Preterm Birth and Surgical Treatment of the Uterine Cervix

Cervical cancer is the second most common cancer among women globally. Most, probably all cases, arise through a precursor, cervical intraepithelial neoplasia (CIN). Effective cytological screening programmes and surgical treatments of precancerous lesions have dramatically reduced its prevalence and related mortality. Although these treatments are effective, they may have adverse effects on future fertility and pregnancy outcomes. The aim of this study was to evaluate the effects of surgical treatment of the uterine cervix on pregnancy and fertility outcomes, with the focus particularly on preterm birth. The general preterm birth rates and risk factors during 1987–2005 were studied. Long-term mortality rates of the treated women were studied. In this study, information from The Medical Birth Register (MBR), The Hospital Discharge Register (HDR), The Cause-of-Death Register (CDR), and hospital records were used. Treatments were performed during 1987–2003 and subsequent deliveries, IVF treatments and deaths were analyzed. The general preterm birth rate in Finland was relatively stable, varying from 5.1% to 5.4% during the study period (1987 to 2005), although the proportion of extremely preterm births had decreased substantially by 12%.The main risk factor as regards preterm birth was multiplicity, followed by elective delivery (induction of delivery or elective cesarean section), primiparity, in vitro fertilization treatment, maternal smoking and advanced maternal age. The risk of preterm birth and low birth weight was increased after any cervical surgical treatment; after conization the risk of preterm birth was almost two-fold (RR 1.99, 95% CI 1.81– 2.20). In the conization group the risk was the highest for very preterm birth (28–31 gestational weeks) and it was also high for extremely preterm birth (less than 28 weeks). In this group the perinatal mortality was also increased. In subgroup analysis, laser ablation was not associated with preterm birth. When comparing deliveries before and after Loop conization, we found that the risk of preterm birth was increased 1.94-fold (95% CI 1.10–3.40). Adjusting for age, parity, or both did not affect our results. Large or repeat cones increased the risk of preterm birth when compared with smaller cones, suggesting that the size of the removed cone plays a role. This was corroborated by the finding that repeat treatment increased the risk as much as five-fold when compared with the background preterm birth rate. We found that the proportion of IVF deliveries (1.6% vs. 1.5%) was not increased after treatment for CIN when adjusted for year of delivery, maternal age, or parity. Those women who received both treatment for CIN and IVF treatment were older and more often primiparous, which explained the increased risk of preterm birth. We also found that mortality rates were 17% higher among women previously treated for CIN. This excess mortality was particularly seen as regards increased general disease mortality and alcohol poisoning (by 13%), suicide (by 67%) and injury death (by 31%). The risk of cervical cancer was high, as expected (SMR 7.69, 95% CI 4.23–11.15). Women treated for CIN and having a subsequent delivery had decreased general mortality rate (by -22%), and decreased disease mortality (by -37%). However, those with preterm birth had increased general mortality (SMR 2.51, 95% CI 1.24–3.78), as a result of cardiovascular diseases, alcohol-related causes, and injuries. In conclusion, the general preterm birth rate has not increased in Finland, as in many other developed countries. The rate of extremely preterm births has even decreased. While other risk factors of preterm birth, such as multiplicity and smoking during pregnancy have decreased, surgical treatments of the uterine cervix have become more important risk factors as regards preterm birth. Cervical conization is a predisposing factor as regards preterm birth, low birth weight and even perinatal mortality. The most frequently used treatment modality, Loop conization, is also associated with the increased risk of preterm birth. Treatments should be tailored individually; low-grade lesions should not be treated at all among young women. The first treatment should be curative, because repeat treatments are especially harmful. The proportion of IVF deliveries was not increased after treatment for CIN, suggesting that current treatment modalities do not strongly impair fertility. The long-term risk of cervical cancer remains high even after many years post-treatment; therefore careful surveillance is necessary. In addition, accidental deaths and deaths from injury were common among treated women, suggesting risk-taking behavior of these women. Preterm birth seems be associated with extremely high mortality rates, due to cardiovascular, alcohol-related and injury deaths. These women could benefit from health counseling, for example encouragement in quitting smoking.

Modern surgical treatment of otosclerosis

The modern unilateral surgical treatment of otosclerosis started in 1956. Simultaneous bilateral surgery has not been reported in stapes surgery and in case of bilateral otosclerosis ears are operated in two different sessions. Simultaneous surgery would give the patient the opportunity to gain advantages of bilateral hearing within one session, with less time spent in hospital and on sick leave. The mechanism for vestibular symptoms and the exact end organ affected after surgery is still unveiled. This thesis presents the results of experimental simultaneous bilateral stapes surgery, and vestibular symptoms and findings before and after unilateral stapes surgery. In addition, we explore reasons for outpatient failures in otosclerosis surgery. -- Study I examines the outcome of simultaneous bilateral surgery. Hearing was evaluated with standard pure tone and speech audiograms and vestibular apparatus with visual feedback posturography (VFP) during the one-year follow-up. Subjective symptoms and quality of life were assessed with questionnaires. In study II, reasons for outpatient failures in stapes surgery were explored. Forty-seven consecutive stapedotomies and stapedectomies performed by the same surgeon were included, and the effect of failures on hearing results were analysed. Vestibular symptoms and the end organ(s) affected after stapes surgery were investigated in studies III and IV. With video-oculography (VOG), nystagmus was measured preoperatively, and at one week, one month and 3 months postoperatively in the first phase (III). In the second phase (IV), recordings were obtained some hours postoperatively. The hearing results of the simultaneous bilateral surgery were comparable with unilateral surgeries reported. Recovery from the surgery was fast. Significant improvement in performance and quality of life was noted already month after operation in subjective evaluations. Based on these results, simultaneous bilateral surgery is a suitable approach in bilateral otosclerosis Significantly more outpatient failures occurred for medical reasons in the stapedectomy group (13%) than in the stapedotomy group (2%). Stapedotomy should be favoured if outpatient surgery is planned. However, unplanned admission did not worsen the prognosis. VOG measurements in study III did not show any specific type of nystagmus in patients having vestibular symptoms postoperatively. However, VOG measurements immediately after surgery (IV) revealed nystagmus consistent with a minor disturbance of the semicircular canals in 33% of the patients. Subjectively, half of the patients reported vestibular symptoms that were probably of diverse origin, and could have originated from both otolith and semicircular canal parts of the vestibular organ. Since vestibular symptoms and signs are mild, patients may be safely discharged some hours after stapes surgery.

Immediate Breast Reconstructions in the Treatment of Breast Cancer

Breast cancer is the most common form of potentially fatal cancer in women in the Western world. Better understanding of the breast cancer disease process together with developments in treatments have led to improved survival and reduced risk of recurrence, significantly influencing the acceptance of breast reconstructions as part of breast cancer treatment. Skin-sparing mastectomy followed by immediate breast reconstruction has proved superior to other forms of breast reconstruction in terms of aesthetic outcome. However, due to the relatively recent introduction of skin-sparing mastectomy concerns on the surgical and oncological safety of the operation persist. The aim of the present study is to evaluate the surgical and oncological safety of skin-sparing mastectomy and immediate breast reconstruction in a consecutive patient series with ensuing follow-up. Subsequent aims of the study are to examine possibilities of reducing surgical complications of the operation and to assess the feasibility of sentinel node biopsy together with immediate breast reconstruction. The study population comprises a consecutive series of patients having undergone skin-sparing mastectomy followed by immediate breast reconstruction at the Helsinki University Central Hospital between 1992 and 2006. In Study I, the hospital records of 207 patients, operated between 1992 and 2001, were analyzed for surgical complications and recurrences of breast cancer during follow-up. In Study II, 60 consecutive patients were randomized into either conventional diathermy or radiofrequency coagulation groups to examine possibilities of reducing skin-flap complications. Study III consists of 62 consecutive breast cancer patients evaluated for the feasibility of sentinel node biopsy simultaneously with immediate breast reconstruction. In Study IV, hospital records were analyzed to examine local recurrence of breast cancer in a consecutive series of 146 patients with Stage I or II disease. Post-operative complications in Study I included native skin-flap necrosis (10.1%), hematoma (10.1%), anastomose thrombosis (5.3%), infection (3.4%), hernia (2.6%) and loss of one microvascular flap (0.7%). The Stage I and II patients in Study IV had a local recurrence rate of 2.7%, an isolated regional lymph node recurrence rate of 2.1% and a systemic recurrence rate of 2.7%, during a mean follow-up time of 51 months. The Stage III patients in study I had a locoregional recurrence rate of 31.3% during follow-up. Radiofrequency coagulation in Study II did not decrease skin-flap complications when compared with conventional diathermy. An increased skin-flap complication rate in Study II was associated with smoking and the type of skin incision used. In Study III, eleven patients had tumor positive sentinel nodes, nine of which were detected intraoperatively. Skin-sparing mastectomy followed by immediate breast reconstruction is a safe procedure both surgically and oncologically, especially for early stage breast cancer. Tennis racket type incision is associated with an increased skin-flap complication rate. Sentinel node biopsy with intraoperative assessment of sentinel node metastases is feasible in patients undergoing immediate breast reconstruction.

Cardiac function before and after treatment for various types of loading conditions and in myocardial restriction : A prospective study on pediatric patients with two- and three-dimensional echocardiography and measurement of serum natriuretic peptides

Background: The incidence of all forms of congenital heart defects is 0.75%. For patients with congenital heart defects, life-expectancy has improved with new treatment modalities. Structural heart defects may require surgical or catheter treatment which may be corrective or palliative. Even those with corrective therapy need regular follow-up due to residual lesions, late sequelae, and possible complications after interventions. Aims: The aim of this thesis was to evaluate cardiac function before and after treatment for volume overload of the right ventricle (RV) caused by atrial septal defect (ASD), volume overload of the left ventricle (LV) caused by patent ductus arteriosus (PDA), and pressure overload of the LV caused by coarctation of the aorta (CoA), and to evaluate cardiac function in patients with Mulibrey nanism. Methods: In Study I, of the 24 children with ASD, 7 underwent surgical correction and 17 percutaneous occlusion of ASD. Study II had 33 patients with PDA undergoing percutaneous occlusion. In Study III, 28 patients with CoA underwent either surgical correction or percutaneous balloon dilatation of CoA. Study IV comprised 26 children with Mulibrey nanism. A total of 76 healthy voluntary children were examined as a control group. In each study, controls were matched to patients. All patients and controls underwent clinical cardiovascular examinations, two-dimensional (2D) and three-dimensional (3D) echocardiographic examinations, and blood sampling for measurement of natriuretic peptides prior to the intervention and twice or three times thereafter. Control children were examined once by 2D and 3D echocardiography. M-mode echocardiography was performed from the parasternal long axis view directed by 2D echocardiography. The left atrium-to-aorta (LA/Ao) ratio was calculated as an index of LA size. The end-diastolic and end-systolic dimensions of LV as well as the end-diastolic thicknesses of the interventricular septum and LV posterior wall were measured. LV volumes, and the fractional shortening (FS) and ejection fraction (EF) as indices of contractility were then calculated, and the z scores of LV dimensions determined. Diastolic function of LV was estimated from the mitral inflow signal obtained by Doppler echocardiography. In three-dimensional echocardiography, time-volume curves were used to determine end-diastolic and end-systolic volumes, stroke volume, and EF. Diastolic and systolic function of LV was estimated from the calculated first derivatives of these curves. Results: (I): In all children with ASD, during the one-year follow-up, the z score of the RV end-diastolic diameter decreased and that of LV increased. However, dilatation of RV did not resolve entirely during the follow-up in either treatment group. In addition, the size of LV increased more slowly in the surgical subgroup but reached control levels in both groups. Concentrations of natriuretic peptides in patients treated percutaneously increased during the first month after ASD closure and normalized thereafter, but in patients treated surgically, they remained higher than in controls. (II): In the PDA group, at baseline, the end-diastolic diameter of LV measured over 2SD in 5 of 33 patients. The median N-terminal pro-brain natriuretic peptide (proBNP) concentration before closure measured 72 ng/l in the control group and 141 ng/l in the PDA group (P = 0.001) and 6 months after closure measured 78.5 ng/l (P = NS). Patients differed from control subjects in indices of LV diastolic and systolic function at baseline, but by the end of follow-up, all these differences had disappeared. Even in the subgroup of patients with normal-sized LV at baseline, the LV end-diastolic volume decreased significantly during follow-up. (III): Before repair, the size and wall thickness of LV were higher in patients with CoA than in controls. Systolic blood pressure measured a median 123 mm Hg in patients before repair (P < 0.001) and 103 mm Hg one year thereafter, and 101 mm Hg in controls. The diameter of the coarctation segment measured a median 3.0 mm at baseline, and 7.9 at the 12-month (P = 0.006) follow-up. Thicknesses of the interventricular septum and posterior wall of the LV decreased after repair but increased to the initial level one year thereafter. The velocity time integrals of mitral inflow increased, but no changes were evident in LV dimensions or contractility. During follow-up, serum levels of natriuretic peptides decreased correlating with diastolic and systolic indices of LV function in 2D and 3D echocardiography. (IV): In 2D echocardiography, the interventricular septum and LV posterior wall were thicker, and velocity time integrals of mitral inflow shorter in patients with Mulibrey nanism than in controls. In 3D echocardiography, LV end-diastolic volume measured a median 51.9 (range 33.3 to 73.4) ml/m² in patients and 59.7 (range 37.6 to 87.6) ml/m² in controls (P = 0.040), and serum levels of ANPN and proBNP a median 0.54 (range 0.04 to 4.7) nmol/l and 289 (range 18 to 9170) ng/l, in patients and 0.28 (range 0.09 to 0.72) nmol/l (P < 0.001) and 54 (range 26 to 139) ng/l (P < 0.001) in controls. They correlated with several indices of diastolic LV function. Conclusions (I): During the one-year follow-up after the ASD closure, RV size decreased but did not normalize in all patients. The size of the LV normalized after ASD closure but the increase in LV size was slower in patients treated surgically than in those treated with the percutaneous technique. Serum levels of ANPN and proBNP were elevated prior to ASD closure but decreased thereafter to control levels in patients treated with the percutaneous technique but not in those treated surgically. (II): Changes in LV volume and function caused by PDA disappeared by 6 months after percutaneous closure. Even the children with normal-sized LV benefited from the procedure. (III): After repair of CoA, the RV size and the velocity time integrals of mitral inflow increased, and serum levels of natriuretic peptides decreased. Patients need close follow-up, despite cessation of LV pressure overload, since LV hypertrophy persisted even in normotensive patients with normal growth of the coarctation segment. (IV): In children with Mulibrey nanism, the LV wall was hypertrophied, with myocardial restriction and impairment of LV function. Significant correlations appeared between indices of LV function, size of the left atrium, and levels of natriuretic peptides, indicating that measurement of serum levels of natriuretic peptides can be used in the clinical follow-up of this patient group despite its dependence on loading conditions.

Sentinel lymph node biopsy as a diagnostic tool in the treatment of breast cancer

The purpose of this study was to evaluate the use of sentinel node biopsy (SNB) in the axillary nodal staging in breast cancer. A special interest was in sentinel node (SN) visualization, intraoperative detection of SN metastases, the feasibility of SNB in patients with pure tubular carcinoma (PTC) and in those with ductal carcinoma in situ (DCIS) in core needle biopsy (CNB) and additionally in the detection of axillary recurrences after tumour negative SNB. Patients and methods. 1580 clinically stage T1-T2 node-negative breast cancer patients, who underwent lymphoscintigraphy (LS), SNB and breast surgery between June 2000 - 2004 at the Breast Surgery Unit. The CNB samples were obtained from women, who participated the biennial, population based mammography screening at the Mammography Screening Centre of Helsinki 2001 - 2004.In the follow- up, a cohort of 205 patients who avoided AC due to negative SNB findings were evaluated using ultrasonography one and three years after breast surgery. Results. The visualization rate of axillary SNs was not enhanced by adjusting radioisotope doses according to BMI. The sensitivity of the intraoperative diagnosis of SN metastases of invasive lobular carcinoma (ILC) was higher, 87%, with rapid, intraoperative immunohistochemistry (IHC) group compared to 66% without it. The prevalence of tumour positive SN findings was 27% in the 33 patients with breast tumours diagnosed as PTC. The median histological tumour size was similar in patients with or without axillary metastases. After the histopathological review, six out of 27 patients with true PTC had axillary metastases, with no significant change in the risk factors for axillary metastases. Of the 67 patients with DCIS in the preoperative percutaneous biopsy specimen , 30% had invasion in the surgical specimen. The strongest predictive factor for invasion was the visibility of the lesion in ultrasound. In the three year follow-up, axillary recurrence was found in only two (0.5%) of the total of 383 ultrasound examinations performed during the study, and only one of the 369 examinations revealed cancer. None of the ultrasound examinations were false positive, and no study participant was subjected to unnecessary surgery due to ultrasound monitoring. Conclusions. Adjusting the dose of the radioactive tracer according to patient BMI does not increase the visualization rate of SNs. The intraoperative diagnosis of SN metastases is enhanced by rapid IHC particularly in patients with ILC. SNB seems to be a feasible method for axillary staging of pure tubular carcinoma in patients with a low prevalence of axillary metatastases. SNB also appears to be a sensible method in patients undergoing mastectomy due to DCIS in CNB. It also seems useful in patients with lesions visible in breast US. During follow-up, routine monitoring of the ipsilateral axilla using US is not worthwhile among breast cancer patients who avoided AC due to negative SN findings.

Injection laryngoplasty with autologous fascia for treatment of unilateral vocal fold paralysis

The purpose of this dissertation was to study the applicability of minced autologous fascia graft for injection laryngoplasty of unilateral vocal fold paralysis (UVFP). Permanence of augmentation and host versus graft tissue reactions were of special interest. The topic deals with phonosurgery, which is a subdivision of the Ear, Nose and Throat-speciality of medicine. UVFP results from an injury to the recurrent or the vagal nerve. The main symptom is a hoarse and weak voice. Surgery is warranted for patients in whom spontaneous reinnervation and a course of voice therapy fails to improve the voice. Injection laryngoplasty is a widespread surgical technique which aims to restore glottic closure by augmenting the atrophied vocal muscle, and also by turning the paralyzed vocal fold towards midline. Currently, there exists a great diversity of synthetic, xenologous, homologous, and autologous substances available for injection. An autologous graft is perfect in terms of biocompatibility. Free fascia grafts have been successfully used in the head and neck surgery for decades, but fascia had not been previously applied into the vocal fold. The fascia is harvested from the lateral thigh under local anesthesia and minced into paste by scissors. Injection of the vocal fold is performed in laryngomicroscopy under general anesthesia. Three series of clinical trials of injection laryngoplasty with autologous fascia (ILAF) for patients with UVFP were conducted at the Department of Otorhinolaryngology of the Helsinki University Central Hospital. The follow-up ranged from a few months to ten years. The aim was to document the vocal results and possible morbidity related to graft harvesting and vocal fold injection. To address the tissue reactions and the degree of reabsoprtion of the graft, an animal study with a follow-up ranging from 3 days to 12 months was performed at the National Laboratory Animal Center, University of Kuopio. Harvesting of the graft and injection was met with minor morbidity. Histological analysis of the vocal fold tissue showed that fascia was well tolerated. Although some resorption or compaction of the graft during the first months is evident, graft volume is maintained well. When injected deep and laterally into the vocalis muscle, the fascia graft allows normal vibration of the vocal fold mucosa to occur during phonation. Improvement of voice quality was seen in all series by multiple objective parameters of voice evaluation. However, the vocal results were poor in cases where the nerve trauma was severe, such as UVFP after chest surgery. ILAF is most suitable for correction of mild to moderate glottic gaps related to less severe nerve damage. Our results indicate that autologous fascia is a feasible and safe new injection material with good and stable vocal results. It offers a practical solution for surgeons who treat this complex issue.

Cyclosporine A in the treatment of Interstitial Cystitis

Painful bladder syndrome/interstitial cystitis (PBS/IC) is a chronic urinary bladder disorder of unknown etiology characterized by symptoms of bladder pain and urinary frequency. PBS/IC is a chronic disease in which drug therapy has not led to significant success over the course of time. If the symptoms of PBS/IC are refractory to standard treatments, a possible cure might demand surgical intervention involving cystectomy. The eventual autoimmune etiology in mind, immunosuppressive drug therapy with cyclosporine A (CyA) was started to patients with refractory PBS/IC. CyA is a potent anti-inflammatory drug, a calcineurin inhibitor which inhibits T lymphocyte IL-2 produc-tion. T cells are present in abundance in inflammation of the bladder in PBS/IC. On the basis of a pilot, short-term study with CyA on PBS/IC, use of CyA was continued empirically over the long term. We conducted a prospective, randomized, six-month study in 64 patients comparing the effect of CyA with the FDA approved treatment, pentosan polysulfate sodium (PPS). We measured the drug effect on patient s symptoms, the potassium sensitivity test, and on urinary biomarkers. We further tested the impact of CyA, PPS, DMSO and BCG therapy on a health-related quality of life questionnaire and evaluated the response rate to treatment with these therapies. Long-term use of CyA was safe and effective in PBS/IC patients. The good clinical effect matured individually during the years in which CyA was continued. Cessation of medication led to the reappearance of symptoms, and restarting CyA to renewed alleviation, so that CyA was administered as continuous medication. The response rate to CyA increased during the study period, comprising 75% of CyA patients at six months. 19% of patients responded to PPS therapy. Adverse effects were more common in the CyA group, underlining the importance of monitoring the drug safety and appropriate titration of the dose. The potassium sensitivity test is positive in the majority of PBS/IC patients. Successful therapy of PBS/IC can alter nerve sensitivity to external potassium. This effect was seen more often after CyA therapy. Successful treatment of PBS/IC with CyA resulted to decreasing urinary levels of EGF. IL-6 levels in urine were higher among older patient with a longer history of PBS/IC. In these patients, reduced levels of urinary IL-6 were measured after CyA therapy. Patients who experience the best treatment response have improved quality of life according to the post-treatment health-related quality of life (HRQOL) questionnaire. CyA had more impact on the ma-jority of the aspects of QoL than PPS. Despite DMSO therapy being more successful than BCG in the count of responders, DMSO and BCG had equal effects on the HRQOL questionnaire.

Childhood otitis media - risk factors and surgical management

Background: Otitis media (OM) is one of the most common childhood diseases. Approximately every third child suffers from recurrent acute otitis media (RAOM), and 5% of all children have persistent middle ear effusion for months during their childhood. Despite numerous studies on the prevention and treatment of OM during the past decades, its management remains challenging and controversial. In this study, the effect of adenoidectomy on the risk for OM, the potential risk factors influencing the development of OM and the frequency of asthma among otitis-prone children were investigated. Subjects and methods: One prospective randomized trial and two retrospective studies were conducted. In the prospective trial, 217 children with RAOM or chronic otitis media with effusion (COME) were randomized to have tympanostomy with or without adenoidectomy. The age of the children at recruitment was between 1 and 4 years. RAOM was defined as having at least 3 episodes of AOM during the last 6 months or at least 5 episodes of AOM during the last 12 months. COME was defined as having persistent middle ear effusion for 2-3 months. The children were followed up for one year. In the first retrospective study, the frequency of childhood infections and allergy was evaluated by a questionnaire among 819 individuals. In the second retrospective study, data of asthma diagnosis were analysed from hospital discharge records of 1616 children who underwent adenoidectomy or had probing of the nasolacrimal duct. Results: In the prospective randomized study, adenoidectomy had no beneficial effect on the prevention of subsequent episodes of AOM. Parental smoking was found to be a significant risk factor for OM even after the insertion of tympanostomy tubes. The frequencies of exposure to tobacco smoke and day-care attendance at the time of randomization were similar among children with RAOM and COME. However, the frequencies of allergy to animal dust and pollen and parental asthma were lower among children with COME than those with RAOM. The questionnaire survey and the hospital discharge data revealed that children who had frequent episodes of OM had an increased risk for asthma. Conclusions: The first surgical intervention to treat an otitis-prone child younger than 4 years should not include adenoidectomy. Interventions to stop parental smoking could significantly reduce the risk for childhood RAOM. Whether an otitis-prone child develops COME or RAOM, seems to be influenced by genetic predisposition more strongly than by environmental risk factors. Children who suffer from repeated upper respiratory tract infections, like OM, may be at increased risk for developing asthma.

Simplified Treatment of Childhood Acute Bone and Joint Infections

Acute childhood osteomyelitis (OM), septic arthritis (SA), and their combination osteomyelitis with adjacent septic arthritis (OM+SA), are treated with long courses of antimicrobials and immediate surgery. We conducted a prospective multi-center randomized trial among Finnish children at age 3 months to 15 years in 1983-2005. According to the two-by-two factorial study design, children with OM or OM+SA received 20 or 30 days of antimicrobials, whereas those with SA were treated for 10 or 30 days. In addition, the whole series was randomized to be treated with clindamycin or a first-generation cephalosporin. Cases were included only if the causative agent was isolated. The treatment was instituted intravenously, but only for the first 2-4 days. Percutaneous aspiration was done to obtain a representative sample for bacteriology, but all other surgical intervention was kept at a minimum. A total of 265 patients fulfilled our strict inclusion criteria and were analyzed; 106 children had OM, 134 SA, and 25 OM+SA. In the OM group, one child in the long and one child in the short-term treatment group developed sequelae. One child with SA twice developed a late re-infection of the same joint, but the causative agents differed. Regarding surgery, diagnostic arthrocentesis or corticotomy was the only surgical procedure performed in most cases. Routine arthrotomy was not required even in hip arthritis. Serum C-reactive protein (CRP) proved to be a reliable laboratory index in the diagnosis and monitoring of osteoarticular infections. The recovery rate was similar regardless of whether clindamycin or a first-generation cephalosporin was used. We conclude that a course of 20 days of these well-absorbing antimicrobials is sufficient for OM or OM+SA, and 10 days for SA in most cases beyond the neonatal age. A short intravenous phase of only 2-5 days often suffices. CRP gives valuable information in monitoring the course of illness. Besides diagnostic aspiration, surgery should be reserved for selected cases.

Non-small cell lung cancer : studies on pathogenesis, tumour targeting and treatment outcomes

Lung cancer accounts for more cancer-related deaths than any other cancer. In Finland, five-year survival ranges from 8% to 13%. The main risk factor for lung cancer is long-term cigarette smoking, but its carcinogenesis requires several other factors. The aim of the present study was to 1) evaluate post-operative quality of life, 2) compare clinical outcomes between minimally invasive and conventional open surgery, 3) evaluate the role of oxidative stress in the carcinogenesis of non-small lung cancer (NSCLC), and 4) to identify and characterise targeted agents for therapeutic and diagnostic use in surgery. For study I, pneumonectomy patients replied to 15D quality of life and baseline dyspnea questionnaires. Study III involved a prospective quality of life assessment using the 15D questionnaire after lobectomy or bi-lobectomy. Study IV was a retrospective comparison of clinical outcomes between 212 patients treated with open thoracotomy and 116 patients who underwent a minimally invasive technique. Study II measured parameters of oxidative metabolism (myeloperoxidase activity, glutathione content and NADPH oxidase activity) and DNA adducts. Study V employed the phage display method and identified a core motif for homing peptides. This method served in cell-binding, cell-localisation, and biodistribution studies. Following both pneumonectomy and lobectomy, NSCLC patients showed significantly decreased long-term quality of life. No significant correlation was noted between post-operative quality of life and pre-operative pulmonary function tests. Women suffered more from increased dyspnea after pneumonectomy which was absent after lobectomy or bi-lobectomy. Patients treated with video-assisted thoracoscopy showed significantly decreased morbidity and shorter periods of hospitalization than did open surgery patients. This improvement was achieved even though the VATS patients were older and suffered more comorbid conditions and poorer pulmonary function. No significant differences in survival were noted between these two groups. An increase in NADPH oxidase activity was noted in tumour samples of both adenocarcinoma and squamous cell carcinoma. This increase was independent from myeloperoxidase activity. Elevated glutathione content was noted in tumour tissue, especially in adenocarcinoma. After panning the clinical tumour samples with the phage display method, an amino acid sequence of ARRPKLD, the Thx, was chosen for further analysis. This method proved selective of tumour tissue in both in vitro and in vivo cell-binding assay, and biodistribution showed tumour accumulation. Because of the significantly reduced quality of life following pneumonectomy, other operative strategies should be implemented as an alternative (e.g. sleeve-lobectomy). To treat this disease, implementation of a minimally invasive surgical technique is safe, and the results showed decreased morbidity and a shorter period of hospitalisation than with thoracotomy. This technique may facilitate operative treatment of elderly patients with comorbid conditions who might otherwise be considered inoperable. Simultaneous exposure to oxidative stress and altered redox states indicates the important role of oxidative stress in the pathogenesis and malignant transformation of NSCLC. The studies showed with great specificity and with favourable biodistribution that Thx peptide is specific to NSCLC tumours. Thx thus shows promise in imaging, targeted therapy, and monitoring of treatment response.

Mid-urethral slings for treatment of stress urinary incontinence : long- and mid-term follow-up

Urinary incontinence is a common problem, affecting one third of the women at least at some time during their lives. The prevalence of urinary incontinence increases with advancing age, and the everyday impact of incontinence on women and on health services is enormous. Urinary incontinence is usually divided into three different subtypes, of which stress urinary incontinence (SUI) is the most common. Surgical treatment is often needed to cure SUI, and modern mid-urethral sling procedures give the possibility to cure this condition with a low risk of adverse events, a problem often associated with the so-called traditional incontinence operations. Life expectancy among women in Western countries has grown beyond 80 years of age. Long-term efficacy of treatment options for urinary incontinence therefore becomes an important issue in a world with limited eco-nomic resources. The purpose of the present study was to prospectively evaluate the long-term efficacy and safety of the first minimally invasive mid-urethral tape procedure, the Tension-free Vaginal Tape (TVT) procedure. The long-term (5-year) follow-up results of the TVT procedure as a repeat operation af-ter an unsuccessful mid-urethral tape operation were studied and the reasons for failure of the first operation were analyzed. Another purpose was to compare the original TVT procedure with a newer modification, the Tension-free Vaginal Tape Obturator (TVT-O) procedure within a multi-centre, randomized context in order to find out possible differences between these procedures re-garding efficacy and complications and the effects on symptoms of urgency. The first study of the present thesis is a prospective, Nordic, three-centre follow-up study of 90 women suffering from SUI, who were treated by means of the TVT procedure. The mean follow-up time was more than eleven years, and the study is the first to be published in connection with more than ten years of follow-up. The second study is a retrospective analysis of 26 women who were treated with a repeat TVT procedure after an unsuccessful primary mid-urethral tape procedure. The third and fourth studies concern 273 women in seven centres in Finland who were ran-domly assigned to the TVT and TVT-O procedures, the 3-year follow-up results of which are pre-sented in this thesis. After eleven years of follow-up, 90% of the women had a negative cough stress test result and a negative 24-h pad test result. The subjective cure rate measured as the women s global impression of cure was 77%, the rate of improvement 20%, and only 3% thought that the treatment had failed. No late-onset adverse effects were found. The repeat TVT procedure was successful in 75% of the cases when women who were cured and women who were significantly improved were included. The reasons for failure of the first operation could be separated into four different groups: tape material-related, operation technique-related, concomitant illness-related and a group with no identifiable reason. There were no intra-operative complications during the repeat operation. In the randomized trial comparing the TVT with the TVT-O procedure a cough stress test results were negative in 94.6% and 89.5% of the women in the two groups, respectively, after a 3-year follow-up period. There were no statistical differences in the cure rate or the rate of complications be-tween the two procedures. Symptoms of urgency were analyzed more closely and the main finding was that the prevalence of urgency symptoms decreased significantly after both mid-urethral sling procedures. The TVT operation was found to be an effective and safe procedure even after eleven years of follow-up. Long-term follow-up after a repeat TVT procedure revealed that the TVT procedure can well be considered after an unsuccessful mid-urethra tape procedure, because 75% of the patients showed significantly improvement of their incontinence. The TVT and TVT-O procedures showed no statistically significant differences in efficacy and rate of complications after three years of follow-up. In most cases these procedures alleviate preoperative symptoms of urgency and the risk of developing de novo urgency is low.

The effectiveness of infrainguinal percutaneous transluminal angioplasty in the treatment of critical limb ischaemia

Critical chronic lower limb ischaemia (CLI) is the most severe form of peripheral arterial disease. Even though the treatment of CLI has evolved during the last decade, CLI is still associated with considerable morbidity, mortality and a decreased quality of life, in addition to a large financial impact on society. ---- Bypass surgery has traditionally been considered the approach of choice to treat CLI patients in order to avoid amputation. However, there are increasing data on the efficacy of endovascular revascularization procedures, such as percutaneous transluminal angioplasty (PTA), to achieve good leg salvage rates as well. Data gathered on all the 2,054 CLI patients revascularized at the Helsinki University Central Hospital between 2000 and 2007 were retrospectively analyzed. This patient cohort was used to compare the results of infrainguinal PTA and bypass surgery as well as to investigate predictors of failure after PTA. This study showed that infrainguinal PTA and bypass surgery yielded rather similar results in terms of survival, amputation-free survival and freedom from any re-intervention. When the femoropoliteal segment was treated, leg salvage was significantly better in the bypass surgery group, whereas no significant difference was observed between the two treatment methods when the revascularization extended to the infrapopliteal segment. PTA resulted in a significantly lower freedom from surgical re-interventions when compared to surgical revascularization. In this study the most important predictors of poor outcome after PTA for CLI were cardiac morbidity, nonambulatory status upon hospital arrival, and gangrene as a manifestation of CLI. Thus, when feasible, PTA seems to be a valid alternative for bypass surgery in the treatment of CLI provided that active redo-surgery is utilized. The optimal revascularization strategy should always be sought for each CLI patient individually considering the clinical state of the leg, the occlusive lesions to be treated, co-morbidities, life-expectancy, and the availability of a suitable vein for bypass.

Optimal Use of Treatment Modalities and Treatment Results of Osteosarcoma and Soft Tissue Sarcomas

Soft tissue sarcomas are malignant tumours of mesenchymal origin. Because of infiltrative growth pattern, simple enucleation of the tumour causes a high rate of local recurrence. Instead, these tumours should be resected with a rim of normal tissue around the tumour. Data on the adequate margin width are scarce. At Helsinki University Central Hospital (HUCH) a multidisciplinary treatment group started in 1987. Surgical resection with a wide margin (2.5 cm) is the primary aim. In case of narrower margin radiation therapy is necessary. The role of adjuvant chemotherapy remains unclear. Our aims were to study local control by the surgical margin and to develop a new prognostic tool to aid decision-making on which patients should receive adjuvant chemotherapy. Patients with soft tissue sarcoma of the extremity or the trunk wall referred to HUCH during 1987-2002 form material in Studies I and II. External validation material comes from the Lund university sarcoma registry. The smallest surgical margin of at least 2.5 centimetres yielded local control of 89 per cent at five years. Amputation rate was 9 per cent. The proposed prognostic model with necrosis, vascular invasion, size on a continuous scale, depth, location and grade worked well both in Helsinki material and in the validation material, and it also showed good calibration. Based on the present study, we recommend the smallest surgical margin of 2-3 centimetres in soft tissue sarcoma irrespective of grade. Improvement in local control was present but modest in margins wider than 1 centimetre. In cases where gaining a wider margin would lead to a considerable loss of function, smaller margin is to be considered combined to radiation therapy. Patients treated with inadequate margins should be offered radiation therapy irrespective of tumour grade. Our new prognostic model to estimate 10-year survival probability in patients with soft tissue sarcoma of the extremities or trunk wall showed good dicscrimination and calibration. For time being the prognostic model is available for scientific use and further validations. In the future, the model may aid in clinical decision-making. For operable osteosarcoma, neoadjuvant multidrug chemotherapy followed by delayed surgery and multidrug adjuvant chemotherapy is the treatment of choice. Overall survival rates at five years are approximately 75 per cent in modern trials with classical osteosarcoma. All patients diagnosed and reported to the Finnish Cancer Registry with osteosarcoma in Finland during 1971-2005 form the material in Studies III and IV. Limb-salvage rate increased from 23 per cent to 78 per cent during 1971-2005. The 10-year sarcoma-specific survival for the whole study population improved from 32 per cent to 62 per cent. It was 75 per cent for patients with a local high-grade osteosarcoma of the extremity diagnosed during 1991-2005. This study outlines the improved prognosis of osteosarcoma patients in Finland with modern chemotherapy. The 10-year survival rates are good also in an international scale. Nonetheless, their limb-salvage rate remains inferior to those seen for highly selected patient series. Overall, the centralisation of osteosarcoma treatment would most likely improve both survival and limb-salvage rates even further.

Myoblast Sheet Transplantation for Treatment of Heart Failure after Myocardial Infarction

Heart failure is a common, severe, and progressive condition associated with high mortality and morbidity. Because of population-aging in the coming decades, heart failure is estimated to reach epidemic proportions. Current medical and surgical treatments have reduced mortality, but the prognosis for patients has remained poor. Transplantation of skeletal myoblasts has raised hope of regenerating the failing heart and compensating for lost cardiac contractile tissue. In the present work, we studied epicardial transplantation of tissue-engineered myoblast sheets for treatment of heart failure. We employed a rat model of myocardial infarction-induced acute and chronic heart failure by left anterior descending coronary artery ligation. We then transplanted myoblast sheets genetically modified to resist cell death after transplantation by expressing antiapoptotic gene bcl2. In addition, we evaluated the regenerative capacity of myoblast sheets expressing the cardioprotective cytokine hepatocyte growth factor in a rat chronic heart failure model. Furthermore, we utilized in vitro cardiomyocyte and endothelial cell culture models as well as microarray gene expression analysis to elucidate molecular mechanisms mediating the therapeutic effects of myoblast sheet transplantation. Our results demonstrate that Bcl2-expression prolonged myoblast sheet survival in rat hearts after transplantation and induced secretion of cardioprotective, proangiogenic cytokines. After acute myocardial infarction, these sheets attenuated left ventricular dysfunction and myocardial damage, and they induced therapeutic angiogenesis. In the chronic heart failure model, inhibition of graft apoptosis by Bcl-2 improved cardiac function, supported survival of cardiomyocytes in the infarcted area, and induced angiogenesis in a vascular endothelial growth factor receptor 1- and 2-dependent mechanism. Hepatocyte growth factor-secreting myoblast sheets further enhanced the angiogenic efficacy of myoblast sheet therapy. Moreover, myoblast-secreted paracrine factors protected cardiomyocytes against oxidative stress in an epidermal growth factor receptor- and c-Met dependent manner. This protection was associated with induction of antioxidative genes and activation of the unfolded protein response. Our results provide evidence that inhibiting myoblast sheet apoptosis can enhance the sheets efficacy for treating heart failure after acute and chronic myocardial infarction. Furthermore, we show that myoblast sheets can serve as vehicles for delivery of growth factors, and induce therapeutic angiogenesis in the chronically ischemic heart. Finally, myoblasts induce, in a paracine manner, a cardiomyocyte-protective response against oxidative stress. Our study elucidates novel mechanisms of myoblast transplantation therapy, and suggests effective means to improve this therapy for the benefit of the heart failure patient.