The effect of hospital operative volume, residual tumor and first-line chemotherapy on survival of ovarian cancer - a prospective nation-wide study in Finland.

OBJECTIVE: Our recent prospective, nation-wide study indicated better surgical outcome in ovarian cancer patients operated at university hospitals compared to other hospitals. Here we report how this is reflected in 5-year cancer-specific survival (CSS). METHODS: Detailed 5-year follow-up data were obtained on 275 patients by using a special questionnaire, and the data were verified from the Finnish Cancer Registry data. The hospitals were categorized to university and other hospitals and by the number of operations performed in 1999 (<10, 10-20, or >20 operations). Data were analyzed using the Cox's proportional hazards regression analysis. RESULTS: The study population covered 90% of the epithelial ovarian cancer patients operated in 1999, in Finland. Eighty-two percent of the patients received platinum-based chemotherapy. The percentage of patients treated with a platinum-taxane combination was higher in university hospitals (63% vs. 49%, P=0.037). The 5-year CSS was 56% and the median disease-free survival (DFS) was 33 months. In multivariate analysis prognostic factors for CSS were stage (P=0.0027), residual tumor (P=0.0001), and primary chemotherapy (P<0.0001). Hospital operative volume was associated with residual tumor (P=0.027). When hospital operative volume increased with ten patients per year, the odds ratio for no residual disease was 1.203 (95% CI 1.022-1.417). CONCLUSION: FIGO stage, residual tumor, and primary chemotherapy are significant prognostic factors for ovarian cancer. Hospital volume is associated with residual tumor. The results favor performance of ovarian cancer surgery in hospitals with higher operative volumes.

Postmenopausal estrogen therapy modulates nocturnal nonlinear heart rate dynamics.

OBJECTIVE: To study the effects of postmenopausal estrogen therapy (ET) on nocturnal nonlinear heart rate variability (HRV). DESIGN: In this prospective, randomized, double-blind, placebo-controlled study, 71 healthy hysterectomized postmenopausal women received either transdermal estradiol or placebo for 3 months. After a washout period of 1 month, the treatments were reversed. Sleep studies were performed after both treatment periods. One steady-state epoch per night of the awake state, stage 2 (light) non-rapid eye movement (REM) sleep, stage 3-4 (deep) non-REM sleep, also known as slow-wave sleep, and REM sleep was extracted. From the electrocardiogram, nonlinear HRV was analyzed as the fractal scaling exponents alpha1 and alpha2, approximate entropy (ApEn), and the Poincaré plot variability coefficients SD1 and SD2. These were correlated to ET use in both different sleep stages and averaged across all sleep stages. RESULTS: During ET, the nocturnal ApEn decreased from 0.80 +/- 0.01 to 0.74 +/- 0.02 (P < 0.05), the most marked reduction occurring during slow-wave sleep (from 0.77 +/- 0.05 to 0.63 +/- 0.06, P < 0.05). In addition, SD2 decreased in slow-wave sleep and REM sleep during ET (P < 0.05 for both). In light non-REM sleep, alpha1 slightly increased during ET (P < 0.05). CONCLUSIONS: ET has a slightly but distinctively attenuating effect on some nocturnal nonlinear measures of HRV, especially on complexity of heart rate dynamics. This implies that ET may have potentially deleterious effects on cardiovascular health during sleep.

Force production and EMG activity of neck muscles in adolescent headache.

PURPOSE: This study compared the maximal force, EMG/force ratio and co-activation characteristics of the neck-shoulder muscles between 30 adolescents with migraine-type headache, 29 with tension-type headache, and 30 headache-free controls. METHOD: Force was measured with surface electromyography (EMG) from the cervical erector spinae (CES), the sternocleidomastoid (SCM) and trapezius muscles during the maximal isometric neck flexion, neck extension and shoulder flexion. RESULTS: Girls with migraine-type headache had higher EMG/force ratios between the EMG of the left agonist SCM muscle and the corresponding maximal neck flexion (p = 0.030) and neck rotation force to the right side (p = 0.024) than the girls with tension-type headache. Migrainous girls had more co-activation of right antagonist CES muscle during maximal neck flexion force than the girls without headache (p = 0.015). Neck force production showed no significant differences between girls. Girls with tension-type headache displayed lower left shoulder flexion force than girls with migraine-type headache (p = 0.005) or with no headache (p = 0.005). In boys, no significant differences were observed. CONCLUSIONS: Girls with tension-type headache and migraine-type headache have differences in neuromuscular function in the neck-shoulder muscles. The data amplify our knowledge of the neck-shoulder muscle dysfunction in adolescent headache, and may encourage the use of specific rehabilitation methods in the management of different types of headache.

Neck flexor muscle fatigue in adolescents with headache: an electromyographic study.

BACKGROUND: Muscular disorders of the neck region may be of importance for the etiology of tension-type headache. However, in adolescents, there are no data on the association between neck muscle fatigue and headache. AIM: To study differences in fatigue characteristics of the neck flexor muscles in adolescents with and without headache. METHODS: A population-based sample of 17-year-old adolescents with migraine-type headache (N=30), tension-type headache (N=29) and healthy controls without headache (N=30) was examined. Surface EMG data were recorded from the sternocleidomastoid (SCM) muscles bilaterally during an isometric neck flexor endurance test. The spectral median frequency (MF) change during the total endurance time (TMF) and the initial time of 30s (IMF) was calculated. The intensity of discomfort in the neck area was assessed with the visual analogue scale (VAS). RESULTS: The rate of decline in TMF of both SCM muscles was significantly increased in the tension-type headache group compared with controls (right SCM, P=0.030, OR 2.0, 95% 1.2-3.7; left SCM, P=0.009, OR 2.5, 95% 1.4-4.9), while no significant differences were found between controls and subjects with migraine. The rate of decline in IMF, the total endurance time (P=0.050), and VAS did not differ significantly among the study groups. CONCLUSIONS: This preliminary finding shows that increased neck flexor muscle fatigue in adolescents seems to be associated with tension-type headache.

Atopic characteristics of wheezing children and responses to prednisolone.

We wanted to test the hypothesis that the efficacy of systemic corticosteroid is associated with atopic characteristics in wheezing children. A randomized controlled trial comparing oral prednisolone (2 mg/kg/day in 3 divided doses for 3 days) with placebo in hospitalized wheezing children (n = 266, median 1.6 years, range 3 months to 15.2 years) was conducted. In this post-hoc analysis, we assessed the link between the efficacy of prednisolone and several atopic characteristics, such as atopy, aeroallergen sensitization, total IgE level, number of sensitizations, eczema, atopic eczema, blood or nasal eosinophils, exhaled nitric oxide, positive modified asthma predictive index/asthma, inhaled corticosteroid medication and parental asthma/allergy. Virology was studied comprehensively. Our primary endpoint was the time until ready for discharge, and the most important secondary endpoint was the occurrence of relapses during the following 2 months. For statistics, we used interaction analyses in uni- and multivariate regression models. Overall, prednisolone did not decrease any of our predefined clinical endpoints. Neither was the efficacy of prednisolone associated with atopy. However, prednisolone significantly decreased the time until ready for discharge in children with positive modified asthma predictive index/asthma, inhaled corticosteroids, or rhinovirus infection and/or in children without azithromycin treatment. Prednisolone significantly decreased relapses in children with eczema, nasal eosinophilia and rhinovirus infection. The multiple clinical, inflammatory and viral markers associating with the efficacy of prednisolone should be confirmed in prospective trials. It is important that corticosteroid intervention trials have strict design for these potentially confounding factors.

Repeatability of electromyography and force measurements of the neck muscles in adolescents with and without headache.

BACKGROUND: Reliable measurements are needed to study the dysfunction of the neck muscles. The aim of this study was to determine the intra-tester repeatability of EMG and isometric force measurements of the neck muscles in adolescents with headache and headache-free controls. METHODS: A group of 30 adolescents with migraine-type headache, 29 with tension-type headache, and 30 headache-free controls were recruited. Maximal isometric neck muscle force with simultaneous recording of surface EMG from the cervical erector spinae and the sternocleidomastoideus muscles was measured twice during one day. FINDINGS: For all groups, intra-class correlation coefficients (ICC) and coefficients of variation (CV) showed acceptable repeatability of all measurements. (Force measurements: ICC 0.98-0.99, CV 0.7-3.7%; EMG measurements: ICC 0.95-0.99, CV 4.9-10.1%.) On the individual level, variation between the consecutive measurements was found to be low in all groups. INTERPRETATION: The present EMG and force measurements of neck muscles indicate acceptable intra-tester repeatability in adolescents. The repeatability was comparable in migraine- and tension-type headache and headache-free groups. The EMG and the force measurements offer the possibility to investigate neck muscle dysfunction in adolescent headache.

Biochemical and clinical approaches in evaluating the prognosis of colon cancer.

BACKGROUND: Colorectal adenocarcinoma is a common malignant neoplasm in the Western world. To achieve optimal treatment results, the risk estimation of recurrence should be as accurate as possible. MATERIALS AND METHODS: Tissue material from tumour and normal mucosa was taken from six patients and was analysed to screen aberrantly expressed genes using cDNA microarray. Selected up-regulated genes were chosen for further analysis by immunohistochemistry. For this purpose a tissue array material of 114 colorectal cancer patients was obtained. In addition to the routinely used proliferation marker Ki-67, the analysed proteins included securin and CDC25B. RESULTS: Processes such as cellular defense, cell structure, motility and cell division were found to be notably represented among the most deregulated genes. A significant portion of the overexpressed genes included those functioning in the cell cycle. Immunohistochemical stainings of securin and CDC25B showed a consistent expression pattern with that of cDNA microarray analysis. There was no statistical association between the studied proliferation markers and survival. Instead, there was a significant association between the Dukes' class and the histological grade (p=0.04), but not between histological grade and survival. The survival of Dukes' B patients was significantly poorer if no regional lymph nodes were studied compared with the Dukes' B patients with even a single lymph node was studied (p=0.04, hazard ratio 2.7). CONCLUSION: Tumour stage is superior in estimating the prognosis of patients with colonic cancer compared with the grading of cell cycle regulators or histological grade of the cancer. The study of regional lymph nodes is essential to identify the patients who would benefit from adjuvant chemotherapy.

Delays in the diagnosis and treatment of lung cancer.

STUDY OBJECTIVES: This study was undertaken to measure delays of diagnosis and to assess the causes for those delays in patients with lung cancer. In addition, the relation of delay times and survival was analyzed. DESIGN: A retrospective study based on patient records. Dates for symptoms, visits to doctors, investigations, treatment, and death were recorded. SETTING: Patients who were found to have lung cancer at Turku University Hospital, Finland, during 2001. PATIENTS: Records of 132 patients were reexamined. RESULTS: The median delay in patient presentation from first symptoms to first appointment with a general practitioner (GP) was 14 days. The median delay by the GP before writing a referral was 16 days, the median referral delay was 8 days, the median delay from the first visit to a specialist until the diagnosis was 15 days, and the median treatment delay was also 15 days. Thirty percent of patients received treatment within 1 month from the first hospital visit, and 61% received treatment within 2 months. The median symptom-to-treatment delay was almost 4 months. The delay in seeing a specialist was shorter in patients with advanced cancer and small cell lung cancer. About half of our patients fulfilled the criteria of the British Thoracic Society recommendations. A longer specialist treatment delay seemed to correlate with better survival in advanced disease, but it was not an independent significant factor for survival. CONCLUSIONS: Several reasons for long delays were found, but on many occasions patients underwent numerous consecutive procedures before a diagnosis of cancer was confirmed. Shortening the diagnostic and treatment delay times might be possible with little extra cost by a multidisciplinary team approach and by rapid access to carefully planned investigations, but decreasing the patient delay might be more difficult. This study shows that long specialist treatment delays are not correlated with worse prognosis in patients with advanced disease. In patients with more limited disease, the delay time may be more critical, and if curative treatment is the goal, the diagnostic process should proceed without needless delay to avoid a situation in which curable disease becomes incurable.

Group IIA phospholipase A as a prognostic marker in prostate cancer: relevance to clinicopathological variables and disease-specific mortality.

Group IIA Phospholipase A(2) (PLA2-IIA), a key enzyme in arachidonic acid and eicosanoid metabolism, participates in a variety of inflammatory processes but possibly also plays a role in tumor progression in vivo. Our aim was to determine the mRNA and protein expression of PLA2-IIA during prostate cancer progression in localized and metastatic prostate tumors. We evaluated the prognostic significance of PLA2-IIA expression in biochemical recurrence, clinical recurrence and disease-specific survival after surgical treatment. The expression of PLA2-IIA was examined by immunohistochemistry and chromogenic in situ hybridization in tissue microarrays of radical prostatectomy specimens and advanced/metastatic carcinomas. The expression data were analyzed in conjunction with clinical follow-up information and clinicopathological variables. The mRNA and protein expression of PLA2-IIA was significantly increased in Gleason pattern grade 2-4 carcinomas compared with benign prostate (p-values 0.042-0.001). In metastases, the expression was significantly lower than in local cancers (p=0.001). The PLA2-IIA expression correlated positively with Ki-67 and alpha-methylacyl CoA racemase (AMACR) expression. The prognostic evaluation revealed decreased PLA2-IIA protein expression among patients who had died of prostate cancer. In conclusion, PLA2-IIA expression is increased in carcinoma when compared with benign prostate. However, metastatic carcinoma showed decreased expression of PLA2-IIA when compared with primary carcinomas. PLA2-IIA may serve as a marker for highly proliferating, possibly poorly differentiated prostate carcinomas. The protein expression of PLA2-IIA may be diminished in patients who consequently die of prostate cancer.

Major lower extremity amputation in elderly patients with peripheral arterial disease: incidence and survival rates.

BACKGROUND AND AIMS: The methods of treating peripheral arterial disease (PAD) have changed and become more prophylactic. This study describes and analyzes 1) the incidence rates of major lower extremity amputation (LEA) due to PAD, 2) occurrence of re-amputation, and 3) the survival of amputees and factors predicting survival. METHODS: The series consisted of 210 patients (mean age 76.6, SD 10.7 yrs, 45.2% men) who underwent their first, i.e. index, major leg amputation because of PAD, in 1998-2002, in the city of Turku, Finland, population 175,000. RESULTS: The age-and gender-standardized incidence rate of combined above-knee and below-knee amputations was 24.1/100,000 person-years during 1998-2002. Thirty-four per cent of amputees underwent repetitive amputation. One-month mortality was 21% (n=45), one-year mortality 52% (n=109) and overall mortality 80% (n=168). Cardiovascular diseases predicted equally well 31-day, one-year, and overall mortality in age- and gender- adjusted analysis. Multiple co-morbidities (p=0.023) and unilateral above-knee amputations (p=0.047) were significant predictors for overall mortality in age- and gender-adjusted analysis. Cardiovascular diseases remained a significant predictor for 31-day and overall mortality in multivariate analysis (p=0.008 and p=0.015, respectively). Amputated patients' previous vascular procedures did not have any effect on mortality in the Cox model. Most revascularizations were performed less than six months before the index/first major LEA. CONCLUSION: Major LEAs seem to have been done late, and mainly for pain relief in the end-stage of patients with peripheral arterial disease.

Neck muscles' cross-sectional area in adolescents with and without headache - MRI study.

BACKGROUND: Cervical musculature may play an important role in the genesis of tension-type headache. However, there are no reports on a possible association between the morphometrical features of the neck flexion and extension muscles and adolescence headache. AIM: To examine differences in neck flexion and extension muscles cross-sectional area (CSA) in adolescents with and without headache. METHODS: A population-based sample of 17-year-old adolescents with migraine (N=19), tension-type headache (N=24) and healthy controls without headache (N=22) was examined. CSA of the neck muscles was measured from axial T1-weighted magnetic resonance images (MRI). RESULTS: Boys with tension-type headache showed significantly smaller CSA of right sternocleidomastoid muscle than boys with migraine and girls with tension-type headache showed significantly smaller CSA of combined right sternocleidomastoid and scalenus muscles than girls with migraine. In addition, boys with migraine had significantly larger CSA of both right sternocleidomastoid and combined right sternocleidomastoid and scalenus muscles, and left semispinalis capitis muscle and combined left semispinalis and splenius muscles than boys without headache. In boys and girls no other significant differences were observed in the CSA of neck flexion or extension muscles. CONCLUSIONS: This preliminary work demonstrates that both girls and boys with tension-type headache and migraine have differences in the size of neck flexion muscles, especially unilaterally. In boys, unilaterally increased size of neck flexion and extension muscles is associated with migraine. These findings, if confirmed in further studies, may have important diagnostic and therapeutic implications for rehabilitation of adolescents with headache.

Comparison of long-term outcome of laparoscopic and conventional nissen fundoplication: a prospective randomized study with an 11-year follow-up.

OBJECTIVE: The aim of this study was to compare the long-term objective and subjective outcomes of laparoscopic and open Nissen fundoplication in a randomized clinical trial with an 11-year follow-up. SUMMARY BACKGROUND DATA: Laparoscopic Nissen fundoplication has become the method of choice in antireflux surgery, replacing its open counterpart despite the lack of long-term results from controlled clinical studies. METHODS: Between April 1992 and June 1995, 110 consecutive patients were randomized to either laparoscopic (LAP) or conventional (open) Nissen fundoplication. The objective long-term follow-up consisted of an upper gastrointestinal endoscopy and a clinical assessment; the subjective long-term outcome was investigated by personal interviews using a structured questionnaire. RESULTS: Forty-nine patients in the LAP group and 37 patients in the open group were available for evaluation. Late subjective results, including postoperative symptoms and evaluation of the surgical result, were similar in both groups. With the benefit of hindsight, 73.7% of the patients in the open group and 81.8% in the LAP group would again choose surgical treatment (P = 0.3042). In the LAP group, there were 5 (13.2%) partially or totally disrupted plications compared with the 14 (40.0%) disrupted plications in the open group (P = 0.0152). There were 10 incisional hernias in the open group compared with none in the LAP group (P < 0.001). CONCLUSIONS: At long-term follow-up, the open and LAP approaches for the Nissen fundoplication have similar long-term subjective symptomatic outcome despite the significantly higher incidence of incisional hernias and defective fundic wraps at endoscopy in the open group defining laparoscopic Nissen fundoplication as the procedure of choice in surgical management of gastroesophageal reflux disease.

Use of antidepressants and suicide rate in Finland: an ecological study.

OBJECTIVE: The suicide rate has decreased in many countries, while the use of antidepressants has increased greatly. The aim of this study was to investigate the associations between use of antidepressants and suicide rate. METHOD: Population-based suicide rates and reimbursed prescriptions of antidepressants between 1994 and 2001 in Finland were analyzed in the whole population, and separately by gender, age, and geographical region. RESULTS: There were significant differences in suicide rates between men and women (p < .0001), but there were no differences between different regions of the country. The decline in the suicide rate was significantly associated with use of antidepressants among men aged 15 to 44 (p < .0001), 45 to 64 (p = .0005), and 75 years and over (p = .001) and men in 3 regions (p < .001). The decline in the suicide rate was significantly associated with the use of antidepressants among 15- to 44-year-old women (p = .008) and women in 1 region (p = .013). Use of antidepressants had a significant association with the decrease in the suicide rate (risk ratio = 0.08, 95% CI 0.02 to 0.30, p < .001), despite the effect of background variables, their interaction, and the course of time. CONCLUSIONS: An increase in the use of antidepressants may decrease the suicide rate. Baseline suicide rate and access to health care may influence this association.

Efficacy of prednisolone in children hospitalized for recurrent wheezing.

Data on the efficacy of corticosteroids on respiratory picornavirus-induced wheezing are limited. To determine whether prednisolone is effective in rhinovirus- or enterovirus-induced recurrent wheezing, we conducted a controlled trial comparing oral prednisolone (2 mg/kg/day in three divided doses for 3 days) with placebo in hospitalized wheezing children and studied post hoc virus-specific efficacy in early wheezing (<3 episodes, reported elsewhere) and in recurrent wheezing (>or=3 episodes). Virus-negative children where excluded. Our primary endpoint was the time until children were ready for discharge. Secondary endpoints included oxygen saturation and exhaled nitric oxide during hospitalization, duration of symptoms, blood eosinophil count, and impulse oscillometry 2 wk after discharge, and occurrence of relapses during the following 2 months. Virus-specific effects were analyzed with interaction analysis in a multivariate regression model. During the study period, 661 patients were hospitalized, 293 randomized, and 59 were accepted in this analysis (mean age 2.6 yr, s.d. 1.3). Prednisolone did not significantly decrease the time until ready for discharge in all patients (prednisolone vs. placebo, medians, 18 vs. 24 h, p = 0.11). However, prednisolone decreased the time until ready for discharge in children with picornavirus infection (respectively, 12 vs. 24 h, p = 0.0022) and more specifically, in children with enterovirus infection (6 vs. 35 h, p = 0.0007). In the secondary endpoints, prednisolone decreased the duration of cough and dyspnea in rhinovirus-affected children (p = 0.033 for both). Prospectively designed clinical trial is needed to test the hypothesis that prednisolone reduces symptoms in picornavirus-affected wheezing children.

Regulation of prostate cell collagen receptors by malignant transformation.

Cell adhesion receptors, including the integrin-type collagen receptors (alpha1beta1, alpha2beta1, alpha10beta1 and alpha11beta1) participate in cancer progression and invasion. Quantitative RT-PCR indicated that all 4 receptors are abundantly expressed in sarcoma-derived cell lines, whereas most carcinoma-derived cells express alpha1beta1 and alpha2beta1 only. This was surprising because alpha11beta1 has been connected previously to the progression of lung adenocarcinomas. To test the hypothesis that alpha11 expression may not persist in cultured cancer cells we analyzed fresh tissue samples of 104 total prostatectomies, keeping in mind that prostate cancer cell lines showed negligible alpha11 mRNA levels. In prostate alpha2 expression was significantly lower in poorly differentiated carcinomas when compared to benign lesions (p = 0.0331). In immunohistochemistry the protein levels of alpha2 integrin decreased significantly (p = 0.0001) and the protein levels of alpha11 subunit increased significantly (p = 0.029) with the increasing grade of carcinoma. Thus alpha11beta1 may replace alpha2beta1 during tumor progression. Our observations support the idea that alpha11beta1 may be expressed in tumors but the corresponding cell lines may lose the expression of this integrin. Previous studies have shown that in cell culture androgen receptor (AR) controls alpha2beta1 expression. We measured AR mRNA levels and the number of AR positive nuclei in the prostate samples and the results showed a significant correlation between alpha2beta1 and AR. Androgen receptors may control the mechanisms regulating integrin expression in prostate.

The effect of PPARgamma-agonism on LDL subclass profile in patients with type 2 diabetes and coronary artery disease.

Patients with type 2 diabetes (T2DM) often present a preponderance of small, dense LDL particles (small-LDL), which are associated with a high risk of myocardial infarction. Some studies suggest that PPARgamma-agonists increase LDL cholesterol but have divergent effects on various LDL subclasses in T2DM patients. We studied the effect of rosiglitazone on the LDL subclass profile in T2DM patients with verified coronary artery disease (CAD). 58 patients with T2DM (HbA1c < 8.5%) and CAD were enrolled in a 16-week, randomized, double-blind and placebo-controlled trial with rosiglitazone 8 mg/day (n = 29) or placebo (n = 29). The LDL subclass profile was measured with gel electrophoresis. Rosiglitazone improved insulin sensitivity and glycemic control. Total cholesterol did not change after rosiglitazone treatment (p = 0.062, ANCOVA adjusted for gender and baseline values), whereas LDL (including IDL) cholesterol increased from 2.33 +/- 0.48 to 2.67 +/- 0.61 mmol/l (p = 0.002 vs. baseline, p = 0.0497 vs. placebo) and large buoyant LDL (large-LDL < 250A) increased from 1.31 +/- 0.36 to 1.46 +/- 0.42 mmol/l (p = 0.010 vs. baseline, p = 0.044 vs. placebo) in the rosiglitazone group. No significant changes occurred to the concentration of small-LDL (< 250A), the average LDL particle size, or HDL or triglyceride concentrations. Whole-body insulin sensitivity was associated with the average LDL particle size after intervention in the whole population (r = 0.40, p = 0.002) and in the rosiglitazone group (r = 0.43, p = 0.020). In conclusion, in T2DM patients with CAD, rosiglitazone treatment significantly increases the concentration of large (buoyant) LDL cholesterol, but not of small dense LDL cholesterol. The long term consequences of this divergent effect of rosiglitazone on LDL subfractions require further exploration.