Trends in surgery for screen-detected and interval breast cancers in a national screening programme.

BACKGROUND: This population-based study aimed to evaluate trends in surgical approach for screen-detected cancer versus interval breast cancer, and to determine the factors associated with positive resection margins. METHODS: Screening mammograms of women aged 50-75 years, who underwent biennial screening in a Dutch breast-screening region between 1997 and 2011, were included. Patient and tumour characteristics were compared between women who underwent mastectomy or breast-conserving surgery (BCS) for screen-detected or interval cancer, and women with a negative or positive resection margin after BCS. RESULTS: Some 417,013 consecutive screening mammograms were included. A total of 2224 screen-detected and 825 interval cancers were diagnosed. The BCS rate remained stable (mean 6.1 per 1000 screened women; P = 0.099), whereas mastectomy rates increased significantly during the study from 0.9 (1997-1998) to 1.9 (2009-2010) per 1000 screened women (P < 0.001). The proportion of positive resection margins for invasive cancer was 19.6 and 7.6 per cent in 1997-1998 and 2009-2010 respectively (P < 0.001), with significant variation between hospitals. Dense breasts, preoperative magnetic resonance imaging, microcalcifications, architectural distortion, tumour size over 20 mm, axillary lymph node metastasis and treating hospital were independent risk factors for mastectomy. Interval cancer, image-guided tumour localization, microcalcifications, breast parenchyma asymmetry, tumour size greater than 20 mm, lobular tumour histology, low tumour grade, extensive invasive component and treating hospital were independent risk factors for positive resection margins. CONCLUSION: Mastectomy rates doubled during a 14-year period of screening mammography and the proportion of positive resection margins decreased, with variation among hospitals. The latter observation stresses the importance of quality control programmes for hospitals treating women with breast cancer.

Variations in screening outcome among pairs of screening radiologists at non-blinded double reading of screening mammograms: a population-based study.

OBJECTIVES: Substantial inter-observer variability in screening mammography interpretation has been reported at single reading. However, screening results of pairs of screening radiologists have not yet been published. We determined variations in screening performances among pairs of screening radiologists at non-blinded double reading. METHODS: We included pairs of screening radiologists with at least 7,500 screening examinations per pair, obtained between 1997 and 2011. During 2-year follow-up, breast imaging reports, surgical reports and pathology results were collected of all referred women and interval cancers. Referral rate, cancer detection rate, positive predictive value and sensitivity were calculated for each pair. RESULTS: A total of 310,906 screening mammograms, read by 26 pairs of screening radiologists, were included for analysis. The referral rate ranged from 1.0 % (95 % CI 0.8 %-1.2 %) to 1.5 % (95 % CI 1.3 %-1.8 %), the cancer detection rate from 4.0 (95 % CI 2.8-5.2) to 6.3 (95 % CI 4.5-8.0) per 1,000 screens. The programme sensitivity and positive predictive value of referral ranged from 55.1 % (95 % CI 45.1 %-65.1 %) to 81.5 % (95 % CI 73.4 %-89.6 %) and from 28.7 % (95 % CI 20.8 %-36.6 %) to 49.5 % (95 % CI 39.7 %-59.3 %), respectively. CONCLUSION: We found significant variations in screening outcomes among pairs of screening radiologists at non-blinded double reading. This stresses the importance of monitoring screening results on a local scale. KEY POINTS: • Substantial inter-observer variability in screening mammography interpretation is known at single reading • Population-based study showed significant variations in outcomes among pairs of screening radiologists • Local monitoring and regular feedback are important to optimise screening outcome.

Trends in breast biopsies for abnormalities detected at screening mammography: a population-based study in the Netherlands.

BACKGROUND: Diagnostic surgical breast biopsies have several disadvantages, therefore, they should be used with hesitation. We determined time trends in types of breast biopsies for the workup of abnormalities detected at screening mammography. We also examined diagnostic delays. METHODS: In a Dutch breast cancer screening region 6230 women were referred for an abnormal screening mammogram between 1 January 1997 and 1 January 2011. During two year follow-up clinical data, breast imaging-, biopsy-, surgery- and pathology-reports were collected of these women. Furthermore, breast cancers diagnosed >3 months after referral (delays) were examined, this included review of mammograms and pathology specimens to determine the cause of the delays. RESULTS: In 41.1% (1997-1998) and in 44.8% (2009-2010) of referred women imaging was sufficient for making the diagnosis (P<0.0001). Fine-needle aspiration cytology decreased from 12.7% (1997-1998) to 4.7% (2009-2010) (P<0.0001), percutaneous core-needle biopsies (CBs) increased from 8.0 to 49.1% (P<0.0001) and surgical biopsies decreased from 37.8 to 1.4% (P<0.0001). Delays in breast cancer diagnosis decreased from 6.7 to 1.8% (P=0.003). CONCLUSION: The use of diagnostic surgical breast biopsies has decreased substantially. They have mostly been replaced by percutaneous CBs and this replacement did not result in an increase of diagnostic delays.

Trends in delayed breast cancer diagnosis after recall at screening mammography.

OBJECTIVES: To determine the extent and characteristics of delay in breast cancer diagnosis in women recalled at screening mammography. METHODS: We included a consecutive series of 817,656 screens of women who received biennial screening mammography in a Dutch breast cancer screening region between 1997 and 2016. During at least 3.5 years follow-up, radiological reports and biopsy reports were collected of all recalled women. The inclusion period was divided into four cohorts of four years each. We determined the number of screen-detected cancers and their characteristics, and assessed the proportion of recalled women who experienced a diagnostic delay of at least 4 months in breast cancer confirmation. RESULTS: The proportion of recalled women who experienced diagnostic delay decreased from 7.5 % in 1997-2001 (47/623) to 3.0 % in 2012-2016 (67/2223, P < 0.001). The proportion of women with a delay of at least two years increased from 27.7 % (13/47) in 1997-2001 to 75.7 % (53/70) in 2012-2016 (P < 0.001). Cancers with a diagnostic delay > 2 years were more frequently invasive (P = 0.009) than cancers with a diagnostic delay of 4-24 months. The most frequent cause of diagnostic delays was incorrect radiological classifications by clinical radiologists (55.2 % overall) after recall. CONCLUSIONS: The proportion of recalled women with a delayed breast cancer diagnosis has more than halved during two decades of screening mammography. Delays in breast cancer diagnosis are characterized by longer delay intervals, although the proportion of these delays among all screen-detected cancers has not increased. Preventing longer delays in breast cancer confirmation may help improve breast cancer survival.

Localization of non-palpable breast cancer using a radiolabelled titanium seed.

BACKGROUND: Resection guided by a radiologically placed hookwire is the most common surgical technique for non-palpable breast cancer. This technique has several well described disadvantages such as incidental migration, kinking or fracture of the wire, and difficult logistics between the radiology, surgical and nuclear medicine departments. Use of an iodine-125-radiolabelled (I-125) seed for localization of non-palpable breast tumours could potentially prevent these problems. METHODS: Data on use of the I-125 seed localization technique in 325 consecutive women were collected prospectively between October 2003 and June 2009. All patients with screen-detected, histologically proven malignancy were included. Patients with a preoperative core biopsy showing either ductal carcinoma in situ or unclear pathology were excluded from this study. RESULTS: The mean(s.d.) age of the women was 59.5(11.9) years. Localization was guided ultrasonographically in 275 procedures, stereotactically in 45 and by both techniques in five. The I-125 seed was removed by surgery after a mean of 4(5) days. The mean duration of operation was 62.9(21.2) min. Complete tumour removal was achieved in 310 procedures (95.4 per cent). CONCLUSION: Localization of impalpable breast cancer using a I-125 seed was safe and led to a high proportion of radical lumpectomies.

Clinical impact of new prostate-specific antigen WHO standardization on biopsy rates and cancer detection.

BACKGROUND: Clinicians may be unaware that replacement of the historical total prostate-specific antigen (tPSA) standard with the WHO 96/670 international standard leads to difficulties in interpreting tPSA results. Our aim was to investigate the relationship between the Hybritech and WHO calibrations of the Beckman Coulter tPSA assay, and to assess the impact on prostate cancer (PCa) detection. METHODS: tPSA concentrations were measured in 106 serum samples with both Hybritech and WHO calibrations. The established relationships were used for an in silico experiment with a cohort of 5865 men. Differences in prostate biopsy rates, PCa detection, and characteristics of missed cancers were calculated at biopsy thresholds of 3.0 and 4.0 microg/L. RESULTS: A linear relationship was observed between the 2 calibrations, with a 20.3% decrease in tPSA values with the WHO standard compared with the Hybritech calibration. Applying the WHO calibration to the cohort of 5865 men yielded a 20% or 19% decrease in prostate biopsies and a 19% or 20% decrease in detected cancers compared with the Hybritech calibration, at a cutoff for biopsy of 3.0 or 4.0 microg/L, respectively. The decrease in detected cancers declined to 9% or 11% if an abnormal result in a digital rectal examination or a transrectal ultrasound evaluation was used as trigger for prostate biopsy (cutoff of 3.0 or 4.0 microg/L, respectively). CONCLUSIONS: Application of the WHO standard for tPSA assays with commonly used tPSA thresholds leads to a significant decrease in PCa detection. Careful assessment of the relationship between the WHO standard and the thresholds used for prostate biopsy is hence necessary.

[A boy with a white striped knee on a radiograph]. / Witte strepen op een röntgenfoto van de knie.

A 10-year-old boy presented at the radiology department with pain in the right knee. Radiographs of the knee revealed dens metaphyseal bands and subchondral epiphyseal sclerosis as a result of periodic bisphosphonate administration for the treatment of Legg-Calvé-Perthes disease three years ago.

[Marked variations in phototherapy policy for neonatal jaundice in Dutch centers]. / Grote verschillen in fototherapiebeleid in Nederlandse centra bij icterus neonatorum.

OBJECTIVE: To determine what guidelines are used in Dutch hospitals in the management of neonatal hyperbilirubinaemia. DESIGN: Descriptive. MATERIAL AND METHOD: Paediatricians in 63 hospitals were sent a standard guideline diagram of phototherapy management and asked to describe how their management differed. The 10 neonatal intensive care units in the Netherlands were asked to send their phototherapy guidelines in more detail. RESULTS: Thirty-four hospitals (54%) and the 10 neonatal centres (100%) responded. The data obtained showed no general agreement; several different guidelines were used, notably with respect to the serum bilirubin concentration levels and the number of postnatal hours. CONCLUSION: We recommend that consensus should be reached on the use of phototherapy. A more restricted use of phototherapy probably would save costs without loss of quality.

[Early amnion rupture as a cause of multiple congenital abnormalities in the newborn infant]. / Vroege amnionruptuur als oorzaak van multipele congenitale afwijkingen bij de pasgeborene.

We describe two children with congenital deformities due to the early amniotic rupture syndrome. One child who had an amniotic band around the upper arm suffered from a distal nerve lesion. This was relieved following surgery. The second child died shortly after birth of multiple congenital malformations. The most usual findings in this syndrome are constriction of a limb by an amniotic band, scoliosis or syndactyly due to oligohydramnion with compression. We discuss one accepted hypothesis (subscribed by an experimental animal study) of the aetiology of the early amniotic rupture syndrome.

Identification of residual breast tumour localization after neo-adjuvant chemotherapy using a radioactive 125 Iodine seed.

INTRODUCTION: The use of neo-adjuvant chemotherapy has increased in the treatment of loco-regionally advanced primarily operable breast cancer. As a result of improved neo-adjuvant chemotherapy regimes the number of clinical as well as radiological responses have increased. In case of a complete response it is difficult to identify residual disease and to perform an adequate radical breast-conserving surgery. Therefore localization of the original tumour bed is mandatory. In this study we propose a novel technique with a seed containing radioactive 125 Iodine ((125)I). The (125)I has a half-time of 60 days and is therefore still recognisable with a gamma probe after admittance of several courses of neo-adjuvant chemotherapy. MATERIAL AND METHODS: In the period from July 2003 and November 2008, 47 consecutive patients had successful (125)I seed localization of a breast tumour before starting neo-adjuvant chemotherapy. RESULTS: The overall clinical response rate to neo-adjuvant chemotherapy was 100%. Complete clinical response occurred in 34 patients, partial clinical response occurred in 13 patients. Complete radiological response occurred in 18 patients, partial radiological response occurred in 29 patients. The initial surgical treatment consisted of breast-conserving surgery for all 47 patients, after a mean of 170 days (range: 70-220) after (125)I seed localization. In 19 patients pathology revealed no residual tumour, 23 patients showed a partial response. Only 3 lumpectomies were irradical. CONCLUSION: This study has shown that (125)I seed localization is a novel and highly successful technique in localizing the tumour bed in patients who receive neo-adjuvant chemotherapy for breast cancer leading to a high percentage of radical margins in case of breast-conserving surgery.

Percutaneous vertebroplasty is not a risk factor for new osteoporotic compression fractures: results from VERTOS II.

BACKGROUND AND PURPOSE: PV is increasingly used as treatment for osteoporotic VCFs. However, controversy exists as to whether PV increases the risk for new VCFs during follow-up. The purpose of our research was to assess the incidence of new VCFs in patients with acute VCFs randomized to PV and conservative therapy. MATERIALS AND METHODS: VERTOS II is a prospective multicenter randomized controlled trial comparing PV with conservative therapy in 202 patients. Incidence, distribution, and timing of new VCFs during follow-up were assessed from spine radiographs. In addition, further height loss during follow-up of treated VCFs was measured. RESULTS: After a mean follow-up of 11.4 months (median, 12.0; range, 1-24 months), 18 new VCFs occurred in 15 of 91 patients after PV and 30 new VCFs in 21 of 85 patients after conservative therapy. This difference was not significant (P = .44). There was no higher fracture risk for adjacent-versus-distant vertebrae. Mean time to new VCF was 16.2 months after PV and 17.8 months after conservative treatment (logrank, P = .45). The baseline number of VCFs was the only risk factor for occurrence (OR, 1.43; 95% CI, 1.05-1.95) and number (P = .01) of new VCFs. After conservative therapy, further height loss of treated vertebrae occurred more frequently (35 of 85 versus 11 of 91 patients, P < .001) and was more severe (P < .001) than after PV. CONCLUSIONS: Incidence of new VCFs was not different after PV compared with conservative therapy after a mean of 11.4 months' follow-up. The only risk factor for new VCFs was the number of VCFs at baseline. PV contributed to preservation of stature by decreasing both the incidence and severity of further height loss in treated vertebrae.

The antischistosomal efficacies of artesunate-sulfamethoxypyrazine-pyrimethamine and artemether-lumefantrine administered as treatment for uncomplicated, Plasmodium falciparum malaria.

Although artemisinin and its derivatives are widely used for the treatment of malaria, they also have antischistosomal activity. In a small study in eastern Sudan, the effects of the treatment of uncomplicated, Plasmodium falciparum malaria with artesunate-sulfamethoxypyrazine-pyrimethamine (AS-SMP) and artemether-lumefantrine (AT-LU) on co-infections with Schistosoma mansoni were therefore investigated. Faecal samples from 14 of the 306 patients screened on presentation, at the start of a clinical trial of antimalarial treatment, were found to contain Schistosoma mansoni eggs. For the treatment of their malaria, the 14 egg-positive cases, who were aged 6-40 years (mean = 13.7 years), were each subsequently treated with three tablets of a fixed combination of AS-SMP, with a 12-h (six patients) or 24-h interval (five patients) between each tablet, or with six doses of AT-LU given over 3 days. When checked 28 and 29 days after the initiation of treatment, all 14 patients were found stool-negative for schistosome eggs. These results indicate that AS-SMP and AT-LU are currently very effective treatments not only for uncomplicated, P. falciparum malaria but also for S. mansoni infections.

VERTOS II: percutaneous vertebroplasty versus conservative therapy in patients with painful osteoporotic vertebral compression fractures; rationale, objectives and design of a multicenter randomized controlled trial.

BACKGROUND: The standard care in patients with a painful osteoporotic vertebral compression fracture (VCF) is conservative therapy. Percutaneous vertebroplasty (PV), a minimally invasive technique, is gaining popularity as a new treatment option. Many prospective and retrospective studies have reported on the effectiveness and safety of PV, but no large randomized controlled trial (RCT) has been published. OBJECTIVE: To estimate cost-effectiveness of PV compared to conservative therapy in terms of: pain reduction, quality of life, complications, secondary fractures and mortality. MATERIALS AND METHODS: The VERTOS II study is designed as a prospective, multicenter RCT. Patients with a painful VCF with bone edema on MR imaging, local back pain for 6 weeks or less, osteopenia and aged 50 years or older, after obtaining informed consent are included and randomized for PV or conservative therapy. In total 200 patients will be enrolled. Follow-up is at regular intervals during a 1-year period with standard questionnaires, addressing: clinical symptoms, pain medication, Visual Analogue Scale (VAS) score, quality of life and cost-effectiveness. Secondary fractures, necessary additional therapies and complications are recorded. CONCLUSION: The VERTOS II study is the first methodologically sound RCT designed to assess the cost-effectiveness of PV compared to conservative therapy in patients with an acute osteoporotic VCF. TRIAL REGISTRATION: http://www.clinicaltrials.gov, NCT00232466.

Separation and structural analysis of vinyl- and isovinyl-azobilirubin derivatives.

The coupling reaction of bilirubin with the diazonium salts of ethyl anthranilate or of aniline yields two isomeric azopigments. These can be separated by t.l.c. as their methyl esters. The mass spectra of each pair of azopigments are very similar, showing that they are isomers. Proton-magnetic-resonance spectrometric studies show that they differ in the positions of the substituents on the pyrrolenone end ring; in one compound the methyl and vinyl groups are interposed compared with the other compound. These azo compounds were used as reference standards for determination of the site of conjugation in bilirubin monoglucuronide prepared enzymically. Analysis showed that conjugation occurs at the carboxyethyl side chain of both sides of the bilirubin molecule. During the preparation of the ethyl anthranilate reference compounds a series of minor azopigments were isolated by t.l.c. Analysis of the mass spectra of many of these showed that three side reactions can occur: (1) methylation of the imide carbonyl group; (2) addition of methanol or water to the vinyl substituent; (3) transmethylation of the ethoxycarbonyl group.

Mass-spectrometric study of the azopigments obtained from bile pigments with diazotized ethyl anthranilate.

The structures of some azopigments obtained by diazotization of conjugated and unconjugated bile pigments with diazotized ethyl anthranilate were studied by mass spectrometry. The alpha(0)-azopigments derived from rat bile and human bile were shown to be identical (t.l.c. and mass spectra) with azobilirubin derived from unconjugated bilirubin. The presence of two methyl vinyl isomers (Ia) and (Ib) in equal amounts was shown by t.l.c. and mass spectrometry. The structure of the delta-azopigment derived from rat bile was studied by two methods: (a) ammonolysis gave rise to an amide having a CH(2).CH(2).CO.NH(2) side chain as shown by its mass spectrum; (b) the mass spectrum of a trimethylsilyl derivative of the delta-azopigment methyl ester confirmed the ester to be a beta-d-monoglucuronide ester of azobilirubin I.

Stepwise compared with rapid application of vacuum in ventouse extraction procedures.

OBJECTIVE: To compare a one-step (rapid) application of negative pressure (vacuum) with conventional stepwise application for ventouse extraction following a prolonged second stage of labour. DESIGN: Randomised controlled study. SETTING: Teaching Hospital. PARTICIPANTS: Forty-seven women were randomised to the rapid vacuum group and 47 to the stepwise group. MAIN OUTCOME MEASURES: Duration of ventouse procedure, effectiveness of methods of application, morbidity of mother and infant. RESULTS: There was no significant difference in frequency of detachment of the cup after rapid or stepwise application of vacuum. A reduction in mean duration of the ventouse procedure of 6 min was realised without significant difference in maternal or neonatal morbidity. CONCLUSION: Rapid application of vacuum significantly reduces the duration of a ventouse extraction procedure without compromise to efficiency and safety.

Electrophysiological profile of bepridil, a new anti-anginal drug with calcium blocking properties.

The electrophysiological effects of intravenously administered bepridil, a new anti-anginal drug with slow calcium current blocking properties, were studied in 20 patients undergoing an endocavitary cardiac exploration for various reasons. Classical techniques of programmed electrical stimulation were used. Bepridil markedly increased the refractory period of the atrium, atrioventricular node and the AH-interval. The effects on HR and ventricular refractory period were minimal, and sinus rate decreased slightly. A pronounced reduction in the heart rate at which the Wenckebach phenomenon was obtained in the anterograde direction (16%) and particularly in the retrograde direction (26%) was observed. During this study the drug appeared beneficial in suppressing atrial flutter, atrial extrasystoles, and ventricular extrasystoles. In two patients with intranodal reciprocal rhythm, the injection of bepridil terminated the tachycardia which could not be reinitiated later. No side-effects occurred and it appears that bundle branch block and prolonged HV interval are not contraindications to the use of bepridil.