy and precision of these models were compared with 7 previously published prediction models using random subsampling cross-validation. Local constants and coefficients were calculated for all models. Root mean square error, R(2), and percentage of predictions within ±10% and ±30% of the reference GFR were calculated for all models. Based on 1,000 runs of the cross-validation procedure, median values and 2.5th and 97.5th quantiles of the validation parameters were calculated. REFERENCE TEST: GFR measurement by (51)Cr-EDTA clearance. RESULTS: The BCM model predicted 98% within ±30% of reference GFR and 66% within ±10%, which was higher than for any other model. The weight model predicted 97.5% within ±30% of reference GFR and 62% within ±10%. The BCM model had the highest R(2) and the smallest root mean square error. LIMITATIONS: Included only 9 children with GFR <60 mL/min/1.73 m(2). Lack of independent validation cohort. CONCLUSIONS: The novel BCM model predicts GFR with higher accuracy than previously published models. The weight model is almost as accurate as the BCM model and allows for GFR estimation without knowledge of BCM. However, endogenous methods are still not sufficiently accurate to replace exogenous markers when GFR must be determined with high accuracy.

An automated plasma D-lactate assay with a new sample preparation method to prevent interference from L-lactate and L-lactate dehydrogenase.

OBJECTIVE: To establish an automated plasma D-lactate assay without interference from L-lactate and L-lactate dehydrogenase (L-LDH). METHODS AND MATERIALS: The D-lactate assay was programmed as a 2-point endpoint assay on the Roche Modular P using the D-lactic acid kit from Biocontrol Systems, USA. In the chemical reaction, D-lactate was oxidized to pyruvate by NAD(+) in the presence of D-lactate dehydrogenase. The resultant pyruvate was converted to alanine in the presence of alanine aminotransferase. The amount of NADH formed in the coupled reaction, measured by the change in the absorbance at 340 nm, was proportional to the concentration of D-lactate in the sample. Human serum albumin (HSA) solutions and plasma from pigs with experimentally-induced gut ischemia were used in this study. Blood samples were collected into Venosafe® tubes. RESULTS: The D-lactate assay was linear up to 1.000 mmol/L in HSA solutions and plasma. The detection limit was 0.003 mmol/L. Within-run CVs ≤ 2.0% and total CVs ≤ 3.2% were obtained in the control material. Recovery was 87.1 ± 5.2 % (Mean ± SD). The L-LDH activity was completely inactivated in plasma samples by the addition of 20 µL of a 5 mol/L NaOH solution to 500 µL of plasma (pH 11.5). No interference could be detected from concentrations of bilirubin < 450 µmol/L, haemoglobin < 0.2 mmol/L or Intralipid® < 2.5 g/L. CONCLUSIONS: The performance of the established D-lactate assay meets the requirements to be implemented into hospital laboratories. The sample preparation method is simple, cheap and requires minimal labour.

d-lactate as a marker of venous-induced intestinal ischemia: an experimental study in pigs.

BACKGROUND: Intestinal ischemia is difficult to diagnose. The search for biomarkers has led to an increased interest in d-lactate. d-lactate measured in higher concentrations arises from bacterial fermentation in the gastrointestinal tract. Permeable intestinal wall is an early consequence of intestinal ischemia, which allows d-lactate to enter the portal circulation. METHODS: The superior mesenteric vein was clamped in eight pigs for two hours to induce ischemia of the intestine. Eight sham-operated pigs served as controls. Systemic and portal plasma d- and l-lactate, l-LDH and leukocytes were measured. RESULTS: Plasma d-lactate increased significantly and nearly simultaneously in the systemic and portal circulation. After 75 min, samples from the jugular vein showed concentrations of .019 ± .008 mmol/L in the sham group and .042 ± .022 mmol/L in the intervention group (P = .023). A similar significant effect was seen in the portal circulation after 90 min. l-lactate increased five minutes after clamping in the portal circulation, with values of 3.396 ± 1.119 mmol/L in the intervention group compared to 1.696 ± .483 mmol/L in the control group (P = .006). l-LDH increased significantly in the intervention group, while leukocytes were unaffected. l-LDH and l-lactate in plasma led to an overestimation of d-lactate if not handled. CONCLUSION: Both systemic d- and l-lactate were markers of venous-induced intestinal ischemia. We speculate that d-lactate may be a valuable aid to the clinician in search of the anaerobic focus, because it may be more specific for mesenteric ischemia than l-lactate, in the sense that it is of bacterial origin.

Performance evaluation of the Roche Tina-quant Cystatin C assay and reference interval for cystatin C in healthy blood donors.

OBJECTIVE: To evaluate the performance of the Roche Diagnostics Tina-quant Cystatin C particle enhanced immuno turbidimetric assay for the measurement of plasma and serum cystatin C, and to establish reference intervals for cystatin C in healthy blood donors. METHODS AND MATERIALS: The cystatin C measurements were performed on the Roche Modular Analytics P automated clinical chemistry analyzer. RESULTS: The cystatin C assay was linear in the measuring range 0.40-7.00 mg/L. Within-run CVs < or = 2.0%, between-run CVs < or = 4.2%, and total CVs < or = 5.5% in plasma pools and in commercial cystatin C control materials (range 1.0-4.7 mg/L). Recovery was 99.4-109.3%. No interference was detected from haemoglobin < 0.9 mmol/L, bilirubin < 330 micromol/L and Intralipid < 20 g/L. Measurement of cystatin C in Li-heparin plasma did not differ significantly from cystatin C measured in serum. Forty patient samples run on the Modular Analytics P (y) were compared to the Siemens Cystatin C assay on the BN II (x): y = 0.817x + 0.270, Sy.x = 0.168 (Deming regression). The non-parametric reference interval for cystatin C was calculated to be 0.41-0.91 mg/L in females (n = 86), and 0.43-0.94 mg/L in males (n = 76). The Mann-Whitney U test showed a significant difference between the two genders (p = 0.015), but the difference was without clinical relevance. A common reference interval for both genders (n = 162) was calculated to be 0.41-0.92 mg/L. CONCLUSION: The performance of the Tina-quant Cystatin C assay was acceptable for clinical use.

Comparison of within- and between-subject variation of serum cystatin C and serum creatinine in children aged 2-13 years.

BACKGROUND: Previously, data on both the within-subject (SD(I)) and the between-subject (SD(G)) variation of cystatin C in children has not been reported. Thus, this study aimed to determine this biological variation including analytical variation (SD(A)) of both cystatin C and creatinine to characterize the two analytes as renal function markers in children. METHODS: On two consecutive days blood samples for duplicate analysis of cystatin C (nephelometric, Dade Behring) and creatinine (enzymatic, Roche) were obtained from 30 children (11 females and 19 males, mean age 8.3 range 2-13 years) referred for GFR measurements by (51)Cr-EDTA clearance. For determination of the between-subject variation only children with normal GFR (n=21) were included. Data were adjusted for the well known age-related increase in creatinine. RESULTS: The results are given as coefficients of variation. The within-subject variations were identical for both analytes (6.4%). The between-subject variation was 11.1% for cystatin C and 28.4% for creatinine, though decreasing to 20.1% after adjusting for age. The analytical variation was 1.7% and 2.5% for cystatin C and creatinine, respectively. The index of individuality (IOI = SD(I)/SD(G)) was 0.65 for cystatin C and 0.25 for creatinine, though increasing to 0.36 after age-adjustment. CONCLUSION: The within-subject variation was identical and low for cystatin C and creatinine suggesting that the two are equally suitable for serial monitoring of renal function in children. Based on the low IOI neither analyte, however, seems suitable as a screening marker of renal function in a healthy population of children using population-based reference intervals.

Biological variation of cystatin C and creatinine.

OBJECTIVE: To evaluate the day-to-day biological variation of cystatin C in comparison with creatinine in healthy subjects and in patients with impaired renal function. MATERIAL AND METHODS: Eight weekly morning blood samples were taken from 20 healthy subjects (13 females and 7 males, median age 44 years, range 25-61) and 19 patients with impaired renal function (8 females and 11 males, median age 61 years, range 35-70). Serum cystatin C was measured using Dade Behring N Latex Cystatin C assay and serum creatinine by an enzymatic method (Roche). RESULTS: In the healthy subjects mean serum cystatin C was 0.70 mg/L (range 0.44-1.09) and mean serum creatinine 77 micromol/L (range 54-100). The analytical variance was 2.0% for cystatin C and 1.6% for creatinine. The intra-individual variance was greater for cystatin C than for creatinine (8.6% vs. 4.7%). The inter-individual variance was similar for both analytes (cystatin C 15.1% vs. creatinine 14.4%). In the patients with impaired renal function mean serum cystatin C was 1.86 mg/L (range 0.45-3.31) and mean serum creatinine 224 micromol/L (range 103-430). The analytical variance was 1.8% for cystatin C and 1.4% for creatinine. The intra-individual variance was greater for cystatin C than for creatinine (16.0% vs. 8.9%). CONCLUSION: In the present study, the intra-individual variance was greater for cystatin C than for creatinine in both healthy subjects and in patients with impaired renal function. Accordingly, serum creatinine is the preferred marker for serial monitoring of renal function in individuals with stable muscle mass.

Stopped-flow kinetic analysis of long-chain fatty acid dissociation from bovine serum albumin.

The kinetics of the interaction of long-chain fatty acids (referred to as fatty acids) with albumin is critical to understanding the role of albumin in fatty acid transport. In this study we have determined the kinetics of fatty acid dissociation from BSA and the BSA-related fatty acid probe BSA-HCA (BSA labelled with 7-hydroxycoumarin-4-acetic acid) by stopped-flow methods. Fatty acid-albumin complexes of a range of natural fatty acid types and albumin molecules (donors) were mixed with three fatty acid-binding acceptor proteins. Dissociation of fatty acids from the donor was monitored by either the time course of donor fluorescence/absorbance or the time course of acceptor fluorescence. The results of these measurements indicate that fatty acid dissociation from BSA as well as BSA-HCA is well described by a single exponential function over the entire range of fatty acid/albumin molar ratios used in these measurements, from 0.5:1 to 6:1. The observed rate constants (k(obs)) for the dissociation of each fatty acid type reveal little or no dependence on the initial fatty acid/albumin ratio. However, dissociation rates were dependent upon the type of fatty acid. In the case of native BSA with an initial fatty acid/BSA molar ratio of 3:1, the order of k(obs) values was stearic acid (1.5 s(-1)) < oleic acid < palmitic acid congruent with linoleic acid

Paclitaxel and carboplatin adjuvant therapy alone or with radiotherapy for resected nonsmall cell lung carcinoma: a feasibility study of the Minnie Pearl Cancer Research Network.

BACKGROUND: The objective of this study was to determine the feasibility and toxicity of paclitaxel and carboplatin given in the adjuvant setting alone for patients with resected Stage IB disease and combined with radiotherapy for patients with resected Stages II and IIIA disease and selected patients with Stage IIIB and IV disease (Revised International System for Staging of Lung Cancer). METHODS: One hundred two patients with resected nonsmall cell lung carcinoma were treated in the postoperative period with 3 courses of paclitaxel 200 mg/m(2) intravenously (i.v.) over 1 hour and carboplatin area under the curve of 6 i.v. every 3 weeks for 3 courses. Patients with Stage IB received no further therapy, and those with higher stages also subsequently received radiotherapy plus concurrent weekly paclitaxel and carboplatin over 6 weeks. The median age was 61 years, with 56 men and 46 women, and the predominant histologic type was adenocarcinoma. Twenty pneumonectomies, 80 lobectomies, and 2 other procedures were performed. Ninety percent of the patients (92 of 102) received all 3 courses of adjuvant paclitaxel and carboplatin (84% received full doses). Seventy-three percent received full doses of radiotherapy and concurrent weekly chemotherapy (49 of 67 patients), and 14 others received greater than 75% of the radiotherapy and concurrent chemotherapy. RESULTS: Toxicity of the chemotherapy was mild with only three hospitalizations for neutropenia and fever and no treatment-related deaths. Severe hypersensitivity occurred in six patients (6%). Concurrent radiation therapy and weekly chemotherapy also was well tolerated with the exception of Grade 3-4 esophagitis observed in 27% (17 of 67 patients). Follow-up was short with a median of 10 months, and 65% of all patients remained progression free. CONCLUSIONS: Three courses of paclitaxel and carboplatin is tolerable, feasible, and can be delivered in most patients in the adjuvant setting. Subsequently, in higher stage patients, concurrent postoperative radiation therapy and weekly paclitaxel and carboplatin is well tolerated and delivered in most patients. Definitive prospective randomized Phase III adjuvant trials are warranted.

Weekly docetaxel in the treatment of elderly patients with advanced breast cancer: a Minnie Pearl Cancer Research Network phase II trial.

PURPOSE: To evaluate the efficacy and toxicity of docetaxel administered weekly to elderly or poor-performance status patients with advanced breast cancer. PATIENTS AND METHODS: Forty-one patients with advanced breast cancer who were either over the age of 65 or considered to be poor candidates for combination chemotherapy received docetaxel 36 mg/m2 weekly for 6 consecutive weeks, followed by 2 weeks without treatment. The median age of patients in this trial was 74 years, and 73% of patients had one or more visceral sites of metastases. Seventy-five percent of patients received weekly docetaxel as first-line treatment for metastatic breast cancer, and the other 25% received it as second-line treatment. Thirty-six patients were assessable for efficacy, and all patients were assessed for toxicity. RESULTS: A total of 448 doses of weekly docetaxel were administered to 41 patients. Thirteen patients (36%) had objective responses to treatment, and an additional 13 patients (36%) had stable disease or minor response. Median time to progression for responding and stable patients was 7 months (range, 3 to 27 months). Median survival for the entire group was 13 months, with 1- and 2-year actuarial survival rates of 61% and 29%, respectively. Severe neutropenia occurred in only 0.4% of courses, and no other hematologic toxicity was observed. Grade 3/4 fatigue was the most common toxicity, occurring in 20% of patients. CONCLUSION: Weekly docetaxel therapy is active and well tolerated by elderly and/or poor-performance status patients with advanced breast cancer. This treatment can be administered with minimal myelosuppression. Weekly docetaxel provides an additional option for treatment in this difficult subgroup of patients with metastatic breast cancer. Well-tolerated combination regimens containing weekly docetaxel merit evaluation for this patient population.

Stimulated secondary emission from semiconductor microcavities.

We find strong influence of final-state stimulation on the time-resolved light emission dynamics from semiconductor microcavities after pulsed excitation allowing angle-resonant polariton-polariton scattering on the lower-polariton branch. The polariton dynamics can be controlled by injection of final-state polaritons at densities below a polariton saturation density of 5x10(8) cm(-2). A bosonic enhancement factor in the dynamics of up to 700 is evaluated.

Taxane-based chemotherapy for patients with carcinoma of unknown primary site.

BACKGROUND: The purpose of this study was to determine the long-term follow-up on survival of patients with carcinoma of unknown primary site treated with taxane-based chemotherapy in a multicenter community-based setting. PATIENTS AND METHODS: Patients were treated with three sequential phase II trials between 1995 and 1998 as follows: Study I: paclitaxel 200 mg/m2 intravenously (i.v.) Day 1, carboplatin AUC = 6 i.v. Day 1, and oral etoposide 50 mg daily alternating with 100 mg daily days 1-10 every 3 weeks; Study II: docetaxel 75 mg/m2 i.v. Day 1, cisplatin 75 mg/m2 i.v. Day 1, repeated every 3 weeks; Study III: docetaxel 65 mg/m2 i.v. Day 1, carboplatin AUC 6 i.v. Day 1, repeated every 3 weeks. A total of 144 patients (71 on Study I, 26 on Study II, 47 on Study III) were treated (45% had well differentiated carcinoma, 48% had poorly differentiated carcinomas, and 6% poorly differentiated neuroendocrine tumors). The majority of the patients had multiple sites of metastatic disease. RESULTS: Thirty-six percent of all evaluable patients responded to therapy (27% partial and 9% complete responses). The median survival was 10 months with 1-, 2-, 3-, and 4-year survivals of 42%, 22%, 17%, and 17%, respectively. Follow-up ranges from 11 to 50 months. Women survived significantly longer than men. Thirty-one patients remain alive and 14 are progression-free. The primary toxicity was leukopenia with the carboplatin regimens and nausea and vomiting with the cisplatin regimen. A review of the survival of several large previously reported series of patients was compared to results after taxane-based chemotherapy. A compelling argument is made that chemotherapy is superior to best supportive care alone and that taxane-based chemotherapy is superior to other forms of chemotherapy. However, prospective randomized trials will be necessary to definitively demonstrate the superiority of this treatment compared to other therapies for these patients. CONCLUSION: Taxane-based chemotherapy for patients with carcinoma of unknown primary site appears to be clinically beneficial and is associated with long-term survival for a minority of patients at 2-, 3-, and 4-year follow-up.

Waveguiding in surface plasmon polariton band gap structures.

Using near-field optical microscopy, we investigate propagation and scattering of surface plasmon polaritons (SPP's) excited in the wavelength range of 780-820 nm at nanostructured gold-film surfaces with areas of 200-nm-wide scatterers arranged in a 400-nm-period triangular lattice containing line defects. We observe the SPP reflection by such an area and SPP guiding along line defects at 782 nm, as well as significant deterioration of these effects is 815 nm, thereby directly demonstrating the SPP band gap effect and showing first examples of SPP channel waveguides in surface band gap structures.