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One strategy for improving detection of fetal growth restriction (FGR) is developing biosensors identifying placental dysfunction as a leading pathogenesis for FGR. The aim of this pilot study was to investigate the performance of a biosensor specified to detect placental dysfunction by means of maternal arterial turbulence acoustics in a low-resource setting. A cohort of 147 singleton pregnant women were prospectively followed with double-blinded biosensor tests, sonographic estimation of fetal weight (EFW) and Doppler flow at 26–28, 32–34 and 37–39 weeks of pregnancy. Full term live births with recorded birth weights (BWs) and without major congenital malformations were included. Outcomes were defined as (A) a solitary biometric measure (BW &lt, 3rd centile) and as (B) a biometric measure and contributory functional measure (BW &lt, 10th centile and antenatally detected umbilical artery pulsatility index &gt, 95th centile). Data from 118 women and 262 antenatal examinations were included. Mean length of pregnancy was 40 weeks (SD ± 8 days), mean BW was 3008 g (SD ± 410 g). Outcome (A) was identified in seven (6%) pregnancies, whereas outcome (B) was identified in one (0.8%) pregnancy. The biosensor tested positive in five (4%) pregnancies. The predictive performance for outcome (A) was sensitivity = 0.29, specificity = 0.97, p = 0.02, positive predictive value (PPV) was 0.40 and negative predictive value (NPV) was 0.96. The predictive performance was higher for outcome (B) with sensitivity = 1.00, specificity = 0.97, p = 0.04, PPV = 0.20 and NPV = 1.00. Conclusively, these pilot-study results show future potential for biosensors as screening modality for FGR in a low-resource setting.

Introduction: Anemia during pregnancy may compromise fetal and newborn's health, however, little is known about how and when the fetoplacental vascularization is most vulnerable to anemia. Methods: Using systematic and isotropic uniform random sampling, placental samples were collected from 189 placentas in a cohort study of Tanzanian women whose hemoglobin concentration was measured throughout pregnancy. Fetoplacental vessels and villi were defined as exerting either a transport or diffusion function. The vascularization patterns for transport and diffusion vessels and villi were assessed by stereology. Blood vessel length, surface area and diffusion distance as well as placental villi volume were calculated. Results: Anemia from a gestational age of 23 weeks was significantly associated with increased fetoplacental vascularization in vessels and villi compared to women who were non-anemic throughout pregnancy. Transport surface vessel area: 0.31 m 2 [95% CI: 0.18–0.55], P = 0.01; Transport villi volume 19.8 cm 3 [95% CI: 6.37–33.2], P = 0.004, Transport vessel diameter 7.23 μm [95% CI: 1.23–13.3], P = 0.02. Diffusion vessel surface: 3.23 m 2 [95% CI: 1.55–4.91], P < 0.001 and diffusion villi volume: 29.8 cm 3 [95% CI: 10.0–49.5], P = 0.003). Finally, all the measured transport vessel and villi significantly parameters and diffusion vessel surface, vessel diameter and diffusion distance were associated with birth weight. Discussion: Increased fetoplacental vascularization related to anemia from a gestational age of 23 weeks in pregnancy together with the association between fetoplacental vascularity and birth weight suggest that the timing of anemia determines the effect on fetoplacental vascularization and underlines the clinical relevance for proper development of fetoplacental vasculature.

Introduction: Peritoneal metastases (PM) originating from colorectal cancer (CRC) and pseudomyxoma peritonei (PMP) can be treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Certain sites in the peritoneal cavity are prone to contain PM and are, therefore, routinely resected. The aim of this study is to investigate the frequency of disease in CRS specimens routinely resected. Secondly, to investigate if the risk of finding PM in routinely resected specimen is associated with involvement of anatomic related peritoneal areas. Materials and methods: This study investigated 433 patients diagnosed with PMP (n = 119) or PM from CRC (n = 314) and operated with CRS + HIPEC between June 2006 and November 2020 at a national center. Baseline data were prospectively registered. Pathology reports were reviewed for the presence of metastases in the routinely resected umbilicus, ligamentum teres hepatis, ovaries and greater omentum. Tumor extent was estimated using the Dutch region count. Results: PM was found in 14.7% of umbilical resections, in 17.4% of the resected ligamentum teres hepatis, in 48.2% of the resected ovaries and in 49.5% of the greater omentum specimens. We found an association between macroscopic disease involvement of the nearest region and risk of PM found in the related resections. Seven of 31 women with no macroscopically visible disease in the pelvis had PM diagnosed in the resected ovaries. Conclusions: A substantial proportion of routine resections held histologic verified PM. Our results may advocate for a routinely performed resection of the umbilicus, ligamentum teres hepatis, ovaries and greater omentum.

Uddrag ‘Postkapitalisme – en guide til vores fremtid’ oversat af Karsten Nielsen

PurposeLow-income and middle-income countries such as Tanzania experience a high prevalence of non-communicable diseases (NCDs), including anaemia. Studying if and how anaemia affects growth, placenta development, epigenetic patterns and newborns’ risk of NCDs may provide approaches to prevent NCDs.ParticipantsThe FOETALforNCD (FOetal Exposure and Epidemiological Transitions: the role of Anaemia in early Life for Non-Communicable Diseases in later life) Study is a population-based preconception, pregnancy and birth cohort study (n=1415, n=538, n=427, respectively), conducted in a rural region of North-East Tanzania. All participants were recruited prior to conception or early in pregnancy and followed throughout pregnancy as well as at birth. Data collection included: maternal blood, screening for NCDs and malaria, ultrasound in each trimester, neonatal anthropometry at birth and at 1 month of age, cord blood, placental and cord biopsies for stereology and epigenetic analyses.Findings to dateAt preconception, the average age, body mass index and blood pressure of the women were 28 years, 23 kg/m2 and 117/75 mm Hg, respectively. In total, 458 (36.7%) women had anaemia (haemoglobin Hb Future plansThe project will provide new knowledge on how health, even before conception, might modify the risk of developing NCDs and how to promote better health during pregnancy. The present project ended data collection 1 month after giving birth, but follow-up is continuing through regular monitoring of growth and development and health events according to the National Road Map Strategic Plan in Tanzania. This data will link fetal adverse event to childhood development, and depending on further grant allocation, through a life course follow-up.

Unmanned Aerial Vehicles (UAVs) paired with image detection and segmentation techniques can be used to extract plant phenotype information of individual breeding or research plots. Each plot contains plants of a single genetic line. Breeders are interested in selecting lines with preferred phenotypes (physical traits) that increase crop yield or resilience. Automated detection and segmentation of plots would enable automatic monitoring and quantification of plot phenotypes, allowing a faster selection process that requires much fewer person-hours compared with manual assessment. A detection algorithm based on Laplacian of Gaussian (LoG) blob detection and a segmentation algorithm based on a combination of unsupervised clustering and random walker image segmentation are proposed to detect and segment lentil plots from multi-spectral aerial images. Our algorithm detects and segments lentil plots from normalized difference vegetative index (NDVI) images. The detection algorithm exhibited an average precision and recall of 96.3% and 97.2% respectively. The average Dice similarity coefficient between a detected segmented plot and its ground truth was 0.906.

Background Pregnancy malaria has a negative impact on fetal outcome. It is uncertain whether infections in early pregnancy have a clinical impact by impeding the development of the placental vasculature. Methods Tanzanian women (n = 138) were closely monitored during pregnancy. Placentas collected at birth were investigated using stereology to establish the characteristics of placental villi and vessels. Placental vasculature measures were compared between women infected with malaria and controls. Results Compared with controls, placentas from women infected with malaria before a gestational age (GA) of 15 weeks had a decreased volume of transport villi (mean decrease [standard deviation], 12.45 [5.39] cm3; P = .02), an increased diffusion distance in diffusion vessels (mean increase, 3.33 [1.27] µm; P = .01), and a compensatory increase in diffusion vessel surface area (mean increase, 1.81 [0.74 m2]; P = .02). In women who had malaria before a GA of 15 weeks diffusion vessel surface area and transport vessel length distance were positive predictors for birth weight (multilinear regression: P = .007 and P = .055 for diffusion surface area and transport length, respectively) and GA at delivery (P = .005 and P = .04). Conclusions Malaria infection in early pregnancy impedes placental vascular development. The resulting phenotypic changes, which can be detected at delivery, are associated with birth weight and gestational length. Clinical Trials Registration NCT02191683.

INTRODUCTION: Despite an intensive screening activity, the incidence of cervical cancer in Denmark has remained stable for the last 15 years, while regional differences have increased. To search for explanations, we investigated possible weaknesses in the screening program.MATERIAL AND METHODS: Data on the screen-targeted women were retrieved from Statistics Denmark. Data on screening activity were retrieved from the annual reports from 2009 to 2015 on quality of cervical screening. Coverage was calculated as proportion of screen-targeted women with at least one cytology sample within recommended time intervals. Insufficient follow-up was calculated as proportion of abnormal and unsatisfactory samples not followed up within recommended time intervals. Diagnostic distribution was calculated for samples with a satisfactory cytology diagnosis.RESULTS: Coverage remained stable at 75%-76% during the study period. Annually, approximately 100,000 women are screened before they are eligible for invitation, and 600,000 invitations and reminders are issued resulting in screening of 200,000 women. In 2009, 21% of abnormal and unsatisfactory samples were not followed up within the recommended time interval; a proportion that had decreased to 15% in 2015. Overall, 11% of satisfactory samples with a cytology diagnosis were abnormal, but with surprising variation from 6% to 15% across regions.DISCUSSION: The success of a screening program depends first of all on coverage and timely follow-up of abnormal findings. Our analysis indicated that the currently high incidence of cervical cancer in Denmark may partly be due to low screening coverage. Also worrisome is a high proportion of non-timely follow-up of abnormal findings. Innovative ways to improve coverage and follow-up are urgently needed.

We examined the learning effect of a workshop for Danish hematopathologists led by an international expert regarding histological subtyping of myeloproliferative neoplasms (MPN). Six hematopathologists evaluated 43 bone marrow (BM) biopsies according to the WHO description (2008), blinded to clinical data. All panelists then participated in the workshop. The case biopsies - mixed with 251 other MPN BM biopsies - were reviewed again. Consensus regarding the histological subtype was significantly improved; from 49% to 72% (Fleiss kappa value 0.302 pre-workshop, 0.474 post-workshop; p = 0.004). There was no significant effect on the isolated morphological characteristics. Agreement between cases with histological consensus and clinical diagnosis was 86% without significant change during workshop sessions. Our study demonstrates that experienced hematopathologists can significantly improve their diagnostic ability by a workshop led by an international expert; not by improving the evaluation of individual histological parameters but by weighting these in their conclusive diagnosis.

Malignant melanoma is a rare type of cancer in the vagina and vulva associated with a poor prognosis due to late diagnosis and early dissemination. Only a limited amount of literature exists on the condition. This study elucidates the effect of current treatment.All patients diagnosed with malignant melanoma in the vagina or vulva at Aarhus University Hospital, Skejby, Denmark, in the period from 1996 to 2013 were included. Data were collected from the electronic patient records and from the Danish Pathology Register.A total of 17 patients were included. The average age at the time of diagnosis was 77 years and the median overall survival time was 21.9 months. The five-year survival in this study was 17.7%. The majority of the melanomas were nodular and all of the superficially spreading melanomas were found in the vulva only. Malignant melanoma in the vagina has a poorer prognosis than in the vulva as it is diagnosed later.Early diagnosis and staging of this cancer is important. Positron emission tomography-computed tom-ography should be the standard method for staging the disease. Older women with vaginal discharge should always have a gynaecological examination. The primary treatment is resection of the tumour, but future treatment might be a combination of resection and immunotherapy.none.not relevant. .

OBJECTIVE: To study the association between endometriosis and risk of pre-eclampsia, cesarean section, postpartum hemorrhage, preterm birth, and small for gestational age (SGA), in a large Danish birth cohort, while taking fertility treatment into account.DESIGN: Population-based study.SETTING: Not applicable.PATIENT(S): A total population of 82,793 singleton pregnancies from the Aarhus Birth Cohort (1989 through 2013); 1,213 women had a diagnosis of endometriosis, affecting 1,719 pregnancies.INTERVENTION(S): None.MAIN OUTCOME MEASURE(S): Pre-eclampsia, cesarean section, postpartum hemorrhage, preterm birth, and SGA.RESULT(S): Endometriosis was associated with an increased risk of preterm birth (adjusted odds ratio [AOR] 1.67, 95% confidence interval [CI] 1.37-2.05), with the risk being highest for very preterm birth (AOR 1.91, 95% CI 1.16-3.15). Compared with unaffected women, women with endometriosis also had an increased risk of pre-eclampsia (AOR 1.37, 95% CI 1.06-1.77) and cesarean section (AOR 1.83, 95% CI 1.60-2.09). Assisted reproductive technology did not explain these findings. No association was found between endometriosis and postpartum hemorrhage or SGA.CONCLUSION(S): Women with endometriosis were at increased risk of pre-eclampsia, preterm birth, and cesarean section, irrespective of use of assisted reproductive technology.

In a study of 41 surgically removed colorectal adenomas of unselected size, the dysplasia was graded as mild in 9, as moderate in 22, and severe in 10 cases. Twenty-four of the lesions were classified as tubular adenomas and 17 as tubulo-villous. The presence of O-acylated sialic mucin was for each of the adenomas assessed as normal (19 cases), intermediate (13 cases) or absent (9 cases). The absence of O-acylated mucin was in the present study found to be highly predictive for severe dysplasia (89%). The morphometric measurements of epithelial structures showed that nuclear shape factor and nuclear stratification index were most significantly related to the grades of dysplasia. In a multivariate analysis, the grading of O-cylated sialic mucin most significantly contributed to the grade of dysplasia, and to a lesser degree, nuclear shape factor and nuclear stratification index. The presence of villous elements and the size of the adenomas had no independent influence on the grade of dysplasia in this statistical analysis.

The presence of carcino-embryonic antigen (CEA) was studied in 92 consecutive cases of gastric adenocarcinoma, using the two-layer conjugated immunoperoxidase technique. Three characteristic patterns of CEA localization were identified. Type I: Intracytoplasmatic granules covering the entire cytoplasm of the malignant cells. Type II. Linear or granular deposits along the glycocalyx or in the apical cytoplasm of the malignant cells. Type III: Tumour cells negative for CEA or only showing a very weak reaction in a few cells. These CEA patterns were significantly related to the histogenetic classification of gastric adenocarcinomas proposed by Mulligan & Rember. The majority of the "mucus cell carcinomas" showed the type I CEA pattern. "Intestinal cell carcinomas" predominantly showed the type II CEA pattern and the "pyloro-cardiac gland carcinomas" the type III CEA pattern. The significance of the CEA patterns in respect of the histogenetic classification is discussed.

The idea that point mutations in exons may affect splicing is intriguing and adds an additional layer of complexity when evaluating their possible effects. Even in the best-studied examples, the molecular mechanisms are not fully understood. Here, we use patient cells, model minigenes, and in vitro assays to show that a missense mutation in exon 5 of the medium-chain acyl-CoA dehydrogenase (MCAD) gene primarily causes exon skipping by inactivating a crucial exonic splicing enhancer (ESE), thus leading to loss of a functional protein and to MCAD deficiency. This ESE functions by antagonizing a juxtaposed exonic splicing silencer (ESS) and is necessary to define a suboptimal 3' splice site. Remarkably, a synonymous polymorphic variation in MCAD exon 5 inactivates the ESS, and, although this has no effect on splicing by itself, it makes splicing immune to deleterious mutations in the ESE. Furthermore, the region of MCAD exon 5 that harbors these elements is nearly identical to the exon 7 region of the survival of motor neuron (SMN) genes that contains the deleterious silent mutation in SMN2, indicating a very similar and finely tuned interplay between regulatory elements in these two genes. Our findings illustrate a mechanism for dramatic context-dependent effects of single-nucleotide polymorphisms on gene-expression regulation and show that it is essential that potential deleterious effects of mutations on splicing be evaluated in the context of the relevant haplotype.

Ulocladium atrum (isolates 385 and 302) consistently inhibited Botrytis aclada sporulation on dead onion leaf pieces under constant moist conditions and with an interrupted wetness period of 9 h. Clonostachys rosea (isolate 201) was as effective as U. atrum under constant moist conditions, but was ineffective if exposed to a drying period. No sporulation of B. aclada was observed 8 and 12 days after inoculation in the presence of U. atrum 302. C. rosea 201 significantly reduced B. aclada sporulation 8 days, but not 12 days after inoculation. When U. atrum 302 or C. rosea 201 was applied 1 day prior to B. aclada the antagonistic effect was higher compared to when the antagonists were applied on the same day. C. rosea 201 and U. atrum 302 did not obstruct the growth of B. aclada from necrotic onion leaf tips into living tissue, when artificially induced necrotic leaf tips were infested with B. aclada 24 h prior to antagonists. Three days after antagonist application, no symptoms could be observed on the healthy leaf tissue, nor was there sporulation on the necrotic leaf tip. However, B. aclada was immunologically detected 2 cm below the inoculation site. We conclude that under constant moist conditions the antagonists C. rosea 201 and U. atrum 302 cannot stop the progress of B. aclada from necrotic into fresh leaf tissue.

Prostate cancer is the most common form of cancer in Danish men, and the incidence is rising. The diag-nosis is made by transrectal prostate biopsy guided by ultrasound. This procedure has several complications, the most severe being sepsis. In our department, this is sought prevented by administering the prophylactic antibiotics metronidazol and ciprofloxacin. This study examined the rate of sepsis in patients who had the procedure performed at our department.The electronic patient records of all patients who had transrectal ultrasound of the prostate with biopsies performed at the Department of Urology at Naestved Hospital in the period from 1 May 2009 to 31 May 2011 were examined, and all admissions to our department (or any department in the same region) due to sepsis within two weeks of the procedure were registered.A total of 438 patients had the procedure performed, some multiple times, which resulted in a total of 511 procedures. In all, four patients were later admitted due to sepsis, corresponding to 0.91%. Three of the patients had positive blood and urine cultures in which Escherichia coli resistant to ciprofloxacin were found, the last had been prescribed antibiotics by a general practitioner the previous day, and no bacteria could be cultured.The frequency of sepsis after transrectal needle biopsies from the prostate at our department was found to be below 1% in this study, which is comparable to international findings. Most of the cases of sepsis were related to ciprofloxacin-resistant bacteria. Further randomised studies are needed to investigate the ideal prophylactic regime.not relevant.not relevant.

43 Background: Recent clinical trial data indicate poor prognosis for patients with late-stage gastric cancer and positive tumor mesenchymal epithelial transition factor (MET) protein expression. However, there is limited information about the real-world prevalence of MET-positive (-pos) cancers and the associated prognosis. Methods: Using medical registries, we identified a cohort of patients with stage IV gastric cancer in a single institution in Northern Denmark from 2003-2010. From these patients, we collected archived (paraffin-embedded) cancer specimens and analyzed MET protein expression by immunohistochemistry (MET-pos if ≥25% of tumor cells showed membrane staining). We calculated the prevalence of patients with MET-pos tumors. We estimated survival using the Kaplan-Meier method and computed mortality rate ratios comparing MET-pos to MET-negative (-neg) patients using Cox proportional hazards models adjusted for age, gender, and Charlson’s Comorbidity Index (score of 0, 1-2, and 3+). Results: 101 patients with stage IV gastric cancer were included in the study of which 55% had MET-pos tumors. The group of patients with MET-pos tumors were younger at diagnosis than patients with MET-neg tumors (median age 65 vs 68 years), included more men, showed higher comorbidity levels, included more poorly differentiated cancers, and were less likely to undergo surgery or chemotherapy. In patients with MET-pos tumors, one-year survival was 18% compared to 39% in patients with MET-neg tumors (mortality rate ratio=2.3, 95% CI: 1.4-3.9). Conclusions: A large proportion of patients with stage IV gastric cancer had tumors demonstrating MET protein expression, and these patients had poor survival compared with patients without tumor MET expression. [Table: see text]

Botrytis aclada has previously been divided into two subgroups (AI and All) based on spore size, chromosome number and genetic markers. A recent study of genetic diversity using universal-primed PCR (UP-PCR) fingerprints showed that subgroup All of B. aclada was a possible hybrid species between B. byssoidea and subgroup Al of B. aclada. To test this hypothesis, we sequenced a UP-PCR fragment (-550 bp) from representative isolates of four Botrytis spe- cies, all causing disease on onions. A mixture of two nucleotides at each nucleotide position was found in all All isolates analyzed at 23 positions in the se- quence. These isolates had 32 chromosomes, whereas all Al isolates had 16 chromosomes. Pair-wise com- parison of the sequences of the four Botrytis species showed that a hybridization event between B. aclada (AI) and B. byssoidea could explain all 23 positions with mixed nucleotides, supporting them as being parental ancestors to All. These results indicate that at least one Botrytis pathogen has evolved through interspecific hybridization.

Systemic treatment with epidermal growth factor (EGF) induces growth of all wall layers of the urinary tract in pigs and rats. In this study, we describe the time-dependent growth of the ureter and bladder. Forty-eight female Wistar rats were allocated into five groups receiving EGF treatment (150 microg/kg per day) for 0 (controls), 1, 2, 3 or 4 weeks before being killed. The 24-h urine excretion was increased only in the group treated for 4 weeks with EGF. Measured by a simple infusion device, EGF significantly increased the bladder capacity by more than 50% in all the EGF-treated groups. The volumes of the wall layers of the ureter and bladder were quantified using stereology. After 4 weeks of treatment with EGF, the total volumes of the ureter and bladder were 1.8- and 2.1-fold larger than in the control group (the urothelium was 2.8- and 3.5-fold larger and the muscular coat 1.6- and 1.6-fold larger in the ureter and bladder, respectively). In conclusion, the EGF-induced growth of the urinary tract is characterized by increased bladder capacity, and increased volume of all wall layers --most prominently the urothelium.

Wastewater from wet lime(stone)-gypsum flue gas desulphurisation (FGD) processes in coal-fired power plants contains nitrate. Where case selective catalytic reduction (SCR) of NOx is applied the wastewater can also contain ammonia. For the removal of both nitrate and ammonia, biological processes are an attractive option. A bottle-neck for application of biological processes might be the high chloride concentration and relatively high temperature of the wastewater. Therefore research work was performed in fluid-bed reactors at pilot-plant scale for both biological nitrification and denitrification. Biological nitrification was studied up to 34 gCl−/l and nitrite was the main product formed. Biological denitrification was effective up to at least 45 gCl−/l. Both nitrate and nitrite were removed effectively.

BACKGROUND It has previously been suggested that epidermal growth factor (EGF) plays a role in the function of the ovary. We administered systemic EGF to assess the influence of EGF receptor stimulation on the morphology of the ovaries. METHODS Forty-eight female Wistar rats were allocated to five groups receiving EGF treatment (150 microgram/kg/day) for 0 (controls), 1, 2, 3 and 4 weeks. All rats were exactly 8 weeks at the start of the experiment and 12 weeks at sacrifice. The EGF was administered in the weeks prior to sacrifice. At sacrifice, the perfusion-fixed ovaries were removed and weighed, and the volumes of tissue components were quantified using stereology. RESULTS EGF administration increased the total weight of the ovaries from 129 +/- 18 mg in the controls to 158 +/- 29 mg (p

The accuracy of preconization cytology and histology was evaluated in 536 patients undergoing combination laser conization. Exact agreement between cytology and cone diagnosis was observed in 41.8% of the patients. The lowest agreement, 13.6% was demonstrated in cytologic cervical intraepithelial neoplasia (CIN) I, the highest in cytologic CIN III, 64.3%. Concerning microinvasive disease, the positive predictive value of cytology was only 27.3%; the negative predictive value 94.6%. When cytology showed CIN II or worse, the cone biopsy showed CIN or invasive disease in 92.8%. Exact agreement between preconization histology and the cone biopsy was found in 59.5%. Highest agreement was observed in CIN III lesions, 67.1%, and the lowest agreement in CIN II lesions, 42.7%. When preconization showed CIN II, a higher grade of lesion was found in the cone biopsy in 29.1%. Cone biopsy revealed invasive disease in 38 cases. In 24 cases, invasive disease was not demonstrated prior to conization, corresponding totally to 4.7% of patients not suspected to have invasive disease prior to conization. Regarding invasive disease, the sensitivity of preconization histology was 36.8%, the positive predictive value 58.3%, and the negative predictive value 95.3%. Kappa statistics demonstrated rather low agreement between cone diagnoses and preconization diagnoses. These results confirm the potential risk of overlooking invasive disease by conventional preconization evaluation and demonstrate the need for excisional methods in the management of cervical intraepithelial neoplasia to provide a sufficient specimen for diagnostic purposes. Combined with the therapeutic results, combination laser conization was a reliable diagnostic and therapeutic method in the management of patients with CIN and microinvasive cancer of the cervix.

Combination laser conization was performed for the treatment of cervical intraepithelial neoplasia (CIN) in 473 patients, who were followed for a mean period of 70 months. In 16 cases (3.4%) CIN was demonstrated during follow up, and in 10 cases (2.1%) within the first year after treatment. The grade of CIN in the cone specimen was of no predictive value to recurrence. When excisional margins were involved recurrence was observed in 8.7% of cases, compared to 2.3% when margins were uninvolved. The risk of recurrence was significantly higher in patients with involvement of the endocervical cone margin. The only case of invasive disease during follow-up was observed more than 2 years after conization; cone biopsy was without involved margins. The results clearly demonstrate the method to be effective and justify an expectant management of all patients after conization by this method.

Background The purpose of this phase II trial was to evaluate the efficacy and safety of cetuximab and irinotecan as second-line treatment in patients with gastro-oesophageal adenocarcinoma. Patients and methods Patients with failure to first-line platinum-based chemotherapy received cetuximab 500 mg/m2 and irinotecan 180 mg/m2 every second week until disease progression. Toxicity was evaluated according to The Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v. 3.0. Antitumour activity was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) v. 1.0. Results Sixty-three patients were enrolled, median age was 60 years, median performance status was 1 (0–1), 35 patients had two or more organs involved. The median number of courses was 5 (range 1–25). Response rate was 11% (6 partial response (PR)) and 37% had stable disease. Median progression free survival was 2.8 months and overall survival (OS) was 6.1 months. Grade 3–4 toxicity included: diarrhoea (6%), fatigue (5%), vomiting (5%) and neutropenia (16%). Two patients developed febrile neutropenia. Forty-six patients (73%) had developed grade 1–2 skin rash. Patients developing skin rash had a prolonged survival with an OS at 7.1 months. Conclusions The combination of cetuximab and irinotecan is active as second-line therapy in patients with gastro-oesophageal cancer. Cetuximab induced skin rash was associated with prolonged survival.

Stereological analysis has been performed to investigate the late changes in the normal mouse bladder one year after radiation alone (10-25 Gy) or radiation (10-15 Gy) combined with cyclophosphamide (CTX), 100 mg/kg, or cis-diamminedichloroplatinum (II) (cis-DDP), 6 mg/kg. A significant increase in total volume of urothelium was found in the group treated with CTX combined with radiation compared with the control. The total volume of connective tissue in the muscular layer in the groups which received X-rays only showed a significant increase compared to the control. There also seemed to be an increase in the amount of connective tissue in muscular tissue, although this was not statistically significant, in the groups treated with CTX and irradiation compared with CTX alone. This indicates the importance of radiation in the development of late damage. Results from bladders treated with cis-DDP alone or combined with radiation were statistically inconclusive due to the small number of animals in each group. The group treated with CTX and radiation (15 Gy) showed a significant decrease in the total volume of lamina propria, but no difference was found in the other treatment groups when comparing connective tissue, the muscular layer or the amount of vessels and capillaries with their corresponding control groups. Stereological analysis seems a feasible method to demonstrate late bladder tissue changes encountered after irradiation alone or combined with chemotherapy.

Udgivelsesdato: 2007-Oct-22 The purpose of this study was to investigate the prognostic value of the primary in situ cellular immune response in cervical squamous cell carcinoma. A study of 102 women treated for stage IB and IIA disease, between 1990 and 2000, was performed. Paraffin-embedded cervical tissue processed at the time of diagnosis was immunostained for CD3+ (T cells), CD4+ (T helper/regulatory T cells) and CD8+ (cytotoxic T cells) cells. Immune cell profile densities were estimated using stereology. Both intra- and peritumoural cell densities were estimated. Using Cox's proportional hazards regression modelling we found an increase in cell density to decrease the risk of relapse for all three cell types. The density of peritumoural CD3+ cells seems to have the strongest potential for predicting relapse. An increase in CD3+ cell density from 795 to 2043 cells per mm(2) (25-75 percentile) reduced the hazard ratio to 0.27.

Objective The purpose of this study was to investigate possible differences in the primary in situ cellular immune response between patients with and without relapse of Stage IB cervical squamous cell carcinoma. Method Paraffin-embedded tissue from 40 patients (20 with and 20 without relapse) was evaluated. Sections were immunostained for CD1a + , CD3 + , CD4 + , CD8 + , CD20 + , CD45RA + , CD45RO + , CD57 + , CD68 + and GrB + cells. Immune cell profile densities were estimated using stereology. Results We found significantly lower densities of CD3 + , CD4 + , CD8 + and CD57 + cells (both intra- and peritumoral) in tissue from patients who had relapse. Also densities of intratumoral CD1a + cells and peritumoral CD20 + , CD45RA + and CD45RO + cells were significantly lower among patients with relapse. Conclusion This study demonstrates striking differences in the cellular immune response between patients with and without relapse within 5 years. The results are of potential value in adjuvant immunotherapy and prediction of prognosis.

Udgivelsesdato: 2007-Dec The aim of this study was to present a method to obtain basic biological data on the in situ cellular immune response towards cancer. Using stereology, we estimated the density and frequency of immune cells of 10 different phenotypes in cone biopsies from 20 patients with FIGO stage I cervical squamous cell carcinoma. The anatomic distribution of immune cells with respect to intraepithelial, periepithelial or stromal compartments was recorded in normal epithelium, dysplastic epithelium and carcinoma. We estimated the number of immune cells per cancer cell, and the 3D total number of immune cells, inside cancer tissue. The tumor volume was estimated in 3D and corrected for shrinkage occurring during tissue processing. We found more immune cells in cancer compared to dysplasia and normal epithelia. A median total number of 278 . 10(3) CD3+, 69.1 . 10(3) CD4+ and 113 . 10(3) CD8+ cells were present in the cancers. A median number of 63 CD3+, 11 CD4+ and 29 CD8+ cells were present per cancer cell. The average volume of tumors in stage IA was significantly smaller than that of stage IB. This method was found to be usable and of potential value in clinical pathology research, and for development and evaluation of immunotherapy.

A total of 185 unrelated Danish males were typed for the Y-chromosome STRs DYS19, DYS385a/b, DYS389-I, DYS389-II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438 and DYS439 using the kits PowerPlex Y (Promega), ReliaGene Y-Plex™6 and ReliaGene Y-Plex™5 (Reliagene Technologies). A total of 163 different haplotypes were observed and among these, 144 haplotypes were unique. The gene diversity was 0.9985. In DYS392, a variant allele migrating as a 10.2 allele was observed. Sequencing of the allele showed a deletion upstream the repeated area.

Since 1990, women in Northern Jutland having the cytologic first-time diagnosis of mild dysplasia have been managed according to age-differentiated guidelines. It was the purpose of this study to evaluate these guidelines focusing on compliance, progression, treatment, and follow-up after treatment.Register-based follow-up study comprising 993 women with the cytologic first-time diagnosis of mild dysplasia entered into the database file of the Department of Pathology of Aalborg Hospital in the period 1990-1991.The first follow-up examination after the initial cytology was performed four months (median) later. The age was negatively associated to the time for the follow-up (p0.0001). 18% of the women were later presenting with a diagnosis of at least moderate dysplasia, among whom four cases of invasive cancer stage 1A1 were observed. Age was not significantly associated to the risk of progression (p = 0.32). In contrast, earlier atypical smear was strongly positively related to later progression (p = 0.003). 39% of the women were treated during the observation period. After treatment the first follow-up examination was performed after 20 (median) months. Younger women were examined later than older women (p0.0001). 6.1% of the women treated were later diagnosed as having cervix neoplasia.1) Compliance was not optimal. 2) Cytologic follow-up after six months is a safe method in the management of mild dysplasia. 3) Age-differentiated follow-up procedure is not justified. 4) Earlier atypical smear was an important risk factor for progression. 5) The follow-up after treatment should be standardized and EDP monitoring implemented.

A novel pulse referenced error correction method for digital PWM switching power amplifiers is proposed called pulse edge delay error correction (PEDEC). The paper presents fundamental theory for the novel control method, modeling and systematic approaches to PEDEC based digital amplifier design. The investigations are supplemented with comprehensive, low level nonlinear PSPICE based system simulation that verify the system model and furthermore illustrates the correction capability towards every error source in a switching power stage. PEDEC is the first method ever to effectively eliminate the fundamental power stage linearity problems in digital PWM power amplifier (Power DACs). The control method is concluded to be a very interesting new approach, that dramatically eases the design of high quality digital audio power amplifiers (Power DACs), since the power stage design can be relaxed and no precision A/D conversion is needed in the control system.

Objective. The aim of this study was to evaluate the efficacy and safety of combination laser conization alone as definitive treatment of adenocarcinoma in situ (AIS) and to evaluate the safety of a conservative expectant strategy irrespective of cone margin status. Methods. Sixty consecutive patients with histologically proven adenocarcinoma in situ were treated with combination laser conization from 1990 to April 2001. In 58 cases this was considered final therapy, and patients were followed for a mean period of 49 months. Results. The mean age was 34.9 years. Preconization evaluation demonstrated AIS in 76.7%. In 58 cases conization was considered final therapy, and in these cone margins were involved in 15 cases. Twenty-seven patients (46.6%) were followed for more than 60 months. Totally, 4 recurrences (6.9%) were observed. One recurrence was observed in patients with involved margins (6.7%) 4 months after conization, and 3 recurrences in patients with uninvolved margins (6.9%) were registered, in 2 cases more than 5 years after conization. No case of invasive disease was diagnosed during follow-up. The mean cone height was 19 mm; 16.7% of the cone biopsies were more than 25 mm. Conclusions. Combination laser conization was an effective treatment of AIS, and an expectant follow-up schedule based on cytology was demonstrated to be safe irrespective of cone margin status after a significant follow-up period. A potential risk of overtreatment and unnecessary worrying of the patients exists if further treatment is based solely on the status of the cone margins. Only prospective studies of similar strategies will give sufficient evidence for valid recommendations concerning the management of AIS.

A case is presented of tubulo-villous adenoma in the vagina of a 43-year-old woman. The possible origin of this rare condition is discussed and the need for careful follow-up is emphasized.

A case of adenocarcinoma development in the trigone 34 years after trigonosigmoidostomy for exstrophy of the bladder is presented. The need for lifelong surveillance is emphasized and endoscopy is recommended annually in patients with urinary diversion to a colonic segment. ( J. Urol., 144: 980–982, 1990 )

Since the start in Italy and Denmark more than 10 years ago the application of fats and oils without trans fatty acids (TFA) has increased all over the world. Today the food industry uses enormous resources to decrease the content of TFA in existing and new products. The food industry has in most cases succeeded in making consumer accepted products without TFA-most of the quality issues have been related to the technological properties of the fat- and oil-based ingredients. The change from the traditional process of selective hydrogenation to fractionation and interesterification has caused a change in the demand of vegetable oils and process capacities in the market, but until now most of these changes has been absorbed by the market without significant changes in the cost of the raw materials.

In an attempt to assess and improve the histological classification of ovarian tumors the value of immunohistochemical techniques has been examined in 50 ovarian tumors. A panel of six immuno-histochemical markers (two cytokeratins, EP4, EMA, CEA, and vimentin) seems to have no additional value in differential diagnosis and typing of ovarian tumors.

Seventy-nine consecutive patients with prostatic cancer diagnosed between 1979 and 1983 were classified with respect to histological grade according to Shelley et al. (23), DNA ploidy (diploid, tetraploid and aneuploid), and mean nuclear volume (mnv) of the cancer cells. Nine patients were still alive at the time of analysis (minimum observation time 7.5 years). Univariate analysis showed that histological grade (p = 0.004), DNA ploidy (p = 0.0002) and mnv (p = 0.009) all had a significant influence on crude survival. A Cox proportional hazards model was used to analyse the prognostic value of these factors and patient age. However, when the two strongest of these four factors, histological grade (p = 0.0025) and DNA ploidy (p = 0.0035), were corrected for, age (p = 0.07) and mnv (p = 0.22) had no independent impact on crude survival.

The present study comprises a retrospective investigation of 126 patients with stage IB squamous cell carcinoma of the cervix, and a similar prospective investigation of 53 patients with stage IB and 6 patients with stage IIA disease. Tumour biopsies from these patients were analysed by means of flow cytometry and a semiquantitative histological grading system. The study showed that a combination of a low tumour cell DNA index and a low score value of the grading system indicated a very low risk of regional lymph node metastases (0% lymph node metastases in patients with low scores vs. 24-46% metastases in patients with high scores, P0.001). In order to study the reproducibility of the histological grading 20 randomly selected cases were studied blindly by three of the participating pathologists and after discussion of the grading criteria. A kappa coefficient of 722 demonstrated a substantial agreement between the observers. These results suggest that by combining flow cytometry with semiquantitative histological grading, a subgroup of patients with early squamous cell cancer of the cervix uteri may be selected that could be sufficiently treated with simple hysterectomy instead of radical hysterectomy including lymphadenectomy, which, in many oncology centres, is the standard treatment of this patient category.

Fifty-eight consecutive patients diagnosed with prostatic cancer at transurethral resection in the period 1979-1983 were classified using histological grade according to Shelley, and using an unbiased estimate of mean nuclear volume. We find that both histological grade and mean nuclear volume appear to be significantly associated with survival. In eight of nine patients still alive after 89-130 months mean nuclear volume at diagnosis was in normal range and the histological grade showed a highly differentiated cancer in eight of the nine cases. These findings suggest highly differentiated cancer and normal range of mean nuclear volume may be important for long-term survival. In patients with advanced disease requiring endocrine treatment both histological grading and mean nuclear volume estimates failed to show any prognostic properties with regards to time to progression and time of survival. In patients not subjected to endocrine treatment histologic grade, but not mean nuclear volume, was found to be significantly associated with survival. Subtle changes in disease progression may be diagnosed early by repeated biopsies due to the accuracy and high reproducibility of mean nuclear volume measurements; however, a single estimate of mean nuclear volume has not been shown to offer advantage over histological grade with respect to prognostic properties. α 1992 Wiley-Liss, inc.

Supplementary prognostic factors should be added to the TNM classification for oral squamous cell carcinomas in order to optimize its clinical value. We have recently published two prognostically valuable malignancy grading systems based on histopathology and immunohistology of the most invasive cells in oral squamous cell carcinomas (OSCCs). However, a major problem with classifications based on histologic features is frequent lack of interobserver agreement which limits the clinical value of subjective histologic classifications. Thirty-eight file cases of OSCCs were therefore graded by three pathologists according to criteria of the histologic malignancy grading system which includes 5 morphologic features, each graded from 1 to 4. Agreement was calculated by kappa statistics, which showed that interobserver agreement was not optimal, but significantly better than by chance alone. We also studied the reproducibility of grading of immunohistologic membrane expression of a tumor-associated marker (blood group antigen H), and found a similar level of agreement. We conclude that the clinical value of our grading systems will increase by improving reproducibility.

Aim: To count the number of cells on the surface of the two commercial hydrophilic catheters, Lofric® and EasiCath® used for intermittent catheterization (IC) after 30–60 s in water without the necessity of catheter jelly. Participants: Twenty spinal cord lesioned (SCL) individuals. Six were women, and 14 men. Methods: IC was performed on average five times a day (range: 4–10). In a randomised cross-over design all catheterizations were performed either with Lofric® or EasiCath® in two consecutive 24 h periods. The catheter used for the last catheterization in each 24 h period was fixed, and divided into pieces of 5 cm. From each of these a piece with the length of 5 mm was taken for surface microscopy after staining. The total number of cells was counted without knowledge of the type of catheter. According to the fractionator principle an unbiased estimate of the total number of cells on the surface of the cateter was calculated. Results: There was no difference in the number of urethral epithelia cells on the catheters. No granulocytes were identified. The number of cells identified on the catheters were from 30 to >10 000. No differences related to age, level of SCL, ASIA impairment scale, months since SCL or type of IC were found. There was a trend that women had higher cell counts than men. Conclusion: No difference was found regarding number of urethral epithelial cells on the surface of the catheters after catheterization. This indicates no difference in urethral trauma between the two catheters.