Local identifiability and sensitivity analysis of neuromuscular blockade and depth of hypnosis models.

This paper addresses the local identifiability and sensitivity properties of two classes of Wiener models for the neuromuscular blockade and depth of hypnosis, when drug dose profiles like the ones commonly administered in the clinical practice are used as model inputs. The local parameter identifiability was assessed based on the singular value decomposition of the normalized sensitivity matrix. For the given input signal excitation, the results show an over-parameterization of the standard pharmacokinetic/pharmacodynamic models. The same identifiability assessment was performed on recently proposed minimally parameterized parsimonious models for both the neuromuscular blockade and the depth of hypnosis. The results show that the majority of the model parameters are identifiable from the available input-output data. This indicates that any identification strategy based on the minimally parameterized parsimonious Wiener models for the neuromuscular blockade and for the depth of hypnosis is likely to be more successful than if standard models are used.

Clinical audit: Development of the criteria of good practices.

Clinical audit is a systematic review of the procedures in order to improve the quality and the outcome of patient care, whereby the procedures are examined against agreed standards for good medical RADIOLOGICAL procedures. The criteria of good procedures (i.e. the good practice) are thus the cornerstones for development of clinical audits: these should be the basis of assessments regardless of the type of the audit--external, internal, comprehensive or partial. A lot of criteria for good practices are available through the recommendations and publications by international and national professional societies and other relevant organisations. For practical use in clinical audits, the criteria need to be compiled, sorted out and agreed on for the particular aims of an audit (comprehensive or partial, external or internal). The national professional and scientific societies can provide valuable contribution to this development. For examination--or treatment-specific criteria--preliminary consensus needs to be obtained with the help of clinical experts, while clinical audits can be useful as a benchmarking tool to improve the criteria.

Docetaxel versus docetaxel alternating with gemcitabine as treatments of advanced breast cancer: final analysis of a randomised trial.

BACKGROUND: Alternating administration of docetaxel and gemcitabine might result in improved time-to-treatment failure (TTF) and fewer adverse events compared with single-agent docetaxel as treatment of advanced breast cancer. PATIENTS AND METHODS: Women diagnosed with advanced breast cancer were randomly allocated to receive 3-weekly docetaxel (group D) or 3-weekly docetaxel alternating with 3-weekly gemcitabine (group D/G) until treatment failure as first-line chemotherapy. The primary end point was TTF. RESULTS: Two hundred and thirty-seven subjects were assigned to treatment (group D, 115; group D/G, 122). The median TTF was 5.6 and 6.2 months in groups D and D/G, respectively (hazard ratio 0.85, 95% confidence interval 0.63-1.16; P = 0.31). There was no significant difference in time-to-disease progression, survival, and response rate between the groups. When adverse events were evaluated for the worst toxicity encountered during treatment, there was little difference between the groups, but when they were assessed per cycle, alternating treatment was associated with fewer severe (grade 3 or 4) adverse effects (P = 0.013), and the difference was highly significant for cycles when gemcitabine was administered in group D/G (P < 0.001). CONCLUSION: The alternating regimen was associated with a similar TTF as single-agent docetaxel but with fewer adverse effects during gemcitabine cycles.

Radiotherapy outcome and prognostic factors in early glottic carcinoma.

OBJECTIVE: To evaluate radiotherapy outcome and prognostic factors in early glottic carcinoma. METHODS: The medical records of 76 patients with glottic T1N0 or T2N0 squamous cell carcinoma diagnosed at Tampere University Hospital from 1970 to 1991 and treated with primary radiotherapy were retrospectively reviewed. Except for three patients treated during the last years of the study period, radiotherapy was delivered by split-course technique with a pause of 1-3 weeks in the middle of the treatment. Primary locoregional control and disease-specific survival were analysed by the Kaplan-Meier method, and the log rank test was applied to compare the survival functions. Prognostic factors were evaluated by uni- and multivariate Cox regression analysis. RESULTS: The 10-year locoregional control rate after radiotherapy was 83 and 48% for patients with T1 and T2 tumours, respectively (P = 0.0005). The 10-year disease-specific survival was 91% for T1 and 69% for T2 disease (P = 0.0018). The larynx could be preserved in 87% of T1 and 44% of T2 cases. Tumour extent expressed by the number of vocal cord thirds involved was the only factor with significant prognostic value in the multivariate analysis of primary locoregional control (hazard ratio (HR) 3.2, 95%CI 1.8-5.8, P = 0.0001). Involvement of the posterior vocal cord third (HR 8.4, 95%CI 1.0-69.5, P = 0.04899) and T-category (HR 3.0, 95% CI 0.9-10.2, P = 0.0790) were connected with poorer prognosis in the multivariate analysis of disease-specific survival. In the multivariate analysis of T1 cases only, higher number of vocal cord thirds involved (HR 5.9, 95%CI 2.2 16.2, P = 0.0005) and longer treatment duration (HR 1.1, 95%CI 1.0-1.3, P = 0.0188) indicated worse locoregional control. Treatment duration (HR 1.2, 95%CI 1.0-1.3, P = 0.0384) together with posterior cord involvement (HR 9.9, 95% CI 1.1-92.7, P= 0.0437) signified poorer survival. CONCLUSION: Our findings indicate that the extent of the tumour is the most important predictor of radiotherapy outcome in early glottic carcinoma. This suggests that a classification based on the actual size of the tumour could be a better prognostic indicator than the conventional T-grouping. Although treatment duration was significant only in separate analysis of T1 cases, the split-course regimen resulting in long treatment times may be considered a major contributor to our relatively low local control rate also in T2 disease.

DNA flow cytometry in surgically treated lung cancer--prognostic significance.

Although DNA aneuploidy and high proliferative activity (S-phase fraction, SPF) of tumour cells, measured by flow cytometry, have proved to be indicators of poor prognosis in most solid tumours, there have been conflicting results in lung cancer studies. During a four-year period we studied the prognostic significance of DNA ploidy and SPF in 99 surgically treated lung cancer patients. Flow cytometric analysis was done from archival, formalin-fixed, paraffin-embedded tumour specimens. DNA index and SPF were determined, using MultiCycle software with sliced nuclear correction to compensate for debris. There were 61 DNA diploid and 38 DNA aneuploid tumours. The median SPF was 10.2%. Neither ploidy nor SPF was associated with previously known prognostic factors. Survival was poorer in patients with aneuploid tumours than in the other patients, but the difference was not statistically significant. DNA ploidy and SPF thus do not seem to be useful prognostic indicators in surgically treated lung cancer.

Prognosis of surgically treated lung cancer.

BACKGROUND AND AIMS: This retrospective study clarifies the prognosis of surgically treated lung cancer in a teaching university hospital. MATERIAL AND METHODS: During a four year period 141 patients were operated for lung cancer in a teaching university hospital. After five years follow up the case records were analysed. The operative and microscopical findings were classified using the AJC pTNM staging system and WHO's histologic classification of lung tumours. There were 120 (85 %) male and 21 (15 %) female. The median age for males was 62 years and females 64 years; range was 29 to 76 years for both sexes. RESULTS AND CONCLUSIONS: The perioperative mortality of all patients was 5,0 %, of 84 patients operated with lobectomy 2.4 %, of 32 patients operated with pneumectomy 15,6 %, and of 25 patients operated with explorative thoracotomy 0 %, respectively. The five year survival of all patients was 33 % including perioperative mortality. The survival was significantly better for 83 patients with stage I disease (49 %) than 17 stage II (6 %), 24 stage IIIa (20.8 %), and 17 stage IIIb or IV disease (0 %). The survival was significantly better after lobectomy (44.1 %) than after pneumectomy (25.0 %) or explorative thoracotomy (8.0 %). Our study shows the good effect of surgery in stage I, and confirms it's usefulness in stage IIIa lung cancer. The histologic types of tumours did not affect survival.

Confirmation of a prognostic index for patients with inoperable non-small cell lung cancer.

BACKGROUND AND PURPOSE: The prognostic index derived from a group of 502 patients with inoperable stages I-IIIb non-small cell lung cancer (NSCLC) from 1974 to 1981 has been tested in an independent population of patients with NSCLC from 1989 to 1993 for the relationship between this index and survival. MATERIALS AND METHODS: This recent population comprised 210 patients treated with radiotherapy; for staging and treatment planning more advanced technology (CT-imaging, CT-based dose-planning) was used. The five most powerful determinants, established in the previous study, were disease extent, clinical symptom score by Feinstein, performance status, tumour size and haemoglobin level. These key prognostic variables of the index had equal impact on survival. Thus, based only on the number of adverse factors, the patient falls into one of the six possible prognostic groups. RESULTS: In the present study we verified with the new patient material that the index applies to patients with inoperable NSCLC. All five factors were significantly predictive of survival and the inclusion of the other known prognostic variables in the multivariate analyses did not result in any further improvement. Furthermore, the composite index turned out to be as informative as the five variables separately and the index discriminates effectively between the low and high risk groups. Ninety-eight patients (47%) with three or more risk factors had a 2-year survival rate of less than 2%, whereas 17 patients (8%) with no risk factor had a survival of 53% during a minimum follow up of 2 years. CONCLUSIONS: As each of the five variables has the advantage of being routinely available the index is simple and can easily be used to guide management in daily clinical practice. The scoring system may also help to design new treatment strategies and facilitate the comparison of different studies.

A practical prognostic index for inoperable non-small-cell lung cancer.

Radical radiotherapy is widely used to treat inoperable non-small-cell lung cancer (NSCLC) although only a small number of patients benefit in the long run from this intensive treatment. There is a small proportion of long-term survivors who might derive advantage from even more aggressive radiotherapy combined with chemotherapy. In order to support optimal treatment selection we have carried out univariate and multivariate analyses of possible prognostic variables in the retrospective data of 502 NSCLC patients treated at one institute with external radiotherapy, both with curative and palliative intent. To obtain more accurate tools for a rational treatment decision, we identified, by using Cox's proportional-hazards model, the five most powerful determinants of overall survival and combined them to a prognostic index. On the basis of only the number of these risk factors (advanced stage, general or metastatic symptoms, poor performance status, anemia and tumor size of at least 7 cm), the patient falls into one of the six possible prognostic groups and these groups turned out to be identifiable as separate prognostic clusters. Thirty-one per cent of the patients have three or more risk factors and a median survival of 5-7 months compared with 18 months for patients without any non-favorable factor. Furthermore, the prognostic factors were so strong that multivariate analyses did not reveal the treatment selection to have any significant influence on survival. As each of the five variables have the advantage of being routinely available, our index is simple enough to be used in daily clinical practice. The clinical value of the prognostic index should be verified by using independent data.

Evaluation of a decision-support system for inoperable non-small cell lung cancer.

The purpose of this study was to find out whether a decision-support system is able to assist a clinician in predicting patient outcome and in selecting optimal treatment in oncology. The domain of the evaluated decision-support prototype was primary therapeutic decision making in inoperable non-small cell lung cancer. The performance of the prototype was tested on retrospective material consisting of 112 patients treated by radiotherapy. Survival was the endpoint for examining whether the treatment decision proposed by the system was more accurate than the decision actually made by the clinician. Certain prognostic variables were used by the system to classify patients into two treatment groups, radical or palliative radiotherapy. The median survival times of these groups were 15 and 7 months, respectively, compared with 9 and 8 months in the corresponding groups classified by the clinician. Our results indicate that clinicians need support in treatment selection and that decision-support systems could be a potential answer.

Radical radiotherapy of inoperable non-small cell lung cancer. Irradiation techniques and tumor characteristics in relation to local control and survival.

The relation between tumor characteristics, irradiation technique, local tumor control and survival was retrospectively studied in 323 patients with non-small cell lung cancer who started radical radiotherapy in 1974-1981. At that time three non-randomized different fractionation schedules were used: 16 x 3.25 Gy, total dose 52 Gy, 3 fractions/week (schedule 1), 11 x 4 Gy, total dose 44 Gy, 2 fractions/week (schedule 2) and 25 x 2 Gy, total dose 50 Gy, 5 fractions/week (schedule 3). The highest survival rates were observed in the patient group treated according to schedule 2. The 2-year survival rate was 30% compared with 18% and 6% in the patients treated according to schedule 1 and 3 respectively. However, this can at least partly be explained by patient selection. A correlation between size of the tumor, target volume and survival was observed: the larger the tumor, the poorer the survival. Pleural effusion showed to be an unfavorable prognostic factor. The prognosis of inoperable lung cancer on the whole remained poor: the 1-year survival rate was 43% and 2-year survival rate 16%. Only 3% of the patients lived at least five years.

Correlation between serum tumor marker levels and tumor proliferation in small cell lung cancer.

We analyzed serum lactate dehydrogenase (LDH), neuron-specific enolase (NSE) and thymidine kinase (TK) levels in 22 patients with small cell lung cancer. Tumor proliferation was expressed as the proportion of S-phase cells (SPF), determined by DNA flow cytometry, from concomitantly taken biopsy samples. A positive correlation between serum NSE (r = 0.41) or LDH (r = 0.65, p = 0.05) levels and tumor SPF was noted, but was not found between serum TK levels and the SPF. The correlation between NSE and SPF was even more pronounced if only patients with extensive disease were considered (r = 0.77). The serum NSE and LDH, but not TK levels, were significantly greater in the patients with extensive disease (NSE 50.4 ng/ml, LDH 621 U/ml) compared to the patients with limited disease (NSE 21.0 ng/ml, LDH 272 U/ml, p = 0.05). Our results suggest that the combined determination of serum LDH and NSE levels gives valuable data on the primary tumor mass and its proliferative activity in small cell lung cancer.