Publications by authors named "Bodil Laub Petersen"

34 Publications

[New disease markers within the chronic myeloproliferative neoplasms].

Ugeskr Laeger 2015 May;177(19)

Hæmatologisk Afdeling, Roskilde Sygehus, Køgevej 7-13, 4000 Roskilde.

The chaperone and calcium storing protein calreticulin is coded by CALR, and newly identified mutations in CALR are found in respectively 49-70% and 56-88% of JAK2- and MPL-negative patients with essential thrombocytaemia (ET) and primary myelofibrosis (PMF). A total of 41 mutations have been identified, all located to exon 9 which codes the protein's C-terminal. CALR mutations are present only in myeloid malignancies and confer a more indolent disease than JAK2-mutated ET and PMF. CALR mutations as a diagnostic and prognostic tool are promising and the mutations are potential targets for immune therapy.
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May 2015

Development and validation of a microRNA based diagnostic assay for primary tumor site classification of liver core biopsies.

Mol Oncol 2015 Jan 1;9(1):68-77. Epub 2014 Aug 1.

Department of Oncology, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark.

Identification of the primary tumor site in patients with metastatic cancer is clinically important, but remains a challenge. Hence, efforts have been made towards establishing new diagnostic tools. Molecular profiling is a promising diagnostic approach, but tissue heterogeneity and inadequacy may negatively affect the accuracy and usability of molecular classifiers. We have developed and validated a microRNA-based classifier, which predicts the primary tumor site of liver biopsies, containing a limited number of tumor cells. Concurrently we explored the influence of surrounding normal tissue on classification. MicroRNA profiling was performed using quantitative Real-Time PCR on formalin-fixed paraffin-embedded samples. 278 primary tumors and liver metastases, representing nine primary tumor classes, as well as normal liver samples were used as a training set. A statistical model was applied to adjust for normal liver tissue contamination. Performance was estimated by cross-validation, followed by independent validation on 55 liver core biopsies with a tumor content as low as 10%. A microRNA classifier developed, using the statistical contamination model, showed an overall classification accuracy of 74.5% upon independent validation. Two-thirds of the samples were classified with high-confidence, with an accuracy of 92% on high-confidence predictions. A classifier trained without adjusting for liver tissue contamination, showed a classification accuracy of 38.2%. Our results indicate that surrounding normal tissue from the biopsy site may critically influence molecular classification. A significant improvement in classification accuracy was obtained when the influence of normal tissue was limited by application of a statistical contamination model.
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http://dx.doi.org/10.1016/j.molonc.2014.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5528690PMC
January 2015

Expression pattern of clinically relevant markers in paediatric germ cell- and sex-cord stromal tumours is similar to adult testicular tumours.

Virchows Arch 2014 Nov 30;465(5):567-77. Epub 2014 Jul 30.

Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Paediatric germ cell tumours (GCTs) are rare and account for less than 3 % of childhood cancers. Like adult GCTs, they probably originate from primordial germ cells, but the pattern of histopathological types is different, and they occur predominantly in extragonadal sites along the body midline. Because they are rare, histology of paediatric GCTs is poorly documented, and it remains unclear to what extent they differ from adult GCTs. We have analysed 35 paediatric germ cell tumours and 5 gonadal sex-cord stromal tumours from prepubertal patients aged 0-15 years, to gain further knowledge, elaborate on clinical-pathological associations and better understand their developmental divergence. The tumours were screened for expression of stemness-related factors (OCT4, AP-2γ, SOX2), classical yolk sac tumours (YSTs; AFP, SALL4), GCTs (HCG, PLAP, PDPN/D2-40), as well as markers for sex-cord stromal tumour (PDPN, GATA4). All YSTs expressed AFP and SALL4, with GATA4 present in 13/14. The majority of teratomas expressed SOX2 and PDPN, whereas SALL4 was found in 8/13 immature teratomas. Adult seminoma markers AP-2γ, OCT4, SALL4 and PDPN were all expressed in dysgerminoma. We further report a previously unrecognised pathogenetic relationship between AFP and SALL4 in YST in that different populations of YST cells express either SALL4 or AFP, which suggests variable differentiation status. We also show that AP-2γ is expressed in the granulosa layer of ovarian follicles and weakly expressed in immature but not in mature granulosa cell tumours. Our findings indicate that the expression pattern of these antigens is similar between paediatric and adult GCTs, even though they develop along different developmental trajectories.
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http://dx.doi.org/10.1007/s00428-014-1635-1DOI Listing
November 2014

Adult immunohistochemical markers fail to detect intratubular germ cell neoplasia in prepubertal boys with cryptorchidism.

J Urol 2014 Apr 3;191(4):1084-9. Epub 2013 Oct 3.

Department of Pediatric Surgery, Rigshospitalet, Copenhagen, Denmark; Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.

Purpose: Intratubular germ cell neoplasia is a precursor to testicular germ cell cancer. The condition is characterized by large germ cells with large nuclei with a hyperchromatic, coarse chromatin pattern, large prominent nucleoli and abundant pale cytoplasm. In prepubertal boys these cells are located centrally and peripherally mixed with normal cells in the seminiferous tubules. We evaluated the impact of adult intratubular germ cell neoplasia marking immunohistochemistry in screening for intratubular germ cell neoplasia in boys with cryptorchidism.

Materials And Methods: Histology sections of 236 testicular biopsies were retrieved from 170 boys 1 month to 15 years old operated on for cryptorchidism (excluding disorders of sex development). Specimens were incubated with primary antibodies, including anti-placental-like alkaline phosphatase, anti-Oct3/4, anti-C-kit and anti-D2-40 receptor.

Results: A 1-year, 1-month-old boy had intratubular germ cell neoplasia and all positive markers. The prevalence of placental-like alkaline phosphatase positive staining of germ cells in testicular biopsies was 98% in boys younger than 1 year, 82% in those 1 to less than 2 years old, 74% in those 2 to less than 3 years old and 60% in those 3 to 15 years. Similarly the prevalence of C-kit positive staining was 71% in boys younger than 1 year, 49% in those 1 to less than 2 years, 16% in those 2 to less than 3 years and 34% in those 3 to 15 years. Placental-like alkaline phosphatase negative germ cells did not express any of the other described antigens. In none of the 116 testes from boys older than 1 year and 7 months were any Oct3/4 or D2-40 positive germ cells identified. Up to that age 33% and 8% of biopsies were Oct3/4 and D2-40 positive, respectively.

Conclusions: Adult intratubular germ cell neoplasia/cancer immunohistochemical markers cannot be used alone for intratubular germ cell neoplasia screening in male infants with cryptorchidism because positive immunohistochemistry is commonly seen within this age group, when most orchiopexies are performed. It is generally not plausible that intratubular germ cell neoplasia originates during fetal development in patients with cryptorchidism.
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http://dx.doi.org/10.1016/j.juro.2013.10.001DOI Listing
April 2014

[Visceral leishmaniasis in two children after vacation in Southern Europe].

Ugeskr Laeger 2013 Sep;175(38):2193-4

BørneUngeKlinikken, Rigshospitalet, Blegdamsvej 9, 2100 København Ø.

Pancytopenia, fever and splenomegaly are frequent causes for referrals to paediatric haematology departments, on the suspicion of acute leukaemia. We report two cases of Danish children with the tropical disease visceral leishmaniasis (VL) contracted on short vacations in Southern Europe. One of the patients developed secondary haemophagocytic lymphohistocytosis (HLH). Both children were successfully treated with liposomal amphotericin B. In Denmark, VL is a rare but important differential diagnosis to acute leukaemia and HLH, and should be ruled out after journeys to endemic areas, including Southern Europe.
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September 2013

[Acute, severe liver insufficiency caused by extrahepatic biliary atresia in a newborn].

Ugeskr Laeger 2013 Apr;175(17):1195-6

Klinik for Klinisk Fysiologi, Nuklearmedicin og PET, Righospitalet, Blegdamsvej 9, 2100 København Ø, Denmark.

A newborn female was hospitalized due to metabolic acidosis and conjugated hyperbilirubinaemia. Extrahepatic biliary atresia (EHBA) was suspected why a (99m)Tc-mebrofenin cholescintigraphy was performed. It showed poor hepatocyte tracer uptake and no drainage to the gut. The hepatocyte dysfunction was caused by an obstructing adrenal gland neuroblastoma later visualised by ultrasound and MRI. The cholescintigraphy is a non-invasive modality to exclude or confirm the suspicion of EHBA. Furthermore neonatal conjugated hyperbilirubinaemia demands the use of a multimodality imaging strategy for differential diagnosis to EHBA.
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April 2013

Prepubertal unilateral gynecomastia and the presence of 47,XXY mosaicism in breast epithelial cells: a case report.

J Pediatr Surg 2013 Feb;48(2):e21-3

Department of Plastic Surgery, Breast Surgery and Burns Treatment, Copenhagen University Hospital, Rigshospitalet, Denmark.

Breast enlargement in prepubertal boys is a rare condition. This case report describes an otherwise healthy 3-year old non-obese boy who developed a large unilateral cystic breast mass measuring approximately 9 × 6 × 4 cm. The mass was initially treated as a lymphatic malformation, and sclerotherapy with Picibanil (OK-432) was attempted without any detectable effect on size. The mass was later excised. The pathological examination revealed mammary gland tissue suggestive of idiopathic gynecomastia. FISH revealed 47, XXY mosaicism in the abnormal breast epithelial cells, but not in peripheral blood lymphocytes.
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http://dx.doi.org/10.1016/j.jpedsurg.2012.11.051DOI Listing
February 2013

The relation between adult dark spermatogonia and other parameters of fertility potential in cryptorchid testes.

J Urol 2013 Oct 25;190(4 Suppl):1566-71. Epub 2013 Jan 25.

Department of Pediatric Surgery, Rigshospitalet, Copenhagen, Denmark; Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark.

Purpose: The fertility potential of boys with cryptorchidism may be related to the number of adult dark spermatogonia per tubular transverse section in testicular biopsies taken at orchiopexy. Placental-like alkaline phosphatase positive gonocytes in testes within year 1 of life indicate preserved ability for germ cell transformation. We related these parameters to the total number of tubular germ cells and other factors associated with fertility potential.

Materials And Methods: The study comprised 89 boys 0.7 to 3 years old (median age 1.8) who underwent bilateral testicular biopsy at bilateral orchiopexy and provided blood samples for gonadotropins and inhibin B.

Results: Of 76 boys with adult dark spermatogonia 44 (58%) had a normal mean number of spermatogonia per tubular transverse section compared to 2 of 13 (15%) without adult dark spermatogonia (p <0.05). In the 30 boys with good fertility potential, including a normal mean number of tubular germ cells, and normal gonadotropins and inhibin B, the mean number of adult dark tubular germ cells was 0.081 vs 0.031 in the 38 with low fertility potential, including impaired tubular germ cells and/or low inhibin B but no reactive increase in gonadotropins (p <0.05). In the 21 patients with increased gonadotropins the mean number of adult dark spermatogonia per tubular transverse section was 0.063. Of the 20 boys with normal mean adult dark spermatogonia per tubular transverse section 12 (60%) had good fertility potential, including a normal mean number of tubular germ cells, normal gonadotropins and normal inhibin B, compared to only 18 of 69 (26%) with an impaired mean number of adult dark spermatogonia per tubular transverse section (p <0.05). Of 46 boys with a normal mean number of tubular germ cells 26 (57%) had placental-like alkaline phosphatase positive cells compared to 14 of 43 (33%) with a decreased mean number of tubular germ cells (p <0.05).

Conclusions: The number of placental-like alkaline phosphatase positive gonocytes and adult dark spermatogonia per tubular transverse section are important parameters related to the fertility potential of boys with cryptorchid testes.
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http://dx.doi.org/10.1016/j.juro.2013.01.058DOI Listing
October 2013

Dysregulation of the mitosis-meiosis switch in testicular carcinoma in situ.

J Pathol 2013 Mar 4;229(4):588-98. Epub 2013 Feb 4.

Department of Growth and Reproduction, Copenhagen University Hospital, Denmark.

Testicular germ cell tumours (TGCT) of young adults arise from the intratubular precursor, carcinoma in situ (CIS). CIS cells are thought to be developmentally arrested and transformed fetal germ cells that survive through childhood and gain invasive capacity after puberty. Given that germ cell neoplasms arise frequently in undervirilized and dysgenetic gonads and the striking physiological difference between meiotic entry in ovaries (fetal life) versus testes (at puberty), this study aimed to investigate whether errors in regulation of meiosis may be implicated in the pathogenesis of CIS or its invasive progression to TGCT. The main focus was on a key sex differentiation and meiosis regulator, DMRT1, which has also been linked to TGCT risk in recent genetic association studies. Expression patterns of DMRT1 and other meiosis regulators (SCP3, DMC1, STRA8, CYP26B1, NANOS2, NANOS3) were investigated in pre- and post-pubertal CIS samples and TGCT by quantitative RT-PCR and immunohistochemistry. The results demonstrated that meiosis markers and meiosis inhibitors were simultaneously expressed in CIS cells, in both pre- and post-pubertal testis samples. DMRT1 was present in a restricted subset of CIS cells, which was relatively greater in pre-pubertal (27%) compared to adult (2.6%) samples. In contrast to the majority of CIS cells, DMRT1-positive CIS cells in adult testes were not proliferating. DMRT1 and most of the other meiosis regulators were absent or expressed at low levels in invasive TGCT, except in spermatocytic seminoma (not derived from CIS). In conclusion, this study indicates that meiosis signalling is dysregulated in CIS cells and that a key regulator of the mitosis-meiosis switch, DMRT1, is expressed in 'early-stage' CIS cells but is down-regulated with further invasive transformation. Whether this mixed meiosis signalling in CIS cells is caused by insufficient virilization of the fetal somatic niche or a partial post-pubertal maturation remains uncertain and requires further study.
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http://dx.doi.org/10.1002/path.4154DOI Listing
March 2013

Bilateral undescended testes classified according to preoperative and postoperative status of gonadotropins and inhibin B in relation to testicular histopathology at bilateral orchiopexy in infant boys.

J Urol 2012 Oct 17;188(4 Suppl):1436-42. Epub 2012 Aug 17.

Department of Pediatric Surgery, Rigshospitalet, Copenhagen, Denmark.

Purpose: In recent series of boys with cryptorchidism gonadotropin levels have been higher and serum inhibin B levels have been lower than normal. To some extent the serum values of inhibin B reflect the state of germinative epithelium in cryptorchid testes. We evaluated whether blood samples of gonadotropins and inhibin B as well as histopathology could be used to classify undescended testes.

Materials And Methods: A total of 69 boys (median age 2 years) who underwent surgery for bilateral cryptorchidism had blood samples taken preoperatively and 3 months to 2.1 years postoperatively. Testicular biopsies were performed bilaterally at orchiopexy. The average germ cell number per tubular transverse tubule was measured.

Results: Group 1 included 17 patients with increased follicle-stimulating hormone levels. Serum follicle-stimulating hormone and luteinizing hormone decreased significantly after surgery. In 77% of patients (13 of 17) follicle-stimulating hormone levels were normalized. Of these boys 35% (6 of 17) had a low postoperative serum inhibin B. Group 2 consisted of 27 patients with a decreased germ cell number and/or low preoperative inhibin B, but not increased serum follicle-stimulating hormone or luteinizing hormone. There were no significant postoperative changes in follicle-stimulating hormone and luteinizing hormone. Of these boys 22% (6 of 27) had a low serum inhibin B postoperatively. In group 3 there were 25 patients with a normal germ cell number, normal preoperative serum inhibin B and normal gonadotropins. There were no significant changes in luteinizing hormone and follicle-stimulating hormone postoperatively. Only 1 boy in this group had a low postoperative serum inhibin B.

Conclusions: Patients with increased gonadotropin levels may have testicular dysgenesis and some may benefit from early surgery. Patients with normal gonadotropin levels and a decreased germ cell number have transient hypothalamus-pituitary-gonadal hypofunction and a poor fertility prognosis. These patients may benefit from gonadotropin treatment after orchiopexy. Patients with normal gonadotropins, inhibin B and germ cell number have a good fertility prognosis after surgery.
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http://dx.doi.org/10.1016/j.juro.2012.02.2551DOI Listing
October 2012

Radiology, histology and short-term outcome of asymptomatic congenital thoracic malformations.

Acta Paediatr 2012 Feb 11;101(2):155-8. Epub 2011 Oct 11.

Pediatric Pulmonary Service, Copenhagen University Hospital, København, Denmark.

Aim: The aim of this study was to evaluate the safety and short-term outcome of our management of asymptomatic children with antenatally diagnosed congenital thoracic malformations (CTM), compared with recommendations from a recent review and meta-analysis.

Methods: Twenty-two asymptomatic children with CTM, born in January 1, 2002 to January 8, 2009 were reviewed. Data on complications and respiratory symptoms were collected.

Results: No severe respiratory symptoms were recorded. Seventeen children were referred to surgery. Complications were seen in one child. The final diagnoses were congenital pulmonary airway malformation (CPAM) in 13 children, two had sequestrations, and two had other significant malformations. Five children had minor malformations and did not undergo surgery. No malignancies were reported.

Conclusion: Elective surgery at 1 year of age is safe and carries no apparent risk to asymptomatic children with CTM. The rate of complications was equal to that reported in a recent review and meta-analysis.
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http://dx.doi.org/10.1111/j.1651-2227.2011.02471.xDOI Listing
February 2012

Bilateral vanished testes diagnosed with a single blood sample showing very high gonadotropins (follicle-stimulating hormone and luteinizing hormone) and very low inhibin B.

Scand J Urol Nephrol 2011 Dec 19;45(6):425-31. Epub 2011 Aug 19.

Departments of Pediatric Surgery, Rigshospitalet, Copenhagen, Denmark.

Objective: In boys with cryptorchidism median serum values of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are higher and median serum values of inhibin B lower than in normal controls. Serum values of inhibin B reflect the state of germinative epithelium in cryptorchid testes. The aim of the study was to evaluate whether a simple blood sample of gonadotropins and inhibin B could diagnose bilateral vanished testes.

Material And Methods: Group I included five boys (4 months to 6 years and 3 months old) with bilateral vanished testes at laparoscopy. Group II included 82 boys with bilateral cryptorchidism younger than 7 years of age at surgery for bilateral cryptorchidism (median age 1 year and 9 months).

Results: The serum levels of hormones for the patients with vanished testes were: inhibin B 5?18 pg/ml, FSH 41-191 IU/l and LH 3.9?56 IU/l. The patients all had karyotype 46,xy. The serum levels of hormones from group II were: inhibin B median 122 (range 20?404) pg/ml, FSH median 0.8 (range 0.2?3.5) IU/l and LH median 0.2 (range 0.1-3.2) IU/l. The serum levels of inhibin B, FSH and LH from the boys with vanished testes were significantly different from the serum levels of the boys with bilateral cryptorchidism (p = 0.0026, p < 0.0001 and p < 0.0001, respectively).

Conclusions: The serum values of gonadotropins and inhibin B from boys with bilateral vanished testes were significantly different from those of bilateral cryptorchid boys, indicating no germinative epithelium, no Sertoli cells and compensatory high gonadotropins. If such abnormal serum values are obtained from boys with bilateral non-palpable testes, tubular tissue is not present and surgery can be avoided.
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http://dx.doi.org/10.3109/00365599.2011.609833DOI Listing
December 2011

Frequency, treatment, and functional outcome in children with hypersensitivity pneumonitis.

Pediatr Pulmonol 2011 Nov 26;46(11):1098-107. Epub 2011 May 26.

Danish ChILD Center, Pediatric Pulmonary Service, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Background: Hypersensitivity pneumonitis is a rare interstitial lung disease and very few data regarding frequency, treatment and outcome exist for children. Children identified with hypersensitivity pneumonia from a Danish national cohort with diffuse interstitial lung disease form the basis of this study focused on disease frequency, treatment, and functional outcome.

Methods: Seventy-three children with clinical and radiological signs of interstitial lung disease verified by lung biopsy were identified over a 12-year period. Histologic material from all cases was reviewed by pathologists from the ChILD Clinical and Research Network, USA. Diagnosis of hypersensitivity pneumonitis was confirmed in 19 cases.

Measurements And Main Results: Incidence of hypersensitivity pneumonitis was approximately 2/year and with a point prevalence of 4/1,000,000 children. The median (range) number of monthly courses with intravenous methylprednisolone was 15 courses (8-34) in resolved cases, but in the vast majority (92%), mono-therapy with high dose pulse methylprednisolone treatment was not sufficient for acceptable improvement. Lung function, DLco and DLco/VA increased significantly after 3 and 6 months of treatment compared to baseline (P < 0.05). However, without reaching normal values [mean SDS (range) FEV(1) -0.66 (-1.88 to 0.41) and FVC -0.67(-1.94 to 0)]. No mortality was seen.

Conclusions: Incidence and point prevalence of hypersensitivity pneumonitis in Denmark was 2/year and 4/1.000.000 children. High dose intravenous methylprednisolone constituted the basic treatment, but in most cases supplemental anti-inflammatory therapy was necessary. Outcome was acceptable without any mortality. Nevertheless, both lung function and diffusion capacity were in subnormal level though without any clinically functional impact.
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http://dx.doi.org/10.1002/ppul.21479DOI Listing
November 2011

MMSET is highly expressed and associated with aggressiveness in neuroblastoma.

Cancer Res 2011 Jun 28;71(12):4226-35. Epub 2011 Apr 28.

Biotech Research and Innovation Centre, University of Copenhagen, Denmark.

MMSET (WHSC1/NSD2) is a SET domain-containing histone lysine methyltransferase the expression of which is deregulated in a subgroup of multiple myelomas with the t(4;14)(p16;q32) translocation associated with poor prognosis. Recent studies have shown that MMSET mRNA levels are increased in other tumor types as well. We have carried out immunohistochemical staining of tissue microarrays and found that MMSET protein is frequently and highly expressed in neuroblastoma (MMSET positive in 75% of neuroblastomas, n = 164). The expression level of MMSET in neuroblastomas was significantly associated with poor survival, negative prognostic factors, and metastatic disease. Moreover, a subset of neuroblastomas for which pre- and postchemotherapy biopsies were available displayed a strong decrease in MMSET protein levels after chemotherapy. In agreement with neuroblastomas becoming more differentiated after treatment, we show that retinoic acid-induced differentiation of human neuroblastoma cells in vitro also leads to a strong decrease in MMSET levels. Furthermore, we show that the high levels of MMSET in normal neural progenitor cells are strongly downregulated during differentiation. Importantly, we show that MMSET is required for proliferation of neuroblastoma cells and brain-derived neural stem cells. Taken together, our results suggest that MMSET is implicated in neuroblastomagenesis possibly by supporting proliferation of progenitor cells and negatively regulating their differentiation. In this respect, MMSET might be a strong candidate therapeutic target in a subset of neuroblastomas with unfavorable prognosis.
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http://dx.doi.org/10.1158/0008-5472.CAN-10-3810DOI Listing
June 2011

18F-FDG PET/CT as a diagnostic tool in patients with extracervical carcinoma of unknown primary site: a literature review.

Oncologist 2011 22;16(4):445-51. Epub 2011 Mar 22.

Department of Oncology 5073, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark.

Background: Carcinoma of unknown primary (CUP) represents a heterogeneous group of metastatic malignancies for which no primary tumor site can be identified after extensive diagnostic workup. Failure to identify the primary site may negatively influence patient management. The aim of this review was to evaluate (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) as a diagnostic tool in patients with extracervical CUP.

Materials And Methods: A comprehensive literature search was performed and four publications were identified (involving 152 patients) evaluating (18)F-FDG PET/CT in CUP patients with extracervical metastases. All studies were retrospective and heterogeneous in inclusion criteria, study design, and diagnostic workup prior to (18)F-FDG PET/CT.

Results: (18)F-FDG PET/CT detected the primary tumor in 39.5% of patients with extracervical CUP. The lung was the most commonly detected primary tumor site (∼50%). The pooled estimates of sensitivity, specificity, and accuracy of (18)F-FDG PET/CT in the detection of the primary tumor site were 87%, 88%, and 87.5%, respectively.

Conclusions: The present review of currently available data indicates that (18)F-FDG PET/CT might contribute to the identification of the primary tumor site in extracervical CUP. However, prospective studies with more uniform inclusion criteria are required to evaluate the exact value of this diagnostic tool.
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http://dx.doi.org/10.1634/theoncologist.2010-0189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3228126PMC
September 2011

[Improved survival in children with neuroblastoma].

Ugeskr Laeger 2010 Oct;172(40):2761-5

Børneafdelingen, Århus Universitetshospital, Skejby, 8200 Århus N, Denmark.

Introduction: The aims of the present study were to analyze whether changes in incidence and mortality rates have taken place in Denmark during the period 1981-2005, and whether the distribution of known prognostic factors has changed during this period.

Material And Methods: A total of 206 children below 15 years of age with neuroblastoma or ganglioneuroblastoma who were diagnosed in Denmark between 1981 and 2005.

Results: The incidence was 8.68 per million children below 15 years of age (world standard 9.6) and 43.5 per million children below 12 months of age and these incidences have remained unchanged since 1970. The mortality rate has decreased steadily during the study period. The prognostic factors age, stage and site of primary tumour did not change during the study period and were not different from those reported by others. 32% of the children were below 12 months of age at diagnosis. 53% of the children had metastatic disease. The overall 5-year survival increased over the study period from 38% in 1981-1985 to 69% in 2001-2005. A significant increase in the survival of children > 12 months of age with stage 4 disease was also observed. Relapse/disease progression more than three years from diagnosis occurred in only 2% of patients. The median time from relapse to death was three months.

Conclusion: The survival of children with neuroblastoma in Denmark has increased significantly over the last 25 years.
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October 2010

Fourteen-year-old girl with endobronchial carcinoid tumour presenting with asthma and lobar emphysema.

Clin Respir J 2010 Apr;4(2):120-4

Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Copenhagen University Hospital, København Ø, Denmark.

Introduction: Bronchial carcinoid tumours seldom occur in children, and represent a rare cause of pulmonary obstruction. Because of low clinical suspicion and the variable ways of presentation, diagnosis may be delayed.

Objectives: We report on a patient with this tumour. It is hoped that increased awareness of the tumour can lead to earlier diagnosis.

Methods: Report of a case.

Results: This case describes a 14-year-old previously healthy girl, presenting with asthma-like symptoms throughout 2 years, decreased lung function and emphysema in left lower lobe on chest x-ray. Computerized tomography (CT) showed an intraluminal process in the left main bronchus and emphysema in both the upper and lower left lobe and showed no signs of metastasis or spread to lung tissue. Bronchoscopy showed an inflammatory polyp. Surgical resection demonstrated a typical carcinoid tumour. Later control biopsy revealed no persisting malignant tissue. The asthma symptoms returned and a new bronchoscopy showed scarring and narrowing of the left bronchus. Treatment comprised of dilatation by bronchoscopy plus daily combination corticosteroids and beta-2-agonist inhalation and the symptoms improved. No signs of relapse 16 months postdiagnosis.

Conclusions: The case clearly shows the delay, which is common in the diagnosis of children with bronchial carcinoid tumours. Symptoms of the obstructive nature of the tumour are variable and might present as emphysema seen on x-ray and CT. Carcinoid tumour should be considered in children with longstanding pulmonary symptoms with no response to conventional treatment. Prognosis is good but long-term follow up is needed.
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http://dx.doi.org/10.1111/j.1752-699X.2009.00149.xDOI Listing
April 2010

Capecitabine and oxaliplatin as second-line treatment in patients with carcinoma of unknown primary site.

Acta Oncol 2010 May;49(4):431-5

Department of Oncology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

Background: Treatment of patients with carcinoma of unknown primary site (CUP) remains a challenge, and no effective second-line treatment has been identified. In CUP patients who are non-responsive or relapse early after first-line platinum/taxane-based regimens, it is likely that gastrointestinal (GI) tract tumours may be overrepresented. These patients could be candidates for GI tract-directed therapy. We here report the results obtained with oxaliplatin and capecitabine as second-line therapy in 25 recurrent/refractory CUP patients following first-line treatment with paclitaxel, cisplatin and gemcitabine.

Patients And Methods: Patients received capecitabine orally (1000 mg/m(2)) twice daily, days 1-14, and oxaliplatin (130 mg/m(2)) intravenously on day 1 in a three-week schedule.

Results: Twenty-five CUP patients received a median of three cycles of capecitabine and oxaliplatin as second-line treatment. Histopathological assessments suggested the primary site to be of GI tract origin in the majority of the patients (76%). We found an objective response rate of 13%, a median progression-free survival and overall survival rate of 2.3 and 3.9 months, respectively, and 32% of patients alive at one year after initiation of second-line therapy. The regimen was well tolerated by most patients.

Conclusions: This study, demonstrates that there is still a significant need for improved second-line therapy in CUP patients.
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http://dx.doi.org/10.3109/02841861003649240DOI Listing
May 2010

Histologic features of the portal plate in extrahepatic biliary atresia and their impact on prognosis--a Danish study.

J Pediatr Surg 2009 Jul;44(7):1344-8

Department of Pathology, University Hospital of Copenhagen, DK-2100 Copenhagen Ø, Denmark.

Background/purpose: The aims of this study are as follows:

Method: From 1979 to 2003, 57 children have been operated by the Kasai procedure. Only 40 of these have had their portal plate removed for histologic examination. We divided the patients according to clinical outcome into a successful and a failure group and compared the histologic features of the portal plates in the 2 groups. Afterward, the portal plate histology from EHBA was compared with the porta hepatis area from patients dead from other causes.

Results: A significant difference between the success and the failure group was found with regard to the number of bile ducts, the maximal length measurable in any direction for bile duct structures, and the proliferation, but not for any type of diameter. The normal portal plate was different from the portal plate of children with biliary atresia by always having 2 large biliary structures and the cells being mucinous and columnar in the largest bile ducts. Only 1 of 4 normal portal plates showed signs of proliferation. There was no significant difference between the normal and the success group with respect to the number, maximal length, and proliferation of the bile ducts. A difference in the diameter between the normal group and the entire EHBA group was significant for the maximal internal diameter but not for the other types of diameter measurements.

Conclusion: The present study shows the following:
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http://dx.doi.org/10.1016/j.jpedsurg.2008.11.054DOI Listing
July 2009

Congenital biliary atresia: liver injury begins at birth.

J Pediatr Surg 2009 Mar;44(3):630-3

Department of Paediatric Surgery, King's College Hospital, London.

Background: The timing of onset of liver injury in biliary atresia (BA) is not known, although in approximately 10% of cases, biliary pathologic condition associated with the biliary atresia splenic malformation syndrome must begin well before birth.

Methods: The study involved retrospective case-note review for infants with definite BA who underwent laparotomy within first week of life.

Results: Three infants were identified who had occlusive BA evident on the first day of life. In all cases, their liver was grossly normal, and histologic changes were trivial.

Conclusion: This suggests that the detrimental cholestatic liver injury, later characteristic of BA, only begins from the time of birth despite a prenatal occlusive biliary pathology. It may be that tissue injury only occurs with the onset of the perinatal bile surge initiating periductal bile leakage and the triggering of an inflammatory and ultimately fibrotic response.
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http://dx.doi.org/10.1016/j.jpedsurg.2008.10.069DOI Listing
March 2009

[Unknown primary tumour--diagnostic strategies and treatment].

Ugeskr Laeger 2008 Nov;170(48):3946-9

Onkologisk Klinik, Finsencentret 5073, Rigshospitalet, DK-2100 København Ø.

Unknown primary tumour (UPT) is defined as a histologically confirmed metastatic malignancy for which no primary site has been detected. It accounts for approximately 3-5% of all malignant neoplasms. UPT represents a group of heterogeneous cancers with rapid progression and random, atypical metastases. This article describes the diagnostic strategies, treatment, prognosis and survival of patients with UPT.
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November 2008

Use of commercially available rabbit monoclonal antibodies for immunofluorescence double staining.

Appl Immunohistochem Mol Morphol 2008 Jul;16(4):387-92

Department of Pathology, Naestved Hospital, Region Sjaelland, Ringstedgade 61, Naestved 4700, Denmark.

Immunohistochemistry, that is, the use of polyclonal and monoclonal antibodies to detect cell and tissue antigens at a microscopical level is a powerful tool for both research and diagnostic purposes. Especially in the field of hematologic disease, there is often a need to detect several antigens synchronously, and we report here a fast and easy technique for demonstrating more than 1 antigen in 1 slide using immunofluorescence. We have used commercially available rabbit monoclonal antibodies (Cyclin D1, CD3, CD5, CD23, etc.) paired with mouse monoclonal antibodies (CD7, CD20, CD79a, Pax-5, etc.) for double immunofluorescence labeling on paraffin-embedded tissue sections. Commercially available rabbit monoclonal antibodies in combination with mouse monoclonal antibodies proved useful in double immunofluorescence labeling on paraffin-embedded tissue, and all combinations used yielded excellent results.
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http://dx.doi.org/10.1097/PAI.0b013e3181594ec6DOI Listing
July 2008

Simultaneous phenotyping and genotyping (FICTION-methodology) on paraffin sections and cytologic specimens: a comparison of 2 different protocols.

Appl Immunohistochem Mol Morphol 2008 May;16(3):279-86

Department of Pathology, Storstrømmens Hospital, Naestved, Denmark.

Combining immunofluorescence labeling with fluorescence in situ hybridization (FISH) is a powerful technique simultaneously studying immunophenotypic markers and genetic abnormalities present in tumor cells [the FICTION method (fluorescence immunophenotyping, and interphase cytogenetics as a tool for the investigation of neoplasms)]. However, few studies have been applied to the technical problems posed by antigen retrieval and accessibility of genetic probes to target-DNA, using formalin-fixed, paraffin-embedded tissue. In this study, we compared 2 immunofluorescence detection systems, the 3-step IF (TIF) method against the Tyramide Signal Amplification techniques (TSA). The FICTION-TSA technique significantly improved the sensitivity for detection of the immunophenotypic markers without influencing specific probe hybridization to target-DNA, compared with the results obtained with the TIF method. The reaction product of the TSA system was robust to the following FISH procedure in contrast to the TIF technique. The TSA technique used also allowed synchronous detection of nuclear antigens and FISH signals using both fusion (IgH/CCND1) and break-apart (CCND1) probes on formalin-fixed paraffin-embedded tissue.
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http://dx.doi.org/10.1097/PAI.0b013e3180de490fDOI Listing
May 2008

Peripheral neuroblastic tumours in eastern Denmark 1972-2002.

APMIS 2007 Jan;115(1):66-74

Department of Pathology, University of Copenhagen, Denmark.

The peripheral neuroblastic tumour group includes neuroblastoma, ganglioneuroblastoma and ganglioneuroma. Neuroblastoma is the most common extracranial solid tumour of childhood. We have evaluated the histological presentation, MYCN gene status, and clinical course of peripheral neuroblastic tumours diagnosed and treated in eastern Denmark from 1972-2002. 125 patients were diagnosed with peripheral neuroblastic tumour during this 30-year period. The histological material was reviewed and classified into three categories in accordance with the Shimada system: unfavourable histology, favourable histology, and benign tumours. MYCN status was determined by fluorescent in situ hybridization (FISH) on paraffin sections from the primary tumour. Clinical information was obtained from hospital records. Diagnostic likelihood ratios in the two groups were calculated to compare the ability of MYCN status and histological classification to predict 5-year outcome. 41 tumours showed unfavourable histology, 30 tumours showed favourable histology, 11 were benign, and 43 were unclassifiable due to limited amounts of primary tumour, bad preservation or inaccessibility of the primary tumour necessitating metastatic tumour biopsy for diagnosis. Unfavourable histology was associated with widespread disease (p<0.001). The overall 5-year survival rate was 45%, which correlates well with the European survival rate reported for this time period. The 5-year survival rate in the unfavourable group was 30% as compared to 100% in the favourable histology group (p<0.001). The survival rate in the unclassifiable group was 13%. 26% of the neuroblastomas were MYCN amplified. MYCN amplification was associated with undifferentiated histology, a histological subtype of the unfavourable histology group (p<0.001). For unfavourable histology the positive diagnostic likelihood ratio was 2.9 as compared to 4.7 for MYCN amplification. The study has confirmed the prognostic significance of the Shimada system in the peripheral neuroblastic tumour group in a retrospective material, and has also demonstrated the prognostic superiority of MYCN compared to histological classification, thus reducing the necessary amounts of tumour tissue.
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http://dx.doi.org/10.1111/j.1600-0463.2007.apm_355.xDOI Listing
January 2007

[The role of pathology in individualized targetted cancer treatment. The Danish Society of Pathologic Anatomy and Cytology].

Ugeskr Laeger 2006 Mar;168(12):1238

Patologisk Anatomisk Institut, Vejle Sygehus, DK-7100 Vejle.

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March 2006

Immunohistochemical detection of the apoptosis-related proteins FADD, FLICE, and FLIP in Langerhans cell histiocytosis.

J Pediatr Hematol Oncol 2005 Jun;27(6):301-6

Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark.

Langerhans cell histiocytosis (LCH) is characterized by an accumulation of dendritic Langerhans cells in granulomatous lesions in various organs. The etiology of LCH remains enigmatic. Fas/APO-1/CD95 belongs to the "death receptor" family of apoptosis regulators and has been implicated in the downregulation of immune responses. The authors examined the expression of three proteins that are engaged in the Fas signaling cascade-FADD/Fas-associated death domain-containing protein, FLICE/FADD-like interleukin-1beta-converting enzyme (both pro-apoptotic), and FLIP/FLICE-inhibitory protein (anti-apoptotic)-in lesions from LCH patients. Immunohistochemistry was performed on paraffin-embedded tissue specimens from 43 children with LCH. The infiltrates were scored according to the amount of positive pathologic Langerhans cells (pLCs). In all investigated specimens, the majority of the pLCs expressed FADD, active FLICE, and FLIP. The clinical outcome of the disease could not be correlated to the expression of the investigated proteins. This study shows a high expression of the apoptosis-related proteins FADD, active FLICE, and FLIP in pLCs. The authors previously showed that pLCs express Fas and Fas ligand. Taken together, these findings suggest that the Fas signaling pathway may be involved in the pathogenesis of LCH.
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http://dx.doi.org/10.1097/01.mph.0000168725.57143.52DOI Listing
June 2005

Testicular neoplasia in undescended testes of cryptorchid boys-does surgical strategy have an impact on the risk of invasive testicular neoplasia?

Turk J Pediatr 2004 ;46 Suppl:35-42

Department of Pediatric Surgery, Rigshospitalet, University of Copenhagen, Denmark.

Unlabelled: We investigated whether or not surgical strategy has an impact on the risk of invasive testicular neoplasia in cases of cryptorchidism. We made a database study of the incidence of testicular neoplasia at surgery for cryptorchidism in childhood, and evaluated if such abnormalities were found in special categories of patients, and also of the incidence of testicular neoplasia after orchiopexy with a simultaneous testicular biopsy in childhood. At surgery for cryptorchidism the risk of testicular neoplasia was 7/182 (4%) in cases with intra-abdominal testis, abnormal external genitalia other than cryptorchidism, or diagnosed abnormal karyotype, versus no case in the 1281 patients without these characteristics (Fisher's exact test, p < 0.00005). These clinical characteristics occurred most often in bilateral cryptorchidism 82/339 (24%) versus 103/1127 (9%) in unilateral cryptorchidism (Fisher's exact test, p < 0.00005). At follow-up, the risk of testicular neoplasia was 7/830 (1%). The relative risk of testicular neoplasia was about 4.

Conclusion: Based on our data and the literature we recommend: 1) Taking a testicular biopsy at surgery for cryptorchidism in childhood in intra-abdominally placed testes, or if the patient has abnormal external genitalia or a known abnormal karyotype. These clinical characteristics occur most often in cases of bilateral cryptorchidism. 2) Surgery for cryptorchidism before 10 years of age 3) Clinical control, after surgery for cryptorchidism. In cases of testicular atrophy orchiectomy must be considered.
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December 2004

[Griscelli syndrome].

Ugeskr Laeger 2004 Feb;166(7):600-2

H:S Rigshospitalet, Paediatrisk klinik II, Patologiafdelingen og Vaevstypelaboratoriet.

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February 2004
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