A closer look to the timing of orchidopexy in undescended testes and adherence to the AWMF-guideline.

BACKGROUND: To lower the risk of testicular malignancies and subfertility, international guidelines recommend orchidopexy for undescended testis (UDT) before the age of 12-18 months. Previous studies reported low rates of 5-15% of timely surgery. Most of these studies are based on DRG and OPS code-based data from healthcare system institutions that do not distinguish between congenital and acquired UDT. METHODS: In a retrospective study data of all boys who underwent orchidopexy in a university hospital and two outpatient surgical departments from 2009 to 2022 were analyzed. The data differentiates congenital from acquired UDT. RESULTS: Out of 2694 patients, 1843 (68.4%) had congenital and 851 (31.6%) had acquired UDT. In 24.9% of congenital cases surgery was performed before the age of 12 months. The median age at surgery for congenital UDT was 16 months (range 7-202). Over the years there was an increased rate of boys operated on before the age of 2 (40% in 2009, 60% in 2022). The median age fluctuated over the years between 21 and 11 months without a trend to younger ages.. The covid pandemic did not lead to an increase of the median age at surgery. The median time between referral and surgery was 46 days (range 1-1836). Reasons for surgery after 12 months of age were a delayed referral to pediatric surgeries (51.2%), followed by relevant comorbidities (28.2%). CONCLUSION: Compared to recent literature, out data show that a closer look at details enables a more realistic approach. Still, there is no trend towards the recommended age for surgical treatment observable, but the rate of timely operated boys with congenital UDT is significantly higher than stated in literature.

Differences between intrinsic and extrinsic ureteropelvic junction obstruction related to crossing vessels: histology and functional analyses.

PURPOSE: In children, ureteropelvic junction obstruction (UPJO) is mostly caused by intrinsic factors (IUPJO); extrinsic UPJO are rare and often due to crossing vessels (CVs). METHODS: We retrospectively reviewed all data of children with UPJO that underwent surgery in our institution from 2004 to 2011. Analyses included age at surgery, gender, preoperative and postoperative results of ultrasound and renal scans [differential renal function (DRF); signs of obstruction], and pathology reports. Available histological specimens of cases with CV were compared to a random selection of intrinsic cases in a blinded fashion. After additional Masson's trichrome staining, the specimens were scored for fibrosis, muscular hypertrophy, and chronic inflammation. RESULTS: Out of 139 patients with UPJO, 39 cases were associated with CV. Median age at surgery was 68 months (range 2-194) in the CV group and 11.5 months (range 0-188) in IUPJO group. Laparoscopic dismembered pyeloplasty (LDMP) was carried out in 134 and open DMP in five patients. Preoperative ultrasound identified 28/39 cases with CV. DRF below 40 % was more frequently seen in CV patients (p = 0.020). Histological analyses revealed no differences between the CV and IUPJO specimens in total. CV patients with higher grades of muscular hypertrophy had lower preoperative DRF, compared to those with higher preoperative DRF (p = 0.026). Functional recovery after (L)DMP was excellent in both groups. CONCLUSION: We could not find any significant histological differences between CV and IUPJO in children. To obtain excellent functional recovery, surgical procedures with a definite correction of the UPJ should be preferred in paediatric patients with CV.

Pharmacological inhibition of beta-catenin in hepatoblastoma cells.

PURPOSE: The proto-oncogene beta-catenin is linked to an abnormal activation of the Wnt/beta-catenin-pathway and shows mutations in 50-90 % of hepatoblastoma (HB). Corresponding, the recently published murine orthotopic HB model differs from the former subcutaneous model by nuclear beta-catenin distribution. As the nuclear localization of beta-catenin is considered to reflect a more aggressive tumor growth, the influence of beta-catenin inhibition on cell viability and drug-efficiency in HB cells was analyzed. METHODS: Beta-catenin distribution in HB cells was analyzed by immunofluorescence. The influence of beta-catenin inhibitors Celecoxib, Etodolac, ICG001, and MET kinase inhibitor (SU11274) alone and in combination with cisplatin (CDDP) on HB cell lines (HuH6, HepT1) was evaluated by cell viability assays and BrdU incorporation. RESULTS: Celecoxib and ICG001 reduced dose-dependently HB cell viability and decreased nuclear beta-catenin in cultivated HB cells. Etodolac was without influence at concentrations up to 100 µM. Combinations of Celecoxib or ICG001 with MET kinase inhibitor or CDDP resulted in additive reduction of cell viability. CONCLUSION: Pharmaceutical beta-catenin inhibitors can modulate the nuclear localization of beta-catenin and reduce cell viability of HB cells in vitro. These promising effects might optimize the outcome of high-risk HB. The orthotopic HB model is a suitable basis for further in vivo studies.

Effect of sorafenib combined with cytostatic agents on hepatoblastoma cell lines and xenografts.

BACKGROUND: Sorafenib has recently been shown to reduce tumour growth in hepatoblastoma (HB) xenografts. The effect of a combined administration with cytostatic agents was now investigated. METHODS: Cell viability after treatment with sorafenib and different cytostatic agents was evaluated in two HB cell lines (HUH6 and HepT1) using MTT assay. ERK signalling was investigated by western blot, NOXA expression by rt-PCR, and formation of DNA adducts using immunocytology. NMRI mice bearing subcutaneous HUH6-derived tumours were treated with sorafenib alone or in combination with cisplatin. Tumour progression, viability, apoptosis, and vascularisation were monitored by tumour volume, AFP levels, TUNEL assay, and CD31 immunostaining, respectively. RESULTS: The combination of sorafenib and cisplatin led to a remarkable decrease in cell viability. The cisplatin-induced enhanced ERK1/2 activation, but not NOXA expression and the formation of DNA adducts was partly abrogated by sorafenib. In HB xenografts, both, sorafenib and alternated application of sorafenib and cisplatin significantly reduced tumour growth (P<0.05). Levels of AFP were lower in both treated groups (P=0.08). Relative apoptotic areas were increased (P=0.003). Mean vascular density was the lowest in the sorafenib/CDDP group (P=0.02). CONCLUSION: The combination of sorafenib with cisplatin might be a promising treatment option for high risk or recurrent HB.

Working and training conditions of residents in pediatric surgery: a nationwide survey in Germany.

PURPOSE: As in other surgical specialties, increasing concern has been expressed worldwide about the shortage of trainees in pediatric surgery training programs. We performed a nationwide survey to investigate the current situation in Germany. METHODS: An internet-based nationwide survey comprising 36 questions on training conditions in pediatric surgery was linked to the homepage of the German Society of Pediatric Surgery from June to September 2008. Statements on the following aspects were evaluated by responding residents using a scale from 1 (I do not agree at all) to 5 (I fully agree): workplace, cooperation with colleagues, head of the department, cooperation with other specialties, training and research conditions. A median value of 3 indicated an unsatisfactory assessment, with at least 50% of respondents giving an indifferent or negative response. RESULTS: 70 questionnaires were completed. Some of the evaluations revealed problematic areas. In particular, statements regarding working hours revealed dissatisfaction among the responding doctors. The median value accorded the statement "I am satisfied with the current working time regulation" was 2.9. With regard to departmental heads, some criticisms were directed against a perceived lack of soft skills. According to the respondents, their involvement in decision-making processes was insufficient ("We are involved in decision-making processes affecting our working conditions" - median value 2.4). Residents were also dissatisfied with the feedback they received for their work ("I get enough feedback regarding my achievement" - median value 2.6). Another problem area was career development ("I will finish my specialist training in time" - median value 2.9). However, these points did not affect overall satisfaction. CONCLUSIONS: Trainee satisfaction with regulations on working hours is low. Despite a general satisfaction with all fields appraised, improvements in various individual areas, e. g., the attitude of departmental heads and strategies of career development, are necessary.

Transplantation of adrenal tissue fragments in a murine model: functional capacities of syngeneic and allogeneic grafts.

Oral hormone substitution for the treatment of Addison's disease inadequately replaces the physiologic circadian secretion of corticosteroids. Alternative therapeutic approaches are reimplantation of healthy autologous adrenal tissue and allogeneic transplantation (Tx), respectively. The aim of our study was to evaluate the functional capacity of adrenal grafts and the influence of intercellular adhesion molecule-1 (ICAM-1) on graft survival. Fragmented adrenal glands of wild-type B10.BR (H-2k) and wild-type or ICAM-1-deficient BALB/c (H-2d) mice were transplanted underneath the kidney capsule of adrenalectomized B10.BR mice [complete major histocompatibility complex (MHC) haplotype disparity in the latter]. Postoperatively, the endocrine function of the adrenal grafts was evaluated by the following parameters: (1) survival analysis of the recipients (termination at day 70 after Tx); (2) reverse transcription-polymerase chain reaction expression analysis of aldosterone synthase (zona glomerulosa-specific) and of 11b-hydroxylase (zona fasciculata-specific); and (3) measurement of basal adrenocorticotropic hormone (ACTH) stimulated serum corticosterone levels. Expression of both enzyme-specific mRNAs was detected in the grafts at any time during the post-Tx period. The adrenal grafts of syngeneic and surviving MHC-disparate mice displayed a similar basal hormone secretion, which was about 60% lower than that in sham-operated animals. In the transplanted mice, ACTH-stimulated corticosterone measurement revealed a 5- to 10-fold decreased functional reserve capacity. ICAM-1 deficiency significantly prolonged the survival of adrenal grafts. Fragmented adrenal grafts are able to maintain physiologic basal corticosterone levels but had markedly reduced reserve capacity. Nevertheless, the results give rise to hopes that autologous or MHC-compatible allogeneic transplantation of adrenal grafts may replace oral hormone substitution in humans.

A murine model of allogeneic adrenocortical cell transplantation: perspectives for the treatment of Addison's disease in humans.

BACKGROUND: Hormone substitution for the treatment of adrenocortical insufficiency (Addison's disease) does not adequately substitute the hormone peaks required in stress situations. Therefore, allogeneic transplantation of adrenal cortex could offer an intriguing alternative. METHODS: Major histocompatibility complex (MHC) class I transgenic mice were used for the implementation of an animal model of adrenocortical cell transplantation in adrenalectomized mice. K(b)-transgenic cells and allogeneic adrenocortical cells were cocultured in mixed lymphocyte cultures to examine the alloimmune response. Lymphocytes from T-cell receptor transgenic mice and normal allogeneic mice served as responder cells. The effect of corticosteroids secreted by adrenocortical cells was antagonized by the steroid receptor antagonist mifepristone (RU486). RESULTS: In vitro coculture experiments showed that MHC class I disparate adrenocortical cells failed to activate B10.BR and T-cell receptor transgenic lymph node cells. In the presence of mifepristone this inhibitory effect was antagonized, resulting in strong lymphocyte proliferation. Activation of B10.BR lymphocytes by K(b)-disparate spleen cells was also abolished in the presence of adrenocortical cells. This effect, however, could not be reversed by mifepristone. CONCLUSIONS: In vitro, the presence of adrenocortical cells potently suppressed allogeneic immune responses. This effect was only in part due to the secretion of corticosteroids, pointing to an additional immunomodulatory property of adrenocortical cells.