Evaluation of antenatal umbilical coiling index at 16-21 weeks of gestation as a predictor of trisomy 21 and other chromosomal defects.

OBJECTIVES: To determine whether there is an association between sonographically assessed hyper- or hypocoiling of the umbilical cord and the presence of trisomy 21, to provide reference values for the antenatal umbilical coiling index (aUCI) at a gestational age of 16-21 weeks and to determine whether these measurements are reliable and reproducible. METHODS: This was a prospective study of 737 pregnancies in which the aUCI was measured between 16 and 21 weeks of gestation by ultrasound at the time of amniocentesis. The aUCI was calculated as the reciprocal value of the mean length of one complete coil in centimeters. We created reference curves and studied the relationship with trisomy 21 and other chromosomal defects. In 30 pregnancies we studied the intra- and interobserver variation in measurements using Bland-Altman plots with associated 95% limits of agreement and intraclass correlation coefficients. RESULTS: aUCI was found to be non-linearly related to gestational age at 16-21 weeks and reference curves were created for the mean aUCI and the 2.3(rd) , 10(th) , 90(th) and 97.7(th) percentiles. There was no significant difference in aUCI values between the reference group (n = 714) and cases with trisomy 21 (n = 16) or other aneuploidies (n = 7) (one-way ANOVA, P = 0.716). There was good intra- and interobserver agreement in aUCI measurements. CONCLUSIONS: The aUCI can be measured reliably and varies according to gestational age at 16-21 weeks. The aUCI was not significantly associated with trisomy 21 or other chromosomal defects.

Impact of nationwide centralization of pancreaticoduodenectomy on hospital mortality.

BACKGROUND: The impact of nationwide centralization of pancreaticoduodenectomy (PD) on mortality is largely unknown. The aim of this study was to analyse changes in hospital volumes and in-hospital mortality after PD in the Netherlands between 2004 and 2009. METHODS: Nationwide data on International Classification of Diseases, ninth revision (ICD-9) code 5-526 (PD, including Whipple), patient age, sex and mortality were retrieved from the independent nationwide KiwaPrismant registry. Based on established cut-off points of annually performed PDs, hospitals were categorized as very low (fewer than 5), low (5-10), medium (11-19) or high (at least 20) volume. A subgroup analysis based on a cut-off age of 70 years was also performed. RESULTS: Some 2155 PDs were included. The number of hospitals performing PD decreased from 48 in 2004 to 30 in 2009 (P = 0·011). In these specific years, the proportion of patients undergoing PD in a medium- or high-volume centre increased from 52·9 to 91·2 per cent (P < 0·001). Nationwide mortality rates after PD decreased from 9·8 to 5·1 per cent (P = 0·044). The mortality rate during the 6-year period was 14·7, 9·8, 6·3 and 3·3 per cent in very low-, low-, medium- and high-volume hospitals respectively (P < 0·001). The difference in mortality between medium- and high-volume centres was statistically significant (P = 0·004). The volume-outcome relationship was not influenced by age (P = 0·467). The mortality rate after PD in patients aged at least 70 years was 10·4 per cent compared with 4·4 per cent in younger patients (P < 0·001). CONCLUSION: With nationwide centralization of PD, the in-hospital mortality rate after this procedure decreased. Further centralization of PD is likely to decrease mortality further, especially in the elderly.

Two-protein signature of novel serological markers apolipoprotein-A2 and serum amyloid alpha predicts prognosis in patients with metastatic renal cell cancer and improves the currently used prognostic survival models.

BACKGROUND: In metastatic renal cell cancer (mRCC), the Memorial Sloan-Kettering Cancer Center (MSKCC) risk model is widely used for clinical trial design and patient management. To improve prognostication, we applied proteomics to identify novel serological proteins associated with overall survival (OS). PATIENTS AND METHODS: Sera from 114 mRCC patients were screened by surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF MS). Identified proteins were related to OS. Three proteins were subsequently validated with enzyme-linked immunosorbent assays and immunoturbidimetry. Prognostic models were statistically bootstrapped to correct for overestimation. RESULTS: SELDI-TOF MS detected 10 proteins associated with OS. Of these, apolipoprotein A2 (ApoA2), serum amyloid alpha (SAA) and transthyretin were validated for their association with OS (P = 5.5 x 10(-9), P = 1.1 x 10(-7) and P = 0.0004, respectively). Combining ApoA2 and SAA yielded a prognostic two-protein signature [Akaike's Information Criteria (AIC) = 732, P = 5.2 x 10(-7)]. Including previously identified prognostic factors, multivariable Cox regression analysis revealed ApoA2, SAA, lactate dehydrogenase, performance status and number of metastasis sites as independent factors for survival. Using these five factors, categorization of patients into three risk groups generated a novel protein-based model predicting patient prognosis (AIC = 713, P = 4.3 x 10(-11)) more robustly than the MSKCC model (AIC = 729, P = 1.3 x 10(-7)). Applying this protein-based model instead of the MSKCC model would have changed the risk group in 38% of the patients. CONCLUSIONS: Proteomics and subsequent validation yielded two novel prognostic markers and survival models which improved prediction of OS in mRCC patients over commonly used risk models. Implementation of these models has the potential to improve current risk stratification, although prospective validation will still be necessary.

Yttrium-90 microsphere radioembolization for the treatment of liver malignancies: a structured meta-analysis.

Radioembolization with yttrium-90 microspheres ((90)Y-RE), either glass- or resin-based, is increasingly applied in patients with unresectable liver malignancies. Clinical results are promising but overall response and survival are not yet known. Therefore a meta-analysis on tumor response and survival in patients who underwent (90)Y-RE was conducted. Based on an extensive literature search, six groups were formed. Determinants were cancer type, microsphere type, chemotherapy protocol used, and stage (deployment in first-line or as salvage therapy). For colorectal liver metastases (mCRC), in a salvage setting, response was 79% for (90)Y-RE combined with 5-fluorouracil/leucovorin (5-FU/LV), and 79% when combined with 5-FU/LV/oxaliplatin or 5-FU/LV/irinotecan, and in a first-line setting 91% and 91%, respectively. For hepatocellular carcinoma (HCC), response was 89% for resin microspheres and 78% for glass microspheres. No statistical method is available to assess median survival based on data presented in the literature. In mCRC, (90)Y-RE delivers high response rates, especially if used neoadjuvant to chemotherapy. In HCC, (90)Y-RE with resin microspheres is significantly more effective than (90)Y-RE with glass microspheres. The impact on survival will become known only when the results of phase III studies are published.

Inter- and intra-observer agreement of intrapartum ST analysis of the fetal electrocardiogram in women monitored by STAN.

OBJECTIVE: The objective of this study was to quantify inter- and intra-observer agreement on classification of the intrapartum cardiotocogram (CTG) and decision to intervene following STAN guidelines. DESIGN: A prospective, observational study. SETTING: Obstetrics Department of a tertiary referral hospital. POPULATION: STAN recordings of 73 women after 36 weeks of gestation with a high-risk pregnancy, induced or oxytocin-augmented labour, meconium-stained amniotic fluid or epidural analgesia. METHODS: Six observers classified 73 STAN recordings and decided if and when they would suggest an intervention. Proportions of specific agreement (Ps) and kappa values (Kappa) were calculated. MAIN OUTCOME MEASURES: Agreement upon classification of the intrapartum CTG and decision to perform an intervention. RESULTS: Agreement for classification of a normal and a (pre)terminal CTG was good (Ps range 0.50-0.84), but poor for the intermediary and abnormal CTG (Ps range 0.34-0.56). Agreement on the decision to intervene was higher, especially on the decision to perform 'no intervention' (Ps range 0.76-0.94). Overall inter-observer agreement on the decision to intervene was considered moderate in five of six observer combinations according to the kappa (Kappa range 0.42-0.73). Intra-observer agreement for CTG classification and decision to intervene was moderate (Kappa range 0.52-0.67 and 0.61-0.75). CONCLUSIONS: Inter-observer agreement on classification of the intrapartum CTG is poor, but addition of information regarding fetal electrocardiogram, especially in case of intermediary or abnormal CTG traces, results in a more standardised decision to intervene.

New algorithm for treatment allocation reduced selection bias and loss of power in small trials.

OBJECTIVE: In clinical trials, patients become available for treatment sequentially. Especially in trials with a small number of patients, loss of power may become an important issue, if treatments are not allocated equally or if prognostic factors differ between the treatment groups. We present a new algorithm for sequential allocation of two treatments in small clinical trials, which is concerned with the reduction of both selection bias and imbalance. STUDY DESIGN AND SETTING: With the algorithm, an element of chance is added to the treatment as allocated by minimization. The amount of chance depends on the actual amount of imbalance of treatment allocations of the patients already enrolled. The sensitivity to imbalance may be tuned. We performed trial simulations with different numbers of patients and prognostic factors, in which we quantified loss of power and selection bias. RESULTS: With our method, selection bias is smaller than with minimization, and loss of power is lower than with pure randomization or treatment allocation according to a biased coin principle. CONCLUSION: Our method combines the conflicting aims of reduction of bias by predictability and reduction of loss of power, as a result of imbalance. The method may be of use in small trials.

Sonographic longitudinal cervical length measurements in nulliparous women at term: prediction of spontaneous onset of labor.

OBJECTIVE: The aim of this study was to predict spontaneous onset of labor by serial transvaginal ultrasound measurement of cervical length (CL) in a homogeneous population of nulliparous women at term. METHODS: 162 nulliparous women with singleton fetuses in cephalic presentation were examined at weekly intervals from 36 weeks' gestation to delivery. CL was measured by transvaginal ultrasound in the supine and upright positions. RESULTS: There was a significant decrease in CL in the last 12 days prior to delivery. However, this decrease was small with substantial variation between individuals. Women with spontaneous onset of labor could be divided into three different groups: those with unchanged CL before delivery; those with a fall in CL in the last 2 weeks prior to delivery; and those with a gradual change in CL starting before the last 2 weeks prior to delivery. A single CL measurement below 30 mm between 37 and 38 weeks of gestation predicted spontaneous onset of labor before 41 weeks' gestation with a sensitivity of 46%, specificity of 78%, positive predictive value (PPV) of 82%, negative predictive value (NPV) of 40% in the supine position; and sensitivity of 53%, specificity of 72%, PPV of 81%, NPV of 40% in the upright position. CONCLUSION: Between 37 and 38 weeks' gestation, spontaneous onset of labor before 41 weeks can be predicted by a CL measurement, but with low sensitivity and NPV. Inter-individual variations in CL and in CL changes are large, which hampers the value of single and repeated CL measurements for the prediction of spontaneous onset of labor at term.

[Less ventilator-associated pneumonia after oral decontamination with chlorhexidine; a randomised trial]. / Minder beademingspneumonieën door orale decontaminatie met chloorhexidine; gerandomiseerde trial.

OBJECTIVE: To determine the effect of oral decontamination with either chlorhexidine (CHX, 2%) or the combination chlorhexidine-colistin (CHX-COL, 2%-2%) on the frequency and the time to onset of ventilator-associated pneumonia in Intensive Care patients. DESIGN: Double blind, placebo-controlled, multicentre, randomised trial. METHODS: Consecutive ICU patients needing at least 48 h of mechanical ventilation were enrolled in a randomized trial with 3 arms: CHX, CHX-COL, and placebo (PLAC). The trial medication was administered in the oral cavity every 6 h. Oropharyngeal swabs were obtained daily and analysed quantitatively for Gram-positive and Gram-negative microorganisms. Endotracheal colonisation was monitored twice weekly. Ventilator-associated pneumonia was diagnosed on the basis of a combination of clinical, radiological and microbiological criteria. RESULTS: Of 385 patients included, 130 received PLAC, 127 CHX and 128 CHX-COL. Baseline characteristics in the three groups were comparable. The daily risk of ventilator-associated pneumonia was reduced in both treatment groups compared to PLAC: 65% (HR= 0.352; 95% CI: 0.160-0.791; p = 0.012) for CHX and 55% (HR= 0.454; 95%/ CI: 0.224-0.925; p = 0.030) for CHX-COL. CHX-COL provided a significant reduction in oropharyngeal colonisation with both Gram-negative and Gram-positive microorganisms, whereas CHX significantly affected only colonisation with Gram-positive microorganisms. There were no differences in the duration of mechanical ventilation, ICU-stay or ICU-survival. CONCLUSION: Oral decontamination of the oropharyngeal cavity with chlorhexidine or the combination chlorhexidine-colistin reduced the incidence and the time to onset ofventilator-associated pneumonia.

Nonrandom ventricular rhythm in horses with atrial fibrillation and its significance for patients.

RR interval sequences during spontaneous atrial fibrillation in eight horses were analyzed as in previous studies in patients and dogs using histograms and serial auto-correlograms. In patients and dogs with spontaneous atrial fibrillation, ventricular rhythms were always random. In the horses, the histograms were skewed with median RR intervals of approximately 1,000 ms. A striking finding in these animals was the presence of long RR intervals up to 5,000 ms in duration. The shortest RR intervals lasted 400 to 600 ms. In contrast to findings in dogs and patients, the serial autocorrelograms showed periodicity that was reenforced by digitalis (n = 3), but eliminated by quinidine (n = 2) and atropine (n = 2). Quinidine and atropine eliminated the longer RR intervals, whereas digitalis increased the number of long RR intervals. In one horse, it was possible to measure intraarterial pressure, and large fluctuations in pressure were observed as the RR intervals varied from over 3,000 to less than 500 ms. It is postulated that these changes in blood pressure are associated with baroreceptor responses that may alter the electrophysiologic behavior of the atria and atrioventricular node. These changes cause the nonrandom patterns of ventricular rhythm in the horse. Because such very long RR intervals do not occur in human beings or dogs during atrial fibrillation, the random ventricular rhythm in these groups is maintained even during digitalis treatment.

Role of atrial fibrillation and atrioventricular conduction (including Wolff-Parkinson-White syndrome) in sudden death.

A short refractory period of the accessory pathway is considered a major threat for sudden death in patients with Wolff-Parkinson-White syndrome and atrial fibrillation. RR interval and QRS signal analysis together with signal analysis of a bipolar high right atrial electrogram were obtained in six patients with Wolff-Parkinson-White syndrome and either induced or spontaneous atrial fibrillation. A record of a sufficiently long episode of atrioventricular (AV) conduction by way of the bypass tract that could be used for satisfactory RR interval sequence and QRS analysis was obtained from only one patient. The results were compared with those of a representative patient with atrial fibrillation and normal AV nodal-His conduction. In a patient with Wolff-Parkinson-White syndrome, atrial fibrillation and AV conduction by way of the bypass tract may exhibit high ventricular rates (median RR intervals of about 300 ms) and long/short RR interval ratios of just over 1 (RR intervals not exceeding 400 ms). The right atrial electrogram showed a noiselike excitation pattern. This study suggests that rather than a short refractory period of the bypass tract, it is lack of concealed conduction, responsible for the presence of long RR intervals, that allows the ventricles to reach very high ventricular rates and at times to fibrillate. The normal AV nodal-His system seems to protect the heart against high ventricular rates and ventricular fibrillation during atrial fibrillation by its relatively long refractory period and capacity to induce long RR intervals by means of concealed conduction.

Comparison of two once-daily regimens with a regimen consisting of nelfinavir, didanosine, and stavudine in antiretroviral therapy-naïve adults: 48-week results from the Antiretroviral Regimen Evaluation Study (ARES).

BACKGROUND: To improve the dosing frequency and pill burden of antiretroviral therapy, we compared two once-daily dosed regimens to a twice-daily dosed regimen. METHOD: HIV-1-infected, antiretroviral drug-naïve adults were randomized to either twice-daily nelfinavir and stavudine and once-daily didanosine (regimen A) or simplified once-daily dosed antiretroviral regimens consisting of nevirapine, didanosine, and lamivudine (regimen B) or saquinavir, ritonavir, didanosine, and lamivudine (regimen C). RESULTS: At 48 weeks of therapy, the proportion of patients with a blood plasma HIV-1 RNA concentration (pVL) <50 copies/mL by intention-to treat analysis was 42.3%, 50.0%, and 56.5% for regimens A (n = 26), B (n = 22), and C (n = 23), respectively. The time to a pVL <50 copies/mL for the first time was significantly shorter in regimen C, and there was significantly more progression to CDC events in regimen B. These differences are possibly due to differences in baseline characteristics. Adverse events were lowest for regimen C; more signs associated with mitochondrial toxicity occurred in regimen A. Increase in CD4 count was comparable between arms. CONCLUSION: No statistically significant difference in efficacy was found between the two investigated once-daily dosed treatment regimens (B and C) and the reference (A). Regimen C possibly had a better virological response and less toxicity than regimens A and B.

Comparison of LysB28, ProB29-human insulin analog and regular human insulin in the correction of incidental hyperglycemia.

OBJECTIVE: To obtain clinically applicable data on the effects of regular human insulin and the LysB28,ProB29-human insulin analogue (lispro) on the correction of incidental hyperglycemia. RESEARCH DESIGN AND METHODS: The insulins were compared in a non-clamped randomized crossover study of 27 male IDDM patients. Hyperglycemia was induced by the withdrawal of the normal evening dose of insulin; the next morning patients fasted and received a single dose of study insulin according to a dosing nomogram. Blood glucose concentration and GR (a measure of glucose corrected for differences in administered insulin dose: GR = glucose concentration X BMI X insulin dose-1) were followed for 4 h. RESULTS: The time courses of blood glucose concentration and GR were significantly different after regular insulin in comparison with lispro (multiple analysis of variance, P < 0.001). At t = 120 min, glucose concentrations had decreased 1.4 mmol/l more with lispro than with regular insulin (95% confidence interval [CI] 0.6-2.3, P = 0.002). Similarly, GR had decreased 4.4 mol.kg.IU-1.m-5 more with lispro than with regular insulin (95% CI 2.6-6.2, P < 0.001). The overall difference in glucose values was 0.87 mmol/l (lispro < regular insulin, P = 0.036), and the overall difference in GR values was 1.96 mol.kg.IU-1.m-5 (lispro < regular insulin, P = NS). Unexpectedly, the intrinsic variability of GR was higher for lispro than for regular insulin. CONCLUSIONS: The more rapid action of lispro is an advantage in the correction of hyperglycemia, even though actual differences in glucose concentrations are smaller than suggested by previous clamped studies.

Acute toxicity of concurrent adjuvant radiotherapy and chemotherapy (CMF or AC) in breast cancer patients. a prospective, comparative, non-randomised study.

The concurrent administration of adjuvant chemotherapy and radiotherapy in breast cancer treatment might lead to an increased incidence of side-effects. In this prospective, non-randomised, comparative study, the acute toxicity of radiotherapy alone (RT) and radiotherapy concurrent with doxorubicin-cyclophosphamide (AC/RT) and radiotherapy concurrent with cyclophosphamide-methotrexate-5-fluorouracil (CMF/RT) was compared. We used the common toxicity criteria (CTC) to score the level of acute toxicity before, during and 6 months after the completion of the period of irradiation. The number of hospital admissions, as well as the compliance of chemotherapy, were noted. We observed that patients treated with AC/RT and CMF/RT had significant higher incidences of (high-grade) skin-toxicity, oesophagitis, dyspnoea, malaise, anorexia, nausea and hospital admission compared with those treated with RT only. The target-volume of radiotherapy was the main predictor of (high-grade) acute skin toxicity and oesophagitis. AC/RT was associated with significant more (high-grade) skin toxicity than CMF/RT. The dose of chemotherapy was reduced to less than 85% of the planned dose in 11% of patients, 17% of patients treated with concurrent chemotherapy and radiotherapy needed admission to hospital. From the results of our study, we conclude that the concurrent administration of adjuvant chemotherapy and radiotherapy leads to an unacceptably high level of acute toxicity.

Radiotherapy in T1 laryngeal cancer: prognostic factors for locoregional control and survival, uni- and multivariate analysis.

From 1975 through 1985, 194 patients with T1 glottic, 37 patients with T1 supraglottic, and 3 patients with T1 subglottic cancer were treated with radiotherapy. Local control and ultimate locoregional control (after salvage surgery) was 91% and 97% for T1 glottic, 84% and 81% for T1 supraglottic, and 2/3 and 3/3, respectively for subglottic tumors. In uni- and multivariate analysis local control for glottic tumors was associated with extension of the tumor on the vocal cord (entire length of vocal cord vs others, p = 0.01) and continuation of smoking after therapy (yes/no, p = 0.03). No prognostic factor for local control was found in supraglottic tumors. However, regional control and survival were impaired by N stage (N0 vs N+, p less than 0.0005), local recurrence (yes/no, p less than 0.0005), and extension of the tumor (one supraglottic subsite vs more than one, p less than 0.05). Mild late complications were seen in 13% of patients without salvage therapy. Following univariate analysis, field size, fraction size (greater than 2 Gy), maximum tumor dose (greater than 70 Gy), age, post-treatment biopsy, and tumor site were associated with complication rate. Following multivariate analysis, site, fraction size, maximum tumor dose, and continuation of smoking after therapy were independent prognostic factors for mild late complications (mostly arytenoid edema).

Cataract-free interval and severity of cataract after total body irradiation and bone marrow transplantation: influence of treatment parameters.

PURPOSE: To determine prospectively the cataract-free interval (latency time) after total body irradiation (TBI) and bone marrow transplantation (BMT) and to assess accurately the final severity of the cataract. METHODS AND MATERIALS: Ninety-three of the patients who received TBI as a part of their conditioning regimen for BMT between 1982 and 1995 were followed with respect to cataract formation. Included were only patients who had a follow-up period of at least 23 months. TBI was applied in one fraction of 8 Gy or two fractions of 5 or 6 Gy. Cataract-free period was assessed and in 56 patients, who could be followed until stabilization of the cataract had occurred, final severity of the cataract was determined using a classification system. With respect to final severity, two groups were analyzed: subclinical low-grade cataract and high-grade cataract. Cataract-free period and final severity were determined with respect to type of transplantation, TBI dose, and posttransplant variables such as graft versus host disease (GVHD) and steroid treatment. RESULTS: Cataract incidence of the analyzed patients was 89%. Median time to develop a cataract was 58 months for autologous transplanted patients. For allogeneic transplanted patients treated or not treated with steroids, median times were 33 and 46 months, respectively. Final severity was not significantly different for autologous or allogeneic patients. In allogeneic patients, however, final severity was significantly different for patients who had or had not been treated with steroids for GVHD: 93% versus 35% high-grade cataract, respectively. Final severity was also different for patients receiving 1 x 8 or 2 x 5 Gy TBI, from patients receiving 2 x 6 Gy as conditioning therapy: 33% versus 79% high-grade cataract, respectively. The group of patients receiving 2 x 6 Gy comprised, however, more patients with steroid treatment for GVHD. So the high percentage of high-grade cataract in the 2 x 6 Gy group might also have been caused to a significant extent by steroid treatment. The percentage of patients with high-grade cataract was lower in allogeneic transplanted patients without steroid treatment for GVHD than in autologous transplanted patients: 35% versus 48%. An explanation for this could be pretransplant therapy containing high-dose steroids. CONCLUSIONS: After high-dose-rate TBI in one or two fractions, steroids for GVHD influence latency time of a cataract and are of great importance for the severity the cataract finally attains. Although a cataract will develop in all patients, a clinically important high-grade cataract is relatively infrequent in patients not treated with steroids. Pretransplant therapy might also influence final severity of cataract.

Interrelationships of DNA-ploidy and cell proliferation markers with T-stage and N-stage in primary laryngeal tumors.

PURPOSE: The purpose of this study was to evaluate the interrelationships of DNA-ploidy and cell proliferation markers with T-stage and N-stage in primary laryngeal tumors. METHODS AND MATERIALS: DNA-index, S-phase fraction (SPF), 5-bromo-2'-deoxy-uridine (BrdUrd)-labeling index (LI), duration of S-phase (Ts), and potential doubling time (Tpot) were determined by flow cytometry. T-stage and N-stage were assessed in accordance with the TNM classification system (UICC 1987). RESULTS: T1-2-, when compared with T3-4-stage tumors, had significantly higher LI values (independent from N-stage) resulting in lower Tpot values. No such relationship was found with respect to N-stage. N1-3 tumors, as opposed to NO tumors, appeared to be characterized by a significantly shorter Ts (and, hence, a shorter Tpot). Ts values appeared to vary considerably (range 1.9-6.2 h). For DNA-aneuploidy, as opposed to DNA-diploidy, a significantly higher geometric mean LI was noted. Locally advanced (T3-4) tumors, when compared with T1-2 tumors, were characterized by a significantly higher percentage of DNA-aneuploidy. CONCLUSIONS: The reported lack of prognostic relevance of cell proliferation markers to predict radiation treatment efficacy may relate to a decreased proliferative capacity (LI, Tpot) in locally advanced (T3-4) tumors, as found in our series. In laryngeal tumors, the predictive value of cell proliferation markers (LI, Tpot) should, therefore, be evaluated after stratification for T-stage. The existence of higher LI values in DNA-aneuploidy tumors was confirmed in our series, stressing the need for distinction of DNA-diploid tumor cells from DNA-diploid normal cells. The prognostic potential of DNA-index was confirmed.

Prognostic significance of cell proliferation markers and DNA-ploidy in head and neck tumors.

PURPOSE: The purpose of this study was to evaluate the prognostic significance of cell proliferation markers and DNA ploidy in patients with a squamous cell carcinoma of the head and neck region. METHODS AND MATERIALS: With flow cytometry, DNA index, G1PF-phase fraction (G1PF), S-phase fraction (SPF), 5-bromo-2'-deoxy-uridine (BrdUrd) labeling-index (LI), and potential doubling time (Tpot), were determined. T-stage and N-stage were assessed in accordance with the TNM classification system (UICC 1987). RESULTS: After multivariate analysis, it appeared that the probability of locoregional recurrent disease was increased by (a) T4-stage, (b) high values of the ratio SPF to LI, (c) DNA tetraploidy. Prognostic significance G1PF for SPF, LI, and Tpot was not demonstrated. However, the treatment regimen was not uniform for the total group of 103 patients. In 45 patients treated with radiation as single treatment and in 49 patients treated with postoperative radiotherapy, prognostic significance for G1PF, SPF, LI, and Tpot could not be demonstrated either. Separate statistical analysis was not executed for nine patients, treated by surgery alone. CONCLUSIONS: Prognostic significance could not be demonstrated for Tpot, LI, SPF, and G1PF in our series. The ratio of SPF to LI was found to be a promising prognosticator and is regarded to be indicative for the size of the hypoxic fraction. Prognostic significance for DNA ploidy was confirmed.

Application of a sequential t-test in a cohort nested case-control study with multiple controls per case.

Application of sequential analysis may avoid unnecessary experimentation and achieve economical use of available biomaterial stored in biological banks. When, as often happens in cohort case-controls studies, cases are scarce, it may be possible to use multiple control observations per case to increase the power of a test for detecting differences between cases and controls. Samples from a biological data bank were analysed. We compared results of a non-sequential analysis with results of sequential t-tests for 1 to 5 controls matched per case in a cohort nested case-control study. Simulations are performed to get an idea of the unreliability and the power of the sequential test. In general the sequential t-tests are too conservative with respect to the achieved power. Average sample numbers are lower for the sequential tests and decrease with multiple controls. More than 3 or 4 controls per case does not give a meaningful increase in efficiency.

Quality of life: patients and doctors don't always agree: a meta-analysis.

OBJECTIVE: In addition to traditional clinical markers, quality-of-life assessment can be helpful to estimate the well-being of patients. Discrepancies in perception of well-being between physicians and patients may interfere with the effectiveness of treatment. A systematic review and meta-analysis were performed to explore the (dis-)agreement in quality-of-life assessments between patients and physicians. STUDY DESIGN AND SETTING: Data on the proportion agreement of paired observations were collected from Medline, Embase, Psychlit, and Social Abstracts. RESULTS: Of the 1,316 articles found, six met the selection criteria, four studied the proportion agreement between children and physicians, and all six the proportion agreement between parents and physicians. None examined the magnitude of over- or underestimation by physicians. The agreement was lower in the more subjective domains (0.54-0.77) in comparison to the more objective domains (0.79-0.94). CONCLUSION: Quality-of-life assessment should be integrated in clinical practice. During long-term treatment the perception of the patients' well-being by physicians and patients themselves can easily diverge from each other, resulting in misunderstandings about the treatment and its usefulness in relation to perceived quality of life, and may even become the base for noncompliance.

Extensive cryoablation of the left ventricular posterior papillary muscle and subjacent ventricular wall. Impact on mitral valve function and hemodynamics.

Ventricular tachycardias that originate from the inferior left ventricular wall may necessitate transmural ablation involving the posterior papillary muscle of the mitral valve. The effect on mitral valve function and hemodynamics of extensive cryoablation of the left ventricular posterior papillary muscle and subjacent ventricular wall was studied in 16 dogs. Two sham experiments were done. All dogs were studied preoperatively and postoperatively by pulsed Doppler and two-dimensional echocardiography. Left ventricular angiographic and hemodynamic studies were performed preoperatively in six treated dogs and two control dogs and in all dogs at the end of follow-up (1, 3, or 6 months). Postmortem studies were performed in all dogs. The cumulative probability of freedom from mitral regurgitation at 2 months was 0.43 +/- 0.14. Thereafter no new cases of mitral regurgitation could be demonstrated. The angiographic degree of mitral regurgitation was mild in five and moderate in two dogs and did not increase from 3 to 6 months. One dog with acute severe mitral regurgitation died early of heart failure. A significant increase in left ventricular end-diastolic and mean pulmonary capillary wedge pressure of 9.4 +/- 2.5 mm Hg and 6.4 +/- 2.6 mm Hg, respectively, was found in treated dogs at 3 months. These results suggest that extensive cryoablation of the left ventricular posterior papillary muscle and subjacent ventricular wall can be accomplished with an acceptable risk of mild to moderate mitral regurgitation, and without serious detrimental effect on left ventricular function. Retraction is probably the main mechanism of mitral regurgitation.