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Background: About 2000 children and adolescents under the age of 18 are diagnosed with cancer each year in Germany. Because of current medical treatment methods, a high survival rate can be reached for many types of the disease. Nevertheless, patients face a number of long-term effects related to the treatment. As a result, physical and psychological consequences have increasingly become the focus of research in recent years. Social dimensions of health have received little attention in health services research in oncology so far. Yet, there are no robust results that allow an estimation of whether and to what extent the disease and treatment impair the participation of children and adolescents and which factors mediate this effect. Social participation is of great importance especially because interactions with peers and experiences in different areas of life are essential for the development of children and adolescents., Methods: Data are collected in a longitudinal, prospective, observational multicenter study. For this purpose, all patients and their parents who are being treated for cancer in one of the participating clinics throughout Germany will be interviewed within the first month after diagnosis (t1), after completion of intensive treatment (t2) and half a year after the end of intensive treatment (t3) using standardized questionnaires. Analysis will be done by descriptive and multivariate methods., Discussion: The results can be used to identify children and adolescents in high-risk situations at an early stage in order to be able to initiate interventions tailored to the needs. Such tailored interventions will finally reduce the risk of impairments in the participation of children and adolescents and increase quality of life., Trial Registration: ClinicalTrials.gov: NCT04101123.

The Li-Fraumeni syndrome (LFS, online Mendelian inheritance in man, OMIM #151623) is considered to be one of the currently known most aggressive cancer predisposition syndromes. The heterogeneous spectrum of tumors is dominated by bone and soft tissue sarcomas, various brain tumors, premenopausal breast cancer and adrenocortical carcinoma (ACC). Even in childhood the cancer risk is very strongly increased and it is not uncommon for people with LFS to develop synchronous and metachronous tumors. Typical histopathological findings and molecular genetic signatures can help towards the diagnosis. Inheritance is autosomal dominant and the penetrance appears to be more variable than previously thought. The prevalence of LFS is approximately 1:5000 with a high interregional variance. The LFS is caused by germline mutations in the TP53 gene coding for the protein p53, an essential cellular transcription factor that initiates antitumor responses to cellular stress, such as DNA damage. In people with LFS, due to the loss of functional p53, the protective mechanism of the cells is weakened resulting in a significantly increased cancer risk. In order to improve the survival of people with LFS, structured tumor early recognition and surveillance strategies are recommended; however, national and international longitudinal observational studies are needed to evaluate the cost-effort-benefit balance. For this reason, the authors have established the LFS cancer predisposition registry in which all patients with LFS and other syndromes predisposing to cancer can be registered. Detailed information can be found at www.cancer-predisposition.org .

We recently presented a novel laser-based infrared (IR) spectroscopic phase-amplitude polarimeter for sub-decisecond and sub - mm 2 measurements of organic thin films [Opt. Lett.44, 4387 (2019)OPLEDP0146-959210.1364/OL.44.004387]. Here we report on the hyperspectral-imaging capabilities of this device. The single-shot polarimeter employs a broadly tunable mid-IR (1318 - 1765   cm -1 ) quantum cascade laser (QCL) and a four-channel beam-division design for simultaneous phase and amplitude measurements. Fast QCL tuning speeds of up to 1500   cm -1 / s enable hyperspectral mapping of large sample areas (50×50   mm 2 ) within several tens of minutes, achieving 120 μm spatial and <0.5   cm -1 spectral resolution. We apply the instrument for imaging both the heterogeneous chemical and structural properties of sub-100 nm thin polymer and fatty-acid films. Our polarimeter opens up new applications regarding laterally resolved IR analyses of complex thin films.

In the last few decades, the use of plasmonics in vibrational spectroscopy has expanded the scope of (bio)analytical investigations. Nevertheless, there is a demand for a combined platform that can be simultaneously efficient for Surface Enhanced Raman Scattering (SERS) and Surface Enhanced Infrared Absorption (SEIRA). Here, we present a solution on the basis of a plasmonic Ag nanoparticle layer with a thickness gradient. The optical resonance along the layer varies from the visible to the infrared range offering optimal and intermediate sites for SERS and SEIRA of the analyte molecule (mercaptobenzonitrile). Enhancement factors for the same mode were determined to be ca. 10 4 and 170 for SERS and SEIRA, respectively. We present a full optical and vibrational characterization and demonstrate further tunability. The platform resolves reproducibility and comparability issues by a combination of the two methods. It also offers individualized solutions for different investigation conditions, i.e. a choice between excitation wavelengths and resonant Raman molecules. The multiple applicabilities of the presented unifying substrate can contribute to the expansion of the vibrational spectroscopic field and to analytics.

We report on the first, to the best of our knowledge, sub-second, sub - mm 2 infrared (IR) spectroscopic measurements of thin organic films employing a laser-based phase-amplitude polarimeter in reflection geometry. The polarimeter uses a broadband mid-IR quantum cascade laser tunable between 1318   cm -1 spectral resolution, while providing unrivaled performance in terms of acquisition times. Spectral measurements within 100 ms and single-wavelength tracking at 16 μs are now possible. Investigating the vibrational properties accessible in the mid-IR, the polarimeter was applied for monitoring changes in molecular interactions of a 150 nm thin myristic acid film during its thermal phase transition around 55°C.cm -1 , as well as a single-shot beam division scheme for simultaneous single-pulse phase and amplitude measurements. The instrument achieves 120 μm spatial and <0.5   cm -1 spectral resolution, while providing unrivaled performance in terms of acquisition times. Spectral measurements within 100 ms and single-wavelength tracking at 16 μs are now possible. Investigating the vibrational properties accessible in the mid-IR, the polarimeter was applied for monitoring changes in molecular interactions of a 150 nm thin myristic acid film during its thermal phase transition around 55°C.

Due to their convergent evolution, dogs have been suggested as a good model for the evolution of human social skills, such as tolerance and cooperativeness. However, recent studies have revealed that wolves (dogs' closest undomesticated relatives) are more tolerant and cooperative with conspecifics than dogs. It is still possible, though, that selection during domestication enhanced cooperative inclinations specifically towards humans, predicting better cooperation with humans in dogs than in wolves. We tested this hypothesis by comparing similarly human-raised wolves and dogs when cooperating with a familiar human partner in a string-pulling task. Both dogs and wolves were highly successful with the human partner, highlighting that dog-human cooperation could have evolved based on wolves' social skills. However, wolves and dogs differed in how they cooperated with their human partners with wolves being more likely to initiate movement leading the interaction with humans, whereas dogs were more likely to wait for the human to initiate action and then follow. Accordingly, we propose that during the course of domestication, after an initial reduction in fear of humans, dogs were selected for increased submissive inclinations (Deferential Behaviour Hypothesis) in order to minimize conflicts over resources, to ensure safe co-habitation and co-working in a way that humans lead and dogs follow.

Constitutional mismatch repair deficiency (CMMRD) is a rare childhood cancer predisposition syndrome caused by biallelic germline mutations in one of four mismatch-repair genes. Besides very high tumour risks, CMMRD phenotypes are often characterised by the presence of signs reminiscent of neurofibromatosis type 1 (NF1). Because NF1 signs may be present prior to tumour onset, CMMRD is a legitimate differential diagnosis in an otherwise healthy child suspected to have NF1/Legius syndrome without a detectable underlying NF1 / SPRED1 germline mutation. However, no guidelines indicate when to counsel and test for CMMRD in this setting. Assuming that CMMRD is rare in these patients and that expected benefits of identifying CMMRD prior to tumour onset should outweigh potential harms associated with CMMRD counselling and testing in this setting, we aimed at elaborating a strategy to preselect, among children suspected to have NF1/Legius syndrome without a causative NF1 / SPRED1  mutation and no overt malignancy, those children who have a higher probability of having CMMRD. At an interdisciplinary workshop, we discussed estimations of the frequency of CMMRD as a differential diagnosis of NF1 and potential benefits and harms of CMMRD counselling and testing in a healthy child with no malignancy. Preselection criteria and strategies for counselling and testing were developed and reviewed in two rounds of critical revisions. Existing diagnostic CMMRD criteria were adapted to serve as a guideline as to when to consider CMMRD as differential diagnosis of NF1/Legius syndrome. In addition, counselling and testing strategies are suggested to minimise potential harms., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Vascular complications such as bleeding due to gastrointestinal telangiectatic anomalies, pulmonary arteriovenous malformations, hepatopulmonary syndrome, and retinal vessel abnormalities are being reported in patients with telomere biology disorders (TBDs) more frequently than previously described. The international clinical care consortium of telomere-associated ailments and family support group Dyskeratosis Congenita Outreach, Inc. held a workshop on vascular abnormalities in the TBDs at the National Cancer Institute in October 2017. Clinicians and basic scientists reviewed current data on vascular complications, hypotheses for the underlying biology and developed new collaborations to address the etiology and clinical management of vascular complications in TBDs.

The effects of β-alanine (BA) and sodium bicarbonate (SB) on energy metabolism during work-matched high-intensity exercise and cycling time-trial performance were examined in 71 male cyclists. They were randomised to receive BA + placebo (BA, n = 18), placebo + SB (SB, n = 17), BA + SB (BASB, n = 19), or placebo + placebo (PLA, n = 18). BA was supplemented for 28 days (6.4 g day -1 ) and SB (0.3 g kg -1 ) ingested 60 min before exercise on the post-supplementation trial. Dextrose and calcium carbonate were placebos for BA and SB, respectively. Before (PRE) and after (POST) supplementation, participants performed a high-intensity intermittent cycling test (HICT-110%) consisting of four 60-s bouts at 110% of their maximal power output (60-s rest between bouts). The estimated contribution of the energy systems was calculated for each bout in 39 of the participants (BA: n = 9; SB: n = 10; BASB: n = 10, PLA: n = 10). Ten minutes after HICT-110%, cycling performance was determined in a 30-kJ time-trial test in all participants. Both groups receiving SB increased estimated glycolytic contribution in the overall HICT-110%, which approached significance (SB: + 23%, p = 0.068 vs. PRE; BASB: + 18%, p = 0.059 vs. PRE). No effects of supplementation were observed for the estimated oxidative and ATP-PCr systems. Time to complete 30 kJ was not significantly changed by any of the treatments, although a trend toward significance was shown in the BASB group (p = 0.06). We conclude that SB, but not BA, increases the estimated glycolytic contribution to high-intensity intermittent exercise when total work done is controlled and that BA and SB, either alone or in combination, do not improve short-duration cycling time-trial performance.

Background: Haemodynamic instability during the induction of anaesthesia and surgery is common and may be related to hypovolaemia caused by pre-operative fasting or chronic diuretic therapy. The aim of our prospective, controlled, randomized study was to test the hypothesis that a predefined fluid bolus given prior to general anaesthesia for minor surgery would increase haemodynamic stability during anaesthetic induction., Methods: Two hundred and nineteen fairly healthy adult patients requiring minor surgery were enrolled. All received standard treatment, including a pulse contour analysing device for non-invasive measurement of cardiac index. Infusion therapy was started in all patients at induction. The intervention group (106 patients) was randomized to receive an additional fluid bolus of 8 mL/kg Ringer's acetate solution before the induction of anaesthesia. The primary endpoint was the incidence of haemodynamic instability, defined as a significant reduction of blood pressure or cardiac index during induction of anaesthesia., Results: The interventional group had a lesser incidence of haemodynamic instability during induction (41.5% vs 56.6%, P = .025). This group also had higher cardiac index, stroke volume index, systolic and mean blood pressure and a greater left ventricular end-diastolic area., Conclusions: A fluid bolus prior to anaesthesia reduced the incidence of haemodynamic instability during induction of general anaesthesia. The total fluid volume was slightly greater in the intervention group compared to the control group (1370 ± 439 mL vs 1219 ± 483 mL, P = .007). We conclude that a defined fluid bolus can help stabilizing haemodynamics in patients undergoing general anaesthesia., (© 2018 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Constitutional MisMatch Repair Deficiency (CMMRD) is caused by homozygous or compound heterozygous germline variants in one of the mismatch repair (MMR) genes (MSH2, MSH6, PMS2, MLH1). This syndrome results in early onset colorectal cancer, leukemia and lymphoma, brain tumors and other malignancies. Children with CMMRD are at high risk of developing multiple cancers and cancer surveillance does not guarantee detection of cancer at a curable stage. The development of a preventive treatment strategy would be a major step forward. Long-term daily use of acetylsalicylic acid (ASA) has been shown to reduce cancer risk in individuals with Lynch syndrome (LS). LS is caused by heterozygous germline variants of MSH2, MSH6, PMS2 and MLH1 and characterized by an increased risk of developing colorectal and endometrial cancer at adult age. Here we discuss the potential use of ASA for cancer prevention in patients with CMMRD.

KBG syndrome is a rare autosomal dominant disorder caused by constitutive haploinsufficiency of the ankyrin repeat domain-containing protein 11 (ANKRD11) being the result of either loss-of-function gene variants or 16q24.3 microdeletions. The syndrome is characterized by a variable clinical phenotype comprising a distinct facial gestalt and variable neurological involvement. ANKRD11 is frequently affected by loss of heterozygosity in cancer. It influences the ligand-dependent transcriptional activation of nuclear receptors and tumor suppressive function of tumor protein TP53. ANKRD11 thus serves as a candidate tumor suppressor gene and it has been speculated that its haploinsufficiency may lead to an increased cancer risk in KBG syndrome patients. While no systematic data are available, we report here on the second KBG syndrome patient who developed a malignancy. At 17 years of age, the patient was diagnosed with a left-sided paratesticular extrarenal malignant rhabdoid tumor. Genetic investigations identified a somatic truncating gene variant in SMARCB1, which was not present in the germline, and a constitutional de novo 16q24.3 microdeletion leading to a loss of the entire ANKRD11 locus. Thus, KBG syndrome was diagnosed, which was in line with the clinical phenotype of the patient. At present, no specific measures for cancer surveillance can be recommended for KBG syndrome patients. However, a systematic follow-up and inclusion of KBG syndrome patients in registries (e.g., those currently established for cancer prone syndromes) will provide empiric data to support or deny an increased cancer risk in KBG syndrome in the future., (© 2018 Wiley Periodicals, Inc.)

Objectives: Intraoperative focused transthoracic echocardiography (TTE) is feasible and has an effect on the management of hemodynamically unstable surgical patients. Furthermore, in noncardiac thoracic surgery, TTE might provide additional information for hemodynamic treatment. Transthoracic accessibility during thoracic surgical interventions is assumed to be difficult. For patients positioned on their right side, a modified subcostal transthoracic view might be helpful., Design: A prospective observational study., Setting: Single-center university hospital., Participants: The study comprised 105 consecutive patients undergoing noncardiac thoracic surgery., Interventions: Focused TTE was performed during anesthetic induction after intubation for mechanical ventilation. Intraoperative focused TTE, after positioning and draping for surgery, was attempted again for all 105 patients. Changes in patient management due to the results of the TTE were documented and analyzed., Measurements and Main Results: Presurgical TTE with mechanical ventilation was applied successfully in 98.1% of 105 patients. Intraoperative imaging was successful in 90 patients (85.7%). Results of intraoperative TTE led to the modification of perioperative management in 39 patients (37.1%), 20 (22.0%) of these during surgery., Conclusions: TTE in noncardiac thoracic surgery is feasible using a modified subcostal view and has an effect on hemodynamic management in a considerable number of patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Beckwith-Wiedemann syndrome (BWS) belongs to the group of imprinting disorders and is characterized by variable clinical features, including overgrowth, macroglossia, abdominal wall defect, neonatal hypoglycemia, body asymmetry and an increased risk for embryonal tumors. In the majority of cases, molecular alterations of the Imprinting Center (IC) regions in the chromosomal region 11p15.5 can be detected, and a correlation of single clinical features with specific genomic and epigenetic changes is obvious. Therefore, the detailed molecular diagnosis is a prerequisite for a precise prediction of the tumor risk and the tumor spectrum. Furthermore, it is the basis for a well-directed genetic counselling of the families. Despite a huge number of comprehensive studies based on a large number of cases, standardized diagnostic criteria and advices for therapeutic management were missing. In the following, the recently published first international consensus guidelines drafted by 41 experts in the field of BWS from 11 European countries and the USA are summarized. Patients support groups had been included as well. In total, 72 consented recommendations for clinical and molecular diagnosis as well as for the clinical management of BWS have been published. They refer both to patients with the classical BWS phenotype and to those with "atypical" phenotypes which are summarized as BWS spectrum (BWSp). A modified clinical scoring system is now suggested, which represents the basis to initiate molecular diagnostics. Therapeutic recommendations comprise the major clinical questions in BWS/BWSp, i. e. early monitoring of an increased tumor risk, treatment of the macroglossia and the abdominal wall defects, and therapeutic interventions for hypoglycemia. However, though there was a broad consensus on the majority of therapeutic interventions, discussions on tumor monitoring are foreseeable. Thus, prospective studies to evaluate the consensus guidelines and their use are planned., Competing Interests: Die Autoren erklären hiermit, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)

Nondestructive label-free bioanalytics of microliter to nanoliter sample volumes with low analyte concentrations requires novel analytic approaches. For this purpose, we present an optofluidic platform that combines surface-enhanced in situ infrared spectroscopy with microfluidics for sensing of surface-immobilized ultrathin biomolecular films in liquid analytes. Submonolayer sensitivity down to surface densities of few ng/cm 2 is demonstrated for the adsorption of the thiolate tripeptide glutathione and for the recognition of streptavidin on a biotinylated enhancement substrate. Nonfunctionalized and functionalized metal island films on planar oxidized silicon substrates are used for signal enhancement with quantifiable enhancement properties. A single-reflection geometry at an incidence angle below the attenuated-total-reflection (ATR) regime is used with ordinary planar, IR-transparent windows. The geometry circumvents the strong IR absorption of common polymer materials and of aqueous environments in the IR fingerprint region. This practice enables straightforward quantitative analyses of, e.g., adsorption kinetics as well as chemical and structural properties in dependence of external stimuli.

We report a novel route for the functionalization of any substrates, including chemically inert substrates. CVD grown graphene is electrochemically functionalized with p-(N-maleimido)phenyl residues and consecutively transferred to various substrates. The transfer process is shown to be without noticeable loss. The functional layer exhibits a thickness of appx. 4.5 nm.

Objectives: In official judo competitions, athletes usually engage in 5-7 matches in the same day, performing numerous high-intensity efforts interspersed by short recovery intervals. Thus, glycolytic demand in judo is high and acidosis may limit performance. Carnosine is a relevant intracellular acid buffer whose content is increased with beta-alanine supplementation. Thus, we hypothesized that beta-alanine supplementation could attenuate acidosis and improve judo performance., Design: Twenty-three highly-trained judo athletes were randomly assigned to receive either beta-alanine (6.4gday -1 ) or placebo (dextrose, same dosage) for 4 weeks., Methods: Performance was assessed before (PRE) and after (POST) supplementation through a 5-min simulated fight (randori) followed by 3 bouts of the Special Judo Fitness Test (SJFT). Blood samples were collected for blood pH, bicarbonate (HCO 3 - ) and lactate determination., Results: Beta-alanine supplementation improved the number of throws per set and the total number of throws (both p<0.05). Placebo did not change these variables (both p>0.05). Blood pH and HCO 3 - reduced after exercise (all p<0.001), with no between-group differences (all p>0.05). However, the lactate response to exercise increased in the beta-alanine group as compared to placebo (p<0.05)., Conclusions: In conclusion, 4 weeks of beta-alanine supplementation effectively enhance judo-related performance in highly-trained athletes., (Copyright © 2016 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Objectives: Focused transthoracic echocardiography (TTE) is used perioperatively for surgical patients. Intraoperative application of TTE is feasible, but its benefits remain unclear. The intention of this study was to investigate the effect of intraoperative TTE on the management of high-risk noncardiac surgery patients., Design: A prospective interventional study., Setting: Single-center university hospital., Participants: Fifty consecutive hemodynamically unstable high-risk patients anesthetized for noncardiac surgery., Interventions: Focused TTE was performed on hemodynamically unstable anesthetized patients whenever circulatory instability (defined as hypotension or low cardiac output) occurred intraoperatively. A cardiac output monitoring system using pulse contour analysis was established before induction of anesthesia. The intended therapy for stabilizing the patient was documented; however, the management actually administered was guided by the results of the TTE. Differences between the 2 lines of management were documented and analyzed., Measurements and Main Results: Intraoperative TTE was applied successfully in all 50 unstable patients. In 33 patients (66%, 95% confidence interval, 52.11-77.61) TTE led to a change of management. Altogether, 82 episodes of hemodynamic instability were recorded, including 38 episodes (46.34%, 95% confidence interval, 35.95-57.06) in which TTE led to a change of treatment. The most common pathologic finding was hypovolemia (66%); in contrast, in 22%, right-heart overload or right-heart failure (4%) was detected., Conclusions: Focused TTE by anesthesiologists can provide new information that may alter the hemodynamic management of unstable high-risk noncardiac surgery patients in the operating room., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Goal directed fluid management in major abdominal surgery has shown to reduce perioperative complications. The approach aims to optimize the intravascular fluid volume by use of minimally invasive devices which calculate flow-directed variables such as stroke volume (SV) and stroke volume variation (SVV)., Objective: We aimed to show the feasibility of routinely implementing this type of hemodynamic monitoring during pancreatic surgery, and to evaluate its effects in terms of perioperative fluid management and postoperative outcomes., Methods: All patients undergoing pancreatic surgery at a university hospital during two successive 12 months periods were included in this retrospective cohort analysis. Twelve months after the implementation of a standard operating procedure for a goal directed therapy (GDT, N = 45) using a pulse contour automated hemodynamic device were compared with a similar period before its use (control, N = 31) regarding mortality, length of hospital and ICU stay, postoperative complications and the use of fluids and vasopressors., Results: Overall, 76 patients were analysed. Significantly less crystalloids were used in the GDT group. Patients receiving GDT showed significantly fewer severe complications (insufficiency of intestinal anastomosis: 0 vs. 5 (P = 0.0053) and renal failure: 0 vs. 4 (P = 0.0133). Mortality for pancreatic surgery was 1 vs. 3 patients, (P = 0.142), and length of stay (LOS) in the intensive care unit (ICU) was 4.38 ± 3.63 vs. 6.87 ± 10.02 (P= 0.0964) days. Use of blood products was significantly less within the GDT group., Conclusions: Implementation of a SOP for a GDT in the daily routine using flow-related parameters is feasible and is associated with better outcomes in pancreatic surgery.

Biallelic PMS2 mutations are responsible for more than half of all cases of constitutional mismatch repair deficiency (CMMRD), a recessively inherited childhood cancer predisposition syndrome. The mismatch repair gene PMS2 is partly embedded within one copy of an inverted 100-kb low-copy repeat (LCR) on 7p22.1. In an individual with CMMRD syndrome, PMS2 was found to be homozygously inactivated by a complex chromosomal rearrangement, which separates the 5'-part from the 3'-part of the gene. The rearrangement involves sequences of the inverted 100-kb LCR and a human endogenous retrovirus element and may be associated with an inversion that is indistinguishable from the known inversion polymorphism affecting the ~0.7-Mb sequence intervening the LCR. Its formation is best explained by a replication-based mechanism (RBM) such as fork stalling and template switching/microhomology-mediated break-induced replication (FoSTeS/MMBIR). This finding supports the hypothesis that the inverted LCR can not only facilitate the formation of the non-allelic homologous recombination-mediated inversion polymorphism but it also promotes the occurrence of more complex rearrangements that can be associated with a large inversion, as well, but are mediated by a RBM. This further suggests that among the inversion polymorphism on 7p22.1, more complex rearrangements might be hidden. Furthermore, as the locus is embedded in a common fragile site (CFS) region, this rearrangement also supports the recently raised hypothesis that CFS sequence motifs may facilitate replication-based rearrangement mechanisms.

Children with Down syndrome are at high risk to develop myeloid leukemia (ML-DS). Despite their excellent prognosis, children with ML-DS particularly suffer from severe therapy-related toxicities and for relapsed ML-DS the cure rates are very poor. Here we report the clinical course of one child with ML-DS treated with the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid) after second relapse. The child had previously received conventional chemotherapy and stem cell transplantation, yet showed a remarkable clinical and hematologic response. Thus, HDAC inhibitor may represent an effective class of drugs for the treatment of ML-DS., (© 2016 Wiley Periodicals, Inc.)

Both human and non-humans species face decisions in their daily lives which may entail taking risks. At the individual level, a propensity for risk-taking has been shown to be positively correlated with explorative tendencies, whereas, at the species level a more variable and less stable feeding ecology has been associated with a greater preference for risky choices. In the current study we compared two closely related species; wolves and dogs, which differ significantly in their feeding ecology and their explorative tendencies. Wolves depend on hunting for survival with a success rate of between 15 and 50%, whereas free-ranging dogs (which make up 80% of the world dog population), are largely scavengers specialized on human produce (i.e., a more geographically and temporally stable resource). Here, we used a foraging paradigm, which allowed subjects to choose between a guaranteed less preferred food vs. a more preferred food, which was however, delivered only 50% of the time (a stone being delivered the rest of time). We compared identically raised adult wolves and dogs and found that in line with the differing feeding ecologies of the two species and their explorative tendencies, wolves were more risk prone than dogs.

Introduction: Colorectal carcinoma (CRC) is the second most common adult cancer in Germany, however, it is extremely rare in children and adolescents. In these patients, previous literature describes aggressive behavior and diagnosis at advanced stage., Method: Thirty-one patients with CRC age ≤ 18 years and treated between 1990 and 2012 have been identified through the structures and registries of the German Society for Pediatric Oncology and Hematology., Results: The age range was 9-18 years (median 13.5 years); the median follow-up time was 43.9 months (range 1-124 months). Twenty-six patients (84%) were tested for a genetic tumor syndrome (GTS); of these, 11 patients (35% of all patients) tested positive (eight cases of Lynch syndrome, one patient with familial adenomatous polyposis, two patients with constitutional mismatch repair deficiency). An unfavorable histology was reported in 55% of the records (n = 17), a poor differentiation (grade III) in 68% of carcinoma (n = 21). Overall survival (OS) and event-free survival at 5 years was 52.0% and 65.6%, respectively. Five-year survival according to stage was 100% in stage II (n = 2), 100% in stage III (n = 13), and 12.9% in stage IV (n = 15; P < 0.001). Five-year OS in patients with and without a defined GTS was 100% and 36.5% (P = 0.019), respectively., Conclusion: Children and adolescents with CRC are frequently diagnosed in advanced stages and have an unfavorable prognosis. In this study, a high percentage of pediatric CRC patients presented with a tumor predisposition syndrome and showed an especially favorable OS., (© 2015 Wiley Periodicals, Inc.)

Noonan syndrome is associated with a range of malignancies including acute lymphoblastic leukemia (ALL). However, little information is available regarding the frequency, natural history, characteristics and prognosis of ALL in Noonan syndrome or RASopathies in general. Cross-referencing data from a large prospective cohort of 1176 patients having a molecularly confirmed RASopathy with data from the French childhood cancer registry allowed us to identify ALL in 6 (0.5%) patients including 4/778 (0.5%) with a germline PTPN11 mutation and 2/94 (2.1%) with a germline SOS1 mutation. None of the patients of our series with CFC syndrome (with germline BRAF or MAP2K1/MAP2K2 mutation - n = 121) or Costello syndrome (with HRAS mutation - n = 35) had an ALL. A total of 19 Noonan-ALL were gathered by adding our patients to those of the International Berlin-Munster-Frankfurt (I-BFM) study group and previously reported patients. Strikingly, all Noonan-associated ALL were B-cell precursor ALL, and high hyperdiploidy with more than 50 chromosomes was found in the leukemia cells of 13/17 (76%) patients with available genetics data. Our data suggest that children with Noonan syndrome are at higher risk to develop ALL. Like what is observed for somatic PTPN11 mutations, NS is preferentially associated with the development of hyperdiploid ALL that will usually respond well to chemotherapy. However, Noonan syndrome patients seem to have a propensity to develop post therapy myelodysplasia that can eventually be fatal. Hence, one should be particularly cautious when treating these patients., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Introduction: The etiology of acute lymphoblastic leukemia remains undisclosed in the majority of cases. A number of rare syndromic conditions are known to predispose to different forms of childhood cancer including ALL. The present study characterized the spectrum and clinical impact of preexisting diseases in a cohort of ALL patients from Germany, Austria and Switzerland with a focus on genetic diseases predisposing to cancer development., Methods: Retrospective database and study chart review included all patients from Germany, Austria and Switzerland (n = 4939) enrolled into multicenter clinical trial AIEOP-BFM ALL 2000 between July 1999 and June 2009. Patients enrolled into study AIEOP-BFM ALL 2009 - which was initiated subsequent to AIEP-BFM ALL 2000 - who were reported with a cancer prone syndrome or chromosomal abnormality were additionally included in this study to increase conclusiveness of observations., Results: A total of 233 patients with at least one reported condition could be identified. The following conditions were reported in more than one patient: Gilbert's disease (n = 13), neurofibromatosis type I (n = 8), ataxia telangiectasia (n = 8), thalassemia (n = 7), Nijmegen Breakage syndrome (n = 6), cystic fibrosis (n = 4), glucose-6-phosphate dehydrogenase deficiency (n = 4), Noonan syndrome (n = 2), Klinefelter syndrome (n = 2), alpha-1-antitrypsin deficiency (n = 2), primary ciliary dyskinesia (n = 2). Especially those syndromes with a known cancer predisposition (NF type I, Ataxia telangiectasia, Nijmegen Breakage syndrome etc.) were associated with certain general and ALL-related characteristics, high therapy-related toxicity and reduced survival., Conclusion: The spectrum of underlying diseases within ALL patients is dispersed. A small number of ALL patients are reported with cancer predisposition syndromes at initial diagnosis which are associated with high rates of therapy-related toxicity and a markedly reduced chance of survival. The true prevalence of these conditions within the ALL population remains unknown due to inapparent clinical presentation. A targeted clinical and/or genetic examination for certain diagnoses like NF type I, Ataxia telangiectasia or Nijmegen Breakage syndrome could identify patients who benefit from adjustment of antileukemic therapy or intensification of supportive care., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Fanconi anemia (FA) is a genomic instability syndrome associated with bone marrow failure, myelodysplastic syndrome (MDS), and/or acute myeloid leukemia (AML) requiring hematopoietic stem cell transplantation (HSCT) to restore normal hematopoiesis. Although low-intensity fludarabine-based preparative regimens without radiation confer excellent outcomes in FA HSCTs with HLA-matched sibling donors, outcomes for FA patients with alternative donors are less encouraging, albeit improving. We present our experience with 17 FA patients who completed mismatched related or unrelated donor HSCT using a non-radiation fludarabine-based preparative regimen at Charité University Medicine Berlin. All patients engrafted; however, one patient had unstable chimerism in the setting of multi-viral infections that necessitated a stem cell boost to revert to full donor chimerism. Forty-seven percent of patients developed grade I acute graft-verus-host disease (aGVHD). No grade II-IV aGVHD or chronic graft-versus-host disease of any severity occurred. At a median follow-up of 30 months, 88 % of patients are alive with normal hematopoiesis. Two patients died of infections 4 months post-transplantation. These results demonstrate that short-term outcomes for FA patients with mismatched and unrelated donor HSCTs can be excellent using chemotherapy only conditioning. Viral reactivation, however, was a major treatment-related complication.

Lynch syndrome (LS) is an autosomal dominant disorder caused by a defect in one of the DNA mismatch repair genes: MLH1, MSH2, MSH6 and PMS2. In the last 15 years, an increasing number of patients have been described with biallelic mismatch repair gene mutations causing a syndrome referred to as 'constitutional mismatch repair-deficiency' (CMMR-D). The spectrum of cancers observed in this syndrome differs from that found in LS, as about half develop brain tumours, around half develop digestive tract cancers and a third develop haematological malignancies. Brain tumours and haematological malignancies are mainly diagnosed in the first decade of life, and colorectal cancer (CRC) and small bowel cancer in the second and third decades of life. Surveillance for CRC in patients with LS is very effective. Therefore, an important question is whether surveillance for the most common CMMR-D-associated cancers will also be effective. Recently, a new European consortium was established with the aim of improving care for patients with CMMR-D. At a workshop of this group held in Paris in June 2013, one of the issues addressed was the development of surveillance guidelines. In 1968, criteria were proposed by WHO that should be met prior to the implementation of screening programmes. These criteria were used to assess surveillance in CMMR-D. The evaluation showed that surveillance for CRC is the only part of the programme that largely complies with the WHO criteria. The values of all other suggested screening protocols are unknown. In particular, it is questionable whether surveillance for haematological malignancies improves the already favourable outcome for patients with these tumours. Based on the available knowledge and the discussions at the workshop, the European consortium proposed a surveillance protocol. Prospective collection of all results of the surveillance is needed to evaluate the effectiveness of the programme.

Three genome-wide association studies of testicular cancer have uncovered predisposition alleles in or near KITLG, BAK1, SPRY4, TERT, ATF7IP and DMRT1. We investigated whether testicular cancer-risk alleles can be utilized in the clinical setting. We employed the receiver operating characteristic curves for genetic risk models to measure the discriminatory power of a risk variant-based risk model, and found that the newly discovered variants provided a discriminatory power of 69.2%. This suggested that about 69.2% of the time, a randomly selected patient with testicular cancer had a higher estimated risk than the risk for a randomly selected control subject. Using a multiplicative model, we estimated that white men in the top 1% of genetic risk as defined by eight risk variants had a relative risk that was 10.5-fold greater than that for the general white male population. This risk differential does not appear to be clinically useful, given the relative rarity and highly curable nature of testicular germ cell tumour (TGCT). In the authors' view, a stratified genetic risk assessment strategy might be useful, theoretically, for men who also have independent clinical risk factors for testicular cancer. Several established TGCT risk factors, such as cryptorchidism (RR=4.8) and male infertility (SIR=2.8) might prove useful in that context, but we currently do not know whether these testicular cancer-risk loci are associated with, or independent of, such clinical risk factors. More research is required before we can utilize testicular cancer-risk loci for clinically meaningful risk prediction., (© 2011 The Authors. International Journal of Andrology © 2011 European Academy of Andrology.)

Background: Biallelic germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 or PMS2 cause a recessive childhood cancer syndrome characterised by early-onset malignancies and signs reminiscent of neurofibromatosis type 1 (NF1). Alluding to the underlying genetic defect, we refer to this syndrome as constitutional mismatch repair-deficiency (CMMR-D) syndrome. The tumour spectrum of CMMR-D syndrome includes haematological neoplasias, brain tumours and Lynch syndrome-associated tumours. Other tumours, such as neuroblastoma, Wilm tumour, ovarian neuroectodermal tumour or infantile myofibromatosis, have so far been found only in individual cases., Results: We analysed two consanguineous families that had members with suspected CMMR-D syndrome who developed rhabdomyosarcoma among other neoplasias. In the first family, we identified a pathogenic PMS2 mutation for which the affected patient was homozygous. In family 2, immunohistochemistry analysis showed isolated loss of PMS2 expression in all tumours in the affected patients, including rhabdomyosarcoma itself and the surrounding normal tissue. Together with the family history and microsatellite instability observed in one tumour this strongly suggests an underlying PMS2 alteration in family 2 also., Conclusion: Together, these two new cases show that rhabdomyosarcoma and possibly other embryonic tumours, such as neuroblastoma and Wilm tumour, belong to the tumour spectrum of CMMR-D syndrome. Given the clinical overlap of CMMR-D syndrome with NF1, we suggest careful examination of the family history in patients with embryonic tumours and signs of NF1 as well as analysis of the tumours for loss of one of the mismatch repair genes and microsatellite instability. Subsequent mutation analysis will lead to a definitive diagnosis of the underlying disorder.

Background: The main features of severe congenital neutropenia are the onset of severe bacterial infections early in life, a paucity of mature neutrophils, and an increased risk of leukemia. In many patients, the genetic causes of severe congenital neutropenia are unknown., Methods: We performed genomewide genotyping and linkage analysis on two consanguineous pedigrees with a total of five children affected with severe congenital neutropenia. Candidate genes from the linkage interval were sequenced. Functional assays and reconstitution experiments were carried out., Results: All index patients were susceptible to bacterial infections and had very few mature neutrophils in the bone marrow; structural heart defects, urogenital abnormalities, and venous angiectasia on the trunk and extremities were additional features. Linkage analysis of the two index families yielded a combined multipoint lod score of 5.74 on a linkage interval on chromosome 17q21. Sequencing of G6PC3, the candidate gene encoding glucose-6-phosphatase, catalytic subunit 3, revealed a homozygous missense mutation in exon 6 that abolished the enzymatic activity of glucose-6-phosphatase in all affected children in the two families. The patients' neutrophils and fibroblasts had increased susceptibility to apoptosis. The myeloid cells showed evidence of increased endoplasmic reticulum stress and increased activity of glycogen synthase kinase 3beta (GSK-3beta). We identified seven additional, unrelated patients who had severe congenital neutropenia with syndromic features and distinct biallelic mutations in G6PC3., Conclusions: Defective function of glucose-6-phosphatase, catalytic subunit 3, underlies a severe congenital neutropenia syndrome associated with cardiac and urogenital malformations., (2009 Massachusetts Medical Society)

Scar formation as a result of burn wounds leads to contraction of the formed granulation tissue, which causes both aesthetic and functional impairment for the patient. Currently, the main treatment methods focus on stretching to prevent tissue contraction. The myofibroblasts play a key role in the contraction of granulation tissue during scar formation, but their presence should normally decrease after wound re-epithelialization. In hypertrophic scars the myofibroblasts persist and is believed to cause further hypertrophy. Previous studies have shown that mechanical tension leads to increased myofibroblast numbers in granulation tissue. In order to evaluate the effect mechanical tension as a result of stretching has on the number of myofibroblasts in burn wound scars, an in vitro model was used. This model used human burn scar biopsies which were stretched and examined after 1 and 6 days to evaluate the effect on the number of myofibroblasts. The stretching caused an increase in the number of myofibroblasts after mechanical stimulation. This indicates that mechanical stimulation using stretching induces fibroblast to myofibroblast transdifferentiation, thus underlining the importance of further investigations of optimal methods of this regime for treating burn scars.

Germline mutations in PTPN11 gene cause Noonan syndrome and the clinically similar LEOPARD syndrome (LS). LS is a rare congenital developmental disorder characterized by multiple lentigines, cardiac abnormalities, facial dysmorphism, retardation of growth, and deafness. Mutations in exons 7 and 12 of the PTPN11 gene can be identified in nearly 90% of patients with LS. PTPN11 gene encodes for an ubiquitously expressed protein tyrosine phosphatase SHP-2 involved in a variety of intracellular signaling processes in development and hematopoiesis. Somatic PTPN11 mutations contribute to leukemogenesis in children with hematologic malignancies including juvenile myelomonocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, and myelodysplasia. Two cases of leukemia (acute myeloid leukemia) have been reported in children with LS. The authors describe for the first time a girl with genetically confirmed LEOPARD syndrome presenting with common acute lymphoblastic leukemia.

The molecular pathogenesis of pediatric astrocytomas is still poorly understood. To further understand the genetic abnormalities associated with these tumors, we performed a genome-wide analysis of DNA copy number aberrations in pediatric low-grade astrocytomas by using array-based comparative genomic hybridization. Duplication of the BRAF protooncogene was the most frequent genomic aberration, and tumors with BRAF duplication showed significantly increased mRNA levels of BRAF and a downstream target, CCND1, as compared with tumors without duplication. Furthermore, denaturing HPLC showed that activating BRAF mutations were detected in some of the tumors without BRAF duplication. Similarly, a marked proportion of low-grade astrocytomas from adult patients also had BRAF duplication. Both the stable silencing of BRAF through shRNA lentiviral transduction and pharmacological inhibition of MEK1/2, the immediate downstream phosphorylation target of BRAF, blocked the proliferation and arrested the growth of cultured tumor cells derived from low-grade gliomas. Our findings implicate aberrant activation of the MAPK pathway due to gene duplication or mutation of BRAF as a molecular mechanism of pathogenesis in low-grade astrocytomas and suggest inhibition of the MAPK pathway as a potential treatment.

Heterozygous germline mutations in one of the mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 cause hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome, a dominantly inherited cancer susceptibility syndrome. Recent reports provide evidence for a novel recessively inherited cancer syndrome with constitutive MMR deficiency due to biallelic germline mutations in one of the MMR genes. MMR-deficiency (MMR-D) syndrome is characterized by childhood brain tumors, hematological and/or gastrointestinal malignancies, and signs of neurofibromatosis type 1 (NF1). We established an RNA-based mutation detection assay for the four MMR genes, since 1) a number of splicing defects may escape detection by the analysis of genomic DNA, and 2) DNA-based mutation detection in the PMS2 gene is severely hampered by the presence of multiple highly similar pseudogenes, including PMS2CL. Using this assay, which is based on direct cDNA sequencing of RT-PCR products, we investigated two families with children suspected to suffer from MMR-D syndrome. We identified a homozygous complex MSH6 splicing alteration in the index patients of the first family and a novel homozygous PMS2 mutation (c.182delA) in the index patient of the second family. Furthermore, we demonstrate, by the analysis of a PMS2/PMS2CL "hybrid" allele carrier, that RNA-based PMS2 testing effectively avoids the caveats of genomic DNA amplification approaches; i.e., pseudogene coamplification as well as allelic dropout, and will, thus, allow more sensitive mutation analysis in MMR deficiency and in HNPCC patients with PMS2 defects., ((c) 2007 Wiley-Liss, Inc.)

Here, a case is presented with two rare genetic disorders, biotinidase deficiency and juvenile myelomonocytic leukemia, in a Turkish infant. This case may serve as a reminder that the diagnosis of a genetic disorder does not exclude the possibility of a second congenital but acquired disease.

Porphobilinogen-synthase (PBG-synthase) is an enzyme extensively used as a bioindicator of metals and other oxidizing agents. The objective of this study was to verify the effects of HgCl(2) (5mg/kg/day, s.c.), a metal that mainly affects the nervous and renal systems, on kidney, liver and brain from rats exposed during one of the phases considered critical for development. Mercury decreased PBG-synthase activity from liver, kidney and brain and altered corporal, renal and cerebral weights. The kidney was the most sensitive tissue. It accumulated a large amount of metal and PBG-synthase activity was decreased up to 50%. The second period seemed to be the most sensitive, because in this phase the rats presented alterations in body, brain and kidney weights, and there was also an expressive inhibition in hepatic and renal PBG-synthase activities. In general, large quantities of metal accumulated in the tissues are in agreement with the inhibition verified in these tissues.

Juvenile myelomonocytic leukemia (JMML) is a malignant hematopoietic disorder whose proliferative component is a result of RAS pathway deregulation caused by somatic mutation in the RAS or PTPN11 oncogenes or in patients with underlying neurofibromatosis type 1 (NF-1), by loss of NF1 gene function. To search for potential collaborating genetic abnormalities, we used oligonucleotide arrays to analyse over 116 000 single-nucleotide polymorphisms across the genome in 16 JMML samples with normal karyotype. Evaluation of the SNP genotypes identified large regions of homozygosity on chromosome 17q, including the NF1 locus, in four of the five samples from patients with JMML and NF-1. The homozygous region was at least 55 million base pairs in each case. The genomic copy number was normal within the homozygous region, indicating uniparental disomy (UPD). In contrast, the array data provided no evidence for 17q UPD in any of the 11 JMML cases without NF-1. We used array-based comparative genomic hybridization to confirm 17q disomy, and microsatellite analysis was performed to verify homozygosity. Mutational analysis demonstrated that the inactivating NF1 lesion was present on both alleles in each case. In summary, our data indicate that a mitotic recombination event in a JMML-initiating cell led to 17q UPD with homozygous loss of normal NF1, provide confirmatory evidence that the NF1 gene is crucial for the increased incidence of JMML in NF-1 patients, and corroborate the concept that RAS pathway deregulation is central to JMML pathogenesis.

The RAS proteins function as fundamental signaling switches that control normal cell growth and differentiation. Deregulated activation of RAS-dependent signaling pathways constitutes a potent mechanism of malignant cell transformation. Juvenile myelomonocytic leukemia (JMML) is a rapidly fatal myeloproliferative disorder of early childhood for which no effective treatment other than hematopoietic stem cell transplantation is currently available. Many aspects of JMML pathobiology are linked to deregulated RAS signaling. Hence, targeting RAS or its interactors on a molecular level is a promising strategy in the development of novel rational therapies for this menacing disease. Here we give an overview of current concepts on the pathogenesis of JMML, present important aspects of cellular RAS biology that can be exploited for pharmacologic manipulation, and discuss mouse models that have greatly advanced our understanding of the role RAS plays in JMML. In addition, we review recent approaches to develop agents that interfere with the RAS network at the level of the granulocyte-macrophage colony-stimulating factor receptor, posttranslational RAS processing (prenylation and endoprotease cleavage), RAF serine/threonine kinase, MEK mitogen-activated protein kinase, and target of rapamycin activity. Preclinical and clinical data of these pharmaceuticals in JMML and other myeloid malignancies is discussed.