Tiina Luukkaala

2-weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer: a randomised, phase 3 trial

BACKGROUND Docetaxel administered every 3 weeks is a standard treatment for castration-resistant advanced prostate cancer. We hypothesised that 2-weekly administration of docetaxel would be better tolerated than 3-weekly docetaxel in patients with castration-resistant advanced prostate cancer, and did a prospective, multicentre, randomised, phase 3 study to compare efficacy and safety. METHODS Eligible patients had advanced prostate cancer (metastasis, a prostate-specific-antigen test result of more than 10·0 ng/mL, and WHO performance status score of 0-2), had received no chemotherapy (except with estramustine), had undergone surgical or chemical castration, and had been referred to a treatment centre in Finland, Ireland, or Sweden. Enrolment and treatment were done between March 1, 2004, and May 31, 2009. Randomisation was done centrally and stratified by centre and WHO performance status score of 0-1 vs 2. Patients were assigned 75 mg/m(2) docetaxel intravenously on day 1 of a 3-week cycle, or 50 mg/m(2) docetaxel intravenously on days 1 and 15 of a 4-week cycle. 10 mg oral prednisolone was administered daily to all patients. The primary endpoint was time to treatment failure (TTTF). We assessed data in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT00255606. FINDINGS 177 patients were randomly assigned to the 2-weekly docetaxel group and 184 to the 3-weekly group. 170 patients in the 2-weekly group and 176 in the 3-weekly group were included in the analysis. The 2-weekly administration was associated with significantly longer TTTF than was 3-weekly administration (5·6 months, 95% CI 5·0-6·2 vs 4·9 months, 4·5-5·4; hazard ratio 1·3, 95% CI 1·1-1·6, p=0·014). Grade 3-4 adverse events occurred more frequently in the 3-weekly than in the 2-weekly administration group, including neutropenia (93 [53%] vs 61 [36%]), leucopenia (51 [29%] vs 22 [13%]), and febrile neutropenia (25 [14%] vs six [4%]). Neutropenic infections were reported more frequently in patients who received docetaxel every 3 weeks (43 [24%] vs 11 [6%], p=0·002). INTERPRETATION Administration of docetaxel every 2 weeks seems to be well tolerated in patients with castration-resistant advanced prostate cancer and could be a useful option when 3-weekly single-dose administration is unlikely to be tolerated. FUNDING Sanofi.

Long-term follow-up study of radioiodine treatment of hyperthyroidism

objective  To determine the cumulative incidence of hypothyroidism during long‐term follow‐up in patients treated for hyperthyroidism by radioactive iodine 131I (RAI) therapy, the significance of clinical factors in predicting the development of hypothyroidism, and the outcome after a fixed 7 mCi (259 MBq) dose of RAI.

Characterization of breast cancer types by texture analysis of magnetic resonance images.

RATIONALE AND OBJECTIVES This novel study aims to investigate texture parameters in distinguishing healthy breast tissue and breast cancer in breast magnetic resonance imaging (MRI). A specific aim was to identify possible differences in the texture characteristics of histological types (lobular and ductal) of invasive breast cancer and to determine the value of these differences for computer-assisted lesion classification. MATERIALS AND METHODS Twenty patients (mean age 50.6 + or - SD 10.6; range 37-70 years), with histopathologically proven invasive breast cancer (10 lobular and 10 ductal) were included in this preliminary study. The median MRI lesion size was 25 mm (range, 7-60 mm). The selected T1-weighted precontrast, post-contrast, and subtracted images were analyzed and classified with texture analysis (TA) software MaZda and additional statistical tests were used for testing the parameters separability. RESULTS All classification methods employed were able to differentiate between cancer and healthy breast tissue and also invasive lobular and ductal carcinoma with classification accuracy varying between 80% and 100%, depending on the used imaging series and the type of region of interest. We found several parameters to be significantly different between the regions of interest studied. The co-occurrence matrix based parameters proved to be superior to other texture parameters used. CONCLUSIONS The results of this study indicate that MRI TA differentiates breast cancer from normal tissue and may be able to distinguish between two histological types of breast cancer providing more accurate characterization of breast lesions thereby offering a new tool for radiological analysis of breast MRI.

Surgically staged high-risk endometrial cancer: Randomized study of adjuvant radiotherapy alone vs. sequential chemo-radiotherapy

OBJECTIVE Our purpose was to establish whether platinum-based chemotherapy combined with standard surgery and radiotherapy will improve overall and disease-free survival and lower the recurrence rate in patients with high-risk endometrial cancer. STUDY DESIGN A total of 156 patients with Stage IA-B Grade 3 (n=28), or Stage IC-IIIA Grade 1-3 (n=128) were postoperatively randomized to receive radiotherapy (56 Gy) only (Group A, n=72) or radiotherapy combined with three courses of cisplatin (50 mg/m(2)), epirubicin (60 mg/m(2)) and cyclophosphamide (500 mg/m(2)) (Group B, n=84). RESULTS The disease-specific overall five-year survival was in Group A 84.7% vs. 82.1% in Group B (p=0.148). The median disease-free survival in A was 18 (range 9-36) months and 25 (range 12-49) months in B (p=0.134), respectively. During a five-year follow-up 32 patients relapsed. Of the recurrences 5 were local and 20 distant, while 7 were combined. As calculated from the operation, the median time to recurrence was 15 (range 6-37) months in Group A, and 20 (range 8-60) months in Group B, respectively (p=0.170). Twenty-six patients died of the disease during the five-year follow-up, 11 in A and 15 in B. The patients succumbing in A lived a median 23 (range 15-44) months as compared to 37 (range 13-50) months in B (p=0.148). Chemotherapy was associated with an acceptable rate of acute toxicity. Less than 8% of the patients complained of Grade 3/4 nausea. The rate of Grade 3/4 leucopenia was at the highest at 16.6% during the third cycle but only 6.2% of the patients had Grade 3 infection. A total of 10 patients developed intestinal complications demanding surgery, 2 in Group A (2.7%) and 8 (9.5%) in Group B, respectively. CONCLUSION Adjuvant chemotherapy with cisplatin, epirubicin and cyclophosphamide failed to improve overall survival or lower the recurrence rate in patients operated on and radiated for high-risk endometrial carcinoma. Chemotherapy was associated with a low rate of acute toxicity but appeared to increase the risk of bowel complications.

Inflammatory Markers and Physical Performance Among Nonagenarians

BACKGROUND Recent studies have suggested that inflammation may play an important role in aging and the development of disabilities, but knowledge about its importance in the development of muscle weakness and functional disabilities in very old people is limited. This study examined associations between inflammatory markers and physical performance among nonagenarians. METHODS The population-based sample consisted of 197 women and 65 men aged 90 years. Physical performance was assessed according to the Barthel Index, the chair stand, and handgrip strength. Plasma levels of interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1Ra), and C-reactive protein (CRP) were determined. RESULTS A gender-adjusted linear regression model showed that high levels of CRP, IL-6, and IL-1Ra were significantly associated with poor handgrip strength (p = .041, p = .023, p < .001, respectively). After adjustment for diseases, smoking and physical exercise high levels of IL-6 and IL-1Ra were still significantly associated with poor hand grip strength (p = .048, p = .004, respectively). In the gender-adjusted model, high levels of CRP, IL-6, and IL-1Ra were significantly associated with a worse Barthel Index (p = .009, p = .004, p = .004, respectively). High levels of CRP and IL-6 were still significantly associated with a worse Barthel Index after adjusted for diseases, smoking and physical exercise (p = .034, p = .041, respectively). In the chair stand, no significant association with inflammatory markers was found. CONCLUSIONS Associations between high levels of inflammatory markers and worse handgrip strength as well as a worse Barthel Index result were evident among nonagenarians. However, the association with the chair stand was not significant.

Intrapartum cardiotocography -- the dilemma of interpretational variation.

Abstract Objective: To evaluate and compare interobserver variation in interpretation of intrapartum cardiotocograms. Subjects: Fifteen senior (experience >4 years) and 16 junior (experience ≤4 years) obstetricians from 10 delivery units. Design: Thirty-one obstetricians interpreted intrapartum cardiotocographic (CTG) readings from 22 parturients. Methods: Inter-observer agreement in CTG interpretation and decision-making was assessed via proportions of agreement (Pa), with 95% confidence intervals (CI). Main outcome measures: The level of inter-observer agreement was analyzed by calculating Pa values for CTG baseline, variability, early, variable and late decelerations, uterine tonus, power of contractions, hypertonus and clinical decision. Results: In assessments of normal cases the Pa were acceptable or good (0.63–0.82) as regards all CTG interpretation elements except for the power of contractions (0.24), but in assessments of abnormal cases the Pa values were lower (0.18–0.60). As regards clinical decisions, a higher Pa was found in cases without recommendation for intervention (0.63, 95% CI 0.62–0.64) than in cases with such recommendation (0.55, 95% CI 0.54–0.56). The Pa in the abnormal cases was better among senior than among junior obstetricians. Conclusions: Inter-observer variation in interpretation of abnormal CTG readings and recommendations for intervention is relatively wide. To improve reliability, uniform classification and standardized training in CTG interpretation are needed, as well as increased use of computerized CTG.

Fecal Calprotectin Levels and Serological Responses to Microbial Antigens Among Children and Adolescents with Inflammatory Bowel Disease

Background: Noninvasive, sensitive, and specific tools for early identification of chronic inflammatory bowel disease (IBD) are needed for clinical practice. The aim was to identify new noninvasive test combinations for characterization of IBD in children and adolescents by comparing serological responses to microbial antigens and fecal calprotectin, a new promising marker for intestinal inflammation. Methods: Our study included 73 children who underwent endoscopies because of suspicion of IBD. Their sera were tested for antibodies to the Pseudomonas fluorescens‐associated sequence I2, a Bacteroides caccae TonB‐linked outer membrane protein, OmpW, and anti‐Saccharomyces cerevisiae (ASCA). Simultaneously, samples for fecal calprotectin measurements were obtained from 55 subjects. Results: IBD was diagnosed in 60 patients (Crohns disease [CD] in 18 patients, ulcerative colitis [UC] in 36, and indeterminate colitis [IC] in 6). Thirteen children had a non‐IBD disease. Fecal calprotectin levels were elevated (≥100 &mgr;g/g) more frequently in IBD patients (89%, 39/44) compared to non‐IBD cases (9%, 1/11, P < 0.001). ASCA antibodies in sera were detected in 67% (12/18) of patients with CD, in 14% (5/36) of the children with UC, and in 50% (3/6) of patients with IC. Seroreactivity for I2 was observed in 42% of the IBD patients, this frequency being higher than in non‐IBD cases (7.7% seropositive; P = 0.025). Serum anti‐I2 IgA levels (median absorbances) were higher in those with IBD compared to those without gut inflammation (P = 0.039). The combination of the measurements of fecal calprotectin and serological responses to microbial antigens (ASCA, I2, and OmpW) identified 100% of CD patients (sensitivity 100%, specificity 36%, positive predictive value [PPV] 66%, negative predictive value [NPV] 100%) and 89% of UC patients (sensitivity 89%, specificity 36%, PPV 77%, NPV 57%). Conclusions: Increased levels of serological responses to microbial antigens (ASCA, I2, and OmpW) and fecal calprotectin are evident in both CD and UC patients. The combination of these markers provides valuable, noninvasive tools for the diagnosis of IBD.

Human papillomavirus infection, risk for subsequent development of cervical neoplasia and associated population attributable fraction.

BACKGROUND Human papillomavirus (HPV) is the major cause of cervical neoplasia but estimates of the population attributable fraction (PAR%), of HPV vary. PAR% has not been derived from longitudinal studies although assessment of HPV exposure prior to the neoplasia diagnosis should increase validity of such estimates. AIMS Systematic review and meta-analysis of longitudinal studies on HPV associated relative risk (RR) for and PAR% of HPV16 in cervical neoplasia. METHODS Pertinent data from longitudinal studies was made available through Medline and substituted by various hand searches. HPV associated weighted mean RR, with 95% confidence interval (CI) of cervical neoplasia, and the PAR% of HPV16 in cervical carcinoma were estimated both for unselected and low HPV prevalence populations. RESULTS HPV associated RR of cervical carcinoma in PCR-based studies was 17 (95% CI 8.2-33). HPV16 associated RRs in seroepidemiological studies were 3.3 (95% CI 2.2-4.9) for the unselected population, HPV16 seroprevalence 11.0%, and 12.5 (95% CI 5.5-29) for a population with low HPV16 seroprevalence of 5.3%. Corresponding PAR% estimates of HPV16 were 27 and 44%, respectively. CONCLUSION Protective vaccination against HPV16 infection would prevent up to 44% of cervical carcinoma.

Perceived Mental Stress and Reactions in Heart Rate Variability—A Pilot Study Among Employees of an Electronics Company

In this study perceived mental stress during occupational work was compared to heart rate variability (HRV) using a traditional questionnaire and a novel wristop heart rate monitor with related software. The aim was to find HRV parameters useful for mental stress detection. We found the highest correlation between perceived mental stress with the differences between the values of triangular interpolation of rythm-to-rythm (RR) interval histogram (TINN) and the root mean square of differences of successive RR intervals (RMSSD) obtained in the morning and during the workday(r = -.73 andr = -.60, respectively). The analysis shows that as the RMSSD and TINN value differences increase from night to morning, the stress decreases.

Parkinson's disease and working capacity.

The purpose of the present study was to establish how Parkinsons disease (PD) affects working capacity. Altogether, 937 (70%) of 1,343 working‐aged members of the Finnish Parkinson Association participated in a questionnaire study. The ages of the subjects were between 29 and 65 years, median 59.0 years; 508 (54%) were men. The median (quartile range) duration of PD symptoms was 7.3 (4.3–11.3) years, and the median self‐estimated severity of the disease on the Hoehn & Yahr scale was 2. Only 150 of 937 subjects (16%) were still working: 112 (12%) full‐time and 38 (4%) part‐time. Among those 343 (37%) who had retired purely because of PD at a median age of 53.4 years, the median working time was 1.7 years after established diagnosis. In part‐time work, PD patients had been able to continue for a median of 4.3 years. PD often leads to early retirement; compared with the general Finnish population of similar age, PD patients had retired on the average 6 years earlier. Young age, mild symptoms, and short duration of the disease as well as adjustments enabling easier employment were associated with the possibility to continue longer in the work force.