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Oncolytic viruses and combinatorial immunotherapy for cancer (this Special Issue) are both part of cancer treatment at IOZK. This review focusses on an individual multimodal cancer immunotherapy concept developed by IOZK, Cologne, Germany. The scientific rationale for employing three main components is explained: (i) oncolytic Newcastle disease virus, (ii) modulated electrohyperthermia and (iii) individual tumor antigen and oncolytic virus modified dendritic cell vaccine (IO-VAC R ). The strategy involves repeated cancer-immunity cycles evoked in cancer patients by systemic oncolytic virus exposure plus hyperthermia pretreatment to induce immunogenic cell death followed by intradermal IO-VAC R vaccination. As an example of the experience at IOZK, we present the latest results from combining the immunotherapy with standard treatment of patients suffering from glioblastoma multiforme. The promising clinical results in terms of overall survival benefit of additional individualized multimodal immunotherapy are presented. The cancer-immunity cycle, as introduced 10 years ago, describes key important steps occurring locally at the sites of both tumor and draining lymph nodes. This view is extended here towards systemic events occuring in blood where immunogenic cell death-induced tumor antigens are transported into the bone marrow. For 20 years it has been known that bone marrow is an antigen-responsive organ in which dendritic cells present tumor antigens to T cells leading to immunological synapse formation, tumor antigen-specific T cell activation and memory T cell formation. Bone marrow is known to be the most prominent source of de novo cellular generation in the body and to play an important role for the storage and maintenance of immunological memory. Its systemic activation is recommended to augment cancer-immunity cycles.

Background and study aim Simulator-based training has been extensively studied in training gastroduodenoscopy and colonoscopy and shown to significantly improve learning curves of novices. Data on simulator-based training in endoscopic retrograde cholangiopancreatography (ERCP) are scarce. We aimed to determine the impact of 2-day intensive hands-on simulator training on the course of the learning curve of novice trainees. Methods We conducted a prospective cohort study using a validated mechanical ERCP simulator (Boškoski-Costamagna ERCP Trainer). Six trainees were allocated to the simulation course program (SG). Each of these trainees were paired with an endoscopy trainee starting regular ERCP training at the same center who had no exposure to a simulation course program (control group; CG). The course included lectures, live ERCP demonstrations, and hands-on ERCP training to educate trainees in basic techniques related to cannulation, stent placement, stone extraction and stricture management. After the course, both the SG and CG started formal ERCP training in their respective centers. The Rotterdam Assessment Form for ERCP was used to register each performed ERCP. Simple moving average was applied to create learning curves based on successful common bile duct (CBD) cannulation. Outcomes were plotted against a historical cohort (HC). Results Thirteen trainees were included, six trainees in the SG and seven trainees in the CG, with a total of 717 ERCPs. Mean successful ERCP cannulation rate was higher for the simulator group at baseline compared to both CG and HC, 64% versus 43% and 42%, respectively. Differences became less explicit after 40 ERCPs, but persisted until a median of 75 ERCPs. Conclusions We demonstrate that 2-day hands-on simulator-based ERCP training course has a positive effect on the learning curves of ERCP trainees and should be considered an integral part of the training curricula for ERCP to develop skills prior to patient-based training., Competing Interests: Conflict of Interest S.E. van der Wiel: no conflicts of interest. E.A.J. Rauws, no conflicts of interest. S. Van Gool, no conflicts of interest. D. Wang, no conflict of interest. Bing Hu, no conflicts of interest. L. Kylänpää: no conflicts of interest. G.J. Webster: no conflict of interest. M.W. James: no conflict of interest. A.D. Koch: no conflicts of interest. M.J. Bruno: Consultant, support for industry and investigator initiated studies Cook Medical and Boston Scientific. Support for investigator initiated studies from Pentax, Mylan and 3M., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Synergistic activity between maintenance temozolomide (TMZm) and individualized multimodal immunotherapy (IMI) during/after first-line treatment has been suggested to improve the overall survival (OS) of adults with IDH1 wild-type MGMT promoter-unmethylated (unmeth) GBM. We expand the data and include the OS of MGMT promoter-methylated (meth) adults with GBM. Unmeth (10 f, 18 m) and meth (12 f, 10 m) patients treated between 27 May 2015 and 1 January 2022 were analyzed retrospectively. There were no differences in age (median: 48 y) or Karnofsky performance index (median: 80). The IMI consisted of 5-day immunogenic cell death (ICD) therapies during TMZm: Newcastle disease virus (NDV) bolus injections and sessions of modulated electrohyperthermia (mEHT); subsequent active specific immunotherapy: dendritic cell (DC) vaccines plus modulatory immunotherapy; and maintenance ICD therapy. There were no differences in the number of vaccines (median: 2), total number of DCs (median: 25.6 × 10 6 ), number of NDV injections (median: 31), and number of mEHT sessions (median: 28) between both groups. The median OS of 28 unmeth patients was 22 m (2y-OS: 39%), confirming previous results. OS of 22 meth patients was significantly better ( p = 0.0414) with 38 m (2y-OS: 81%). There were no major treatment-related adverse reactions. The addition of IMI during/after standard of care should be prospectively explored., Competing Interests: The authors declare no conflict of interest.

Background: Glioblastoma multiforme (GBM) is a WHO grade 4 glioma and the most common malignant primary brain tumour. Recently, there has been outstanding progress in the treatment of GBM. In addition to the newest form of GBM removal using fluorescence, three-dimensional (3D) imaging, tomoradiotherapy, moderate electro-hyperthermia, and adjuvant temozolomide (post-operative chemotherapy), new developments have been made in the fields of immunology, molecular biology, and virotherapy. An unusual and modern treatment has been created, especially for stage 4 GBM, using the latest therapeutic techniques, including immunotherapy and virotherapy. Modern oncological medicine is producing extraordinary and progressive therapeutic methods. Oncological therapy includes individual analysis of the properties of a tumour and targeted therapy using small-molecule inhibitors. Individualised medicine covers the entire patient (tumour and host) in the context of immunotherapy. An example is individualised multimodal immunotherapy (IMI), which relies on individual immunological tumour-host interactions. In addition, IMI is based on the concept of oncolytic virus-induced immunogenic tumour cell death., Summary: In this review, we outline current knowledge of the various available treatment options used in the therapy of GBM including both traditional therapeutic strategy and modern therapies, such as tomotherapy, electro-hyperthermia, and oncolytic virotherapy, which are promising treatment strategies with the potential to improve prognosis in patients with GBM., Key Messages: This newest therapy, immunotherapy combined with virotherapy (oncolytic viruses and cancer vaccines), is displaying encouraging signs for combating GBM. Additionally, the latest 3D imaging is compared to conventional two-dimensional imaging., (© 2023 S. Karger AG, Basel.)

Various stimulants (VS) are chemicals that disrupt the endocrine system - endocrine homeostasis of the reproductive system - which also known as endocrine-disrupting chemicals (EDCs). These substances are found in the human body, in both the blood and urine, amniotic fluid, or, among others, the adipose tissue. This article presents the current state of knowledge of the effect of EDCs and additional factors such as smoking, alcohol consumption, and cannabis on the gonads. The article is an overview of the impact of EDCs and their mechanism of action, with particular emphasis on gonads, based on databases such as PubMed, EMBASE and Google Scholar, and Web of Science available until May 2022. The impact of human exposure to bisphenol A (BPA) is not fully understood, but it has been shown that phthalates show a negative correlation in anti-androgenic activity in the case of men and women for the anti-Müllerian hormone (AMH). Smoking cigarettes and passive exposure to tobacco have a huge impact on the effects of endocrine disorders in both women and men, especially during the reproductive time. Also, the use of large amounts of cannabinoids during the reproductive years can lead to similar disorders. It has been documented that excessive alcohol consumption leads to disturbed function of the hypothalamus-pituitary-gonadal axis (HPG). Excess caffeine consumption may adversely affect male reproductive function, although this is not fully proven. Therefore, the following publication presents various stimulants (BPA, phthalates, nicotine, alcohol, cannabis) that disrupt the function of the endocrine system and, in particular, affect the function of the gonads.

An apparent paradox exists between the evidence for spontaneous systemic T cell- mediated anti-tumor immune responses in cancer patients, observed particularly in their bone marrow, and local tumor growth in the periphery. This phenomenon, known as "concomitant immunity" suggests that the local tumor and its tumor microenvironment (TME) prevent systemic antitumor immunity to become effective. Oncolytic Newcastle disease virus (NDV), an agent with inherent anti-neoplastic and immune stimulatory properties, is capable of breaking therapy resistance and immunosuppression. This review updates latest information about immunosuppression by the TME and discusses mechanisms of how oncolytic viruses, in particular NDV, and cellular immunotherapy can counteract the immunosuppressive effect of the TME. With regard to cellular immunotherapy, the review presents pre-clinical studies of post-operative active-specific immunotherapy and of adoptive T cell-mediated therapy in immunocompetent mice. Memory T cell (MTC) transfer in tumor challenged T cell-deficient nu/nu mice demonstrates longevity and functionality of these cells. Graft-versus-leukemia (GvL) studies in mice demonstrate complete remission of late-stage disease including metastases and cachexia. T cell based immunotherapy studies with human cells in human tumor xenotransplanted NOD/SCID mice demonstrate superiority of bone marrow-derived as compared to blood-derived MTCs. Results from clinical studies presented include vaccination studies using two different types of NDV-modified cancer vaccine and a pilot adoptive T-cell mediated therapy study using re-activated bone marrow-derived cancer-reactive MTCs. As an example for what can be expected from clinical immunotherapy against tumors with an immunosuppressive TME, results from vaccination studies are presented from the aggressive brain tumor glioblastoma multiforme. The last decades of basic research in virology, oncology and immunology can be considered as a success story. Based on discoveries of these research areas, translational research and clinical studies have changed the way of treatment of cancer by introducing and including immunotherapy.

Background: Upper gastrointestinal, non-variceal haemorrhage can be related to various etiologies, including peptic ulcer, neoplasm, gastritis, Dieulafoy lesions and other, rare underlying diseases. Here, we describe another, yet unreported etiology of gastric bleeding., Case Presentation: A 49-year-old man presented with melena; gastroscopy revealed blood in the stomach without active bleeding source. Computed tomography angiography demonstrated a cluster of enlarged gastrosplenic arterial collaterals in the gastric wall and coils in the splenic artery, related to an embolization procedure 30-years ago for splenic trauma. Definitive treatment included catheter-directed glue embolization of the left gastric artery and the enlarged gastrosplenic collaterals. The postinterventional course was uneventful and no recurrence of upper gastrointestinal bleeding was noted after 6 months of follow-up., Conclusions: Upper gastrointestinal bleeding associated with eroded gastrosplenic collaterals, related to previous splenic artery embolization, can be successfully treated with glue-embolization., (© 2022. The Author(s).)

Background: Leadless pacemakers (PMs) capable of atrioventricular (AV) synchronous pacing have recently been introduced. Initial feasibility studies were promising but limited to just a few minutes of AV synchronous pacing. Real-world, long-term data on AV synchrony and programming adjustments affecting AV synchrony in outpatients are lacking., Objective: The purpose of this study was to investigate AV synchrony and influences of PM programming adjustments in outpatients with leadless VDD PMs., Methods: All patients who received a leadless VDD PM (Micra™ AV, Medtronic) between July 2020 and May 2021 at our center were included in this observational study. AV synchrony was assessed repeatedly postoperatively and during follow-up using Holter electrocardiographic (ECG) recordings. AV synchrony was defined as a QRS complex preceded by a p wave within 300 ms. The impact of programming changes during follow-up on AV synchrony was studied., Results: A total of 816 hours of Holter ECG from 20 outpatients were analyzed. During predominantly paced episodes (≥80% ventricular pacing), median AV synchrony was 91% [interquartile range (IQR) 34%-100%] when patients had sinus rates 50-80/min. Median AV synchrony was lower when patients had sinus rates >80/min [33% (29%-46%); P <.001]. During a stepwise optimization protocol, AV synchrony could be improved (P <.038). Multivariate analysis showed that a shorter maximum A3 window end (P <.001), lower A3 threshold (P = .046), and minimum A4 threshold (P <.001) improved AV synchrony., Conclusion: Successful VDD pacing in the outpatient setting during higher sinus rates is more difficult to achieve than can be presumed based on initial feasibility studies. The devices often require multiple reprogramming to maximize AV sequential pacing., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Nowadays, natural killer (NK) cell-based immunotherapy provides a practical therapeutic strategy for patients with advanced solid tumors (STs). This approach is adaptively conducted by the autologous and identical NK cells after in vitro expansion and overnight activation. However, the NK cell-based cancer immunotherapy has been faced with some fundamental and technical limitations. Moreover, the desirable outcomes of the NK cell therapy may not be achieved due to the complex tumor microenvironment by inhibition of intra-tumoral polarization and cytotoxicity of implanted NK cells. Currently, stem cells (SCs) technology provides a powerful opportunity to generate more effective and universal sources of the NK cells. Till now, several strategies have been developed to differentiate types of the pluripotent and adult SCs into the mature NK cells, with both feeder layer-dependent and/or feeder laye-free strategies. Higher cytokine production and intra-tumoral polarization capabilities as well as stronger anti-tumor properties are the main features of these SCs-derived NK cells. The present review article focuses on the principal barriers through the conventional NK cell immunotherapies for patients with advanced STs. It also provides a comprehensive resource of protocols regarding the generation of SCs-derived NK cells in an ex vivo condition., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Patients and Methods: A prospective registration of patients with colorectal cancer and a colonoscopy within the last 10 years. We tried to classify these post-colonoscopy colorectal cancers (PCCRCs) by most reasonable explanation and into subcategories suggested by the World Endoscopy Organization (WEO) and calculated the unadjusted PCCRC rate., Results: 47 PCCRCs were identified. The average age at diagnosis of PCCRC was 73 years. PCCRCs were more located in the right colon with a higher percentage of MSI-positive and B-RAF mutated tumours. The average period between index colonoscopy and diagnosis of PCCRC was 4.2 years. Sixty-eight % of all PCCRCs could be explained by procedural factors. The mean PCCRC-3y of our department was 2.46%., Conclusions: The data of our centre are in line with the data of the literature from which can be concluded that most postcolonoscopy colorectal cancers are preventable. The PCCRC-3y is an important quality measure for screening colonoscopy. Ideally all centres involved in the population screening should measure the PCCRC-3 y annually, with cooperation of the cancer registry and reimbursement data provided by the Intermutualistic Agency (IMA)., Competing Interests: The authors declare that they have no conflict of interest, (© Acta Gastro-Enterologica Belgica.)

This retrospective correlation study investigated the putative link between methylene tetrahydrofolate reductase (MTHFR) A1298C mutations and chemotherapy-related brain function changes in adult childhood-leukemia survivors. To this end, we determined the relationship between the particular MTHFR1298 genotype (AA, AC or CC) of 31 adult childhood-leukemia survivors, and (1) their CSF Tau and phosphorylated Tau (pTau) levels at the time of treatment, (2) their adult performance intelligence quotient (PIQ), and (3) their regional brain connectivity using diffusion magnetic resonance imaging (dMRI) and resting-state functional MRI (rsfMRI). We confirmed that neuropathology markers Tau and pTau significantly increased in CSF of children after intrathecal methotrexate administration. Highest concentrations of these toxicity markers were found during the induction phase of the therapy. Moreover, CSF concentrations of Tau and pTau during treatment were influenced by the children's particular MTHFR1298 genotype. CSF Tau (but not pTau) levels significantly dropped after folinic acid supplementation. At adult age (on average 13.1 years since the end of their treatment), their particular MTHFR1298 genotype (AA, AC or CC) influenced the changes in PIQ and cortical connectivity that we found to be related to their childhood exposure to chemotherapeutics. In summary, we suggest that homozygous MTHFR1298CC individuals are more vulnerable to the adult sequelae of antifolate chemotherapy., Competing Interests: The authors have read the journal’s policy and have the following competing interests: TB is an employee of Icometrix. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Objective: To determine variation in diagnostic strategies for diagnosing dementia between Dutch hospitals., Design: Descriptive, retrospective research based on claim data of Dutch health insurers., Method: Information on the use of diagnostic ancillary services carried out from 2015 to 2018 was collected via national-level insurance claims for patients who received a (new) diagnose-coding for dementia in 2018. Hospitals were included in the analysis if they diagnosed >50 patients with dementia. We distinguished academic medical centres (AMC), non-academic training hospitals (TH) and general hospitals (GH)., Results: In 2018, 20.073 new cases of dementia were diagnosed in 71 hospitals. The percentages of patients undergoing MRI/CT-imaging ranged from 37 to 99% (median 76.7%), neuropsychological-assessment from 0-89% (median 31.8%), cerebrospinal fluid examination from 0-14% (median 2.4%), PET/SPECT-imaging from 0-16% (median 6.2%) and electroencephalography from 1-20% (median 5.8%). Practice variation was comparable in AMCs, THs and GHs and was evidently skewed for PET/SPECT-imaging, electroencephalography and cerebrospinal fluid examination. There were no distinct differences according to case-mix characteristics or hospital volume. The percentage of patients subjected to ancillary diagnostic investigations decreased sharply with increasing age., Conclusion: In the Netherlands, diagnostic ancillary methods used vary widely between hospitals both in frequency and modality. This variation may be driven by limited evidence of diagnostic accuracy and added value of different diagnostic tests, variations in doctor and patient preferences and differences in available diagnostic techniques per hospital. Further exploration of this heterogeneity may help to identify a strategy that combines the most benefit with the least burden.

Resistance to therapy is a major obstacle to cancer treatment. It may exist from the beginning, or it may develop during therapy. The review focusses on oncolytic Newcastle disease virus (NDV) as a biological agent with potential to break therapy resistance. This avian virus combines, upon inoculation into non-permissive hosts such as human, 12 described anti-neoplastic effects with 11 described immune stimulatory properties. Fifty years of clinical application of NDV give witness to the high safety profile of this biological agent. In 2015, an important milestone was achieved, namely the successful production of NDV according to Good Manufacturing Practice (GMP). Based on this, IOZK in Cologne, Germany, obtained a GMP certificate for the production of a dendritic cell vaccine loaded with tumor antigens from a lysate of patient-derived tumor cells together with immunological danger signals from NDV for intracutaneous application. This update includes single case reports and retrospective analyses from patients treated at IOZK. The review also presents future perspectives, including the concept of in situ vaccination and the combination of NDV or other oncolytic viruses with checkpoint inhibitors.

Background: To improve detection of mucosal lesions during colonoscopy a number of imaging modalities have been suggested, including high definition and virtual chromoendoscopy. Given the theoretical advantage of these new imaging techniques, we aimed to investigate their use for the detection of polyps in patients referred for colonoscopy in a large tertiary hospital., Methods: Demographic, endoscopic, and histological data from 1855 consecutive patients undergoing colonoscopy were collected prospectively. Patients were randomly assigned to three endoscopy systems (Fujinon, Olympus, or Pentax) in combination with four modalities: conventional white-light colonoscopy (n = 505), high definition white-light colonoscopy (n = 582), virtual chromoendoscopy (n = 285) and high definition virtual chromoendoscopy (n = 483)., Results: The mean adenoma detection rate (ADR) was 34.9 %, and the adenoma per colonoscopy rate (APCR) was 2.1. No significant differences were noted between the three endoscopy systems. Moreover, no differences in ADR or APCR were observed between the four imaging modalities. High definition white-light colonoscopy resulted in a significantly higher detection of sessile serrated adenomas (8.2 % vs. 3.8 %; P  < 0.01) and adenocarcinomas (2.6 % vs. 0.5 %; P  < 0.05) compared with the conventional procedure., Conclusions: No significant differences in ADR or APCR between different endoscopy systems, high definition, and/or virtual chromoendoscopy could be observed in routine colonoscopies in the general population. High definition endoscopy was associated with a significantly higher detection rate of serrated adenomas and adenocarcinomas., Competing Interests: Dr. Bessissow has received research support from Pentax and speaker fees from Ferring and Pendopharm. Dr. Cuyle has received nonfinancial support (travel expenses) from Norgine. Dr. Ferrante has received consultancy fees from Ferring and speaker fees from Dr. Falk Pharma and Ferring. Dr. Van Assche has received speaker fees from Ferring. Dr. Vermeire has received consultancy fees from Ferring and speaker fees from Dr. Falk Pharma and Ferring. Dr. Bisschops has received speaker fees, consultancy fees, and/or research support from Boston Scientific, CDx Diagnostics, Cook Medical, Fujifilm, Olympus, Medtronic, and Pentax.Dr. Roelandt is supported by Clinical Mandate from Belgian Foundation against Cancer (Stichting tegen Kanker). Drs. Ferrante, Van Assche, and Vermeire are senior clinical investigators of the Research Foundation – Flanders (FWO). Dr. Bisschops is supported by a grant from the Research Foundation – Flanders (FWO)., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Achalasia patients with longstanding disease are considered to be at risk for developing esophageal cancer. Endoscopic screening is not standardized and detection of dysplastic lesions is difficult, for which Lugol chromoendoscopy could be helpful. Aim was to evaluate the efficacy of screening for esophageal dysplasia and carcinoma in patients with longstanding achalasia using Lugol chromoendoscopy., Methods: In this cohort study achalasia patients underwent three-annual screening by Lugol chromoendoscopy between January 2000 and March 2016. Patients with low-grade dysplasia (LGD) underwent yearly screening, patients with high-grade dysplasia (HGD) or carcinoma were treated., Results: In total, 230 achalasia patients (144 male, median age 52 years (IQR 43-63) at first endoscopy) were included. Three patients (1.3%, 2 male, age 68 years (range 50-87)) developed esophageal squamous cell carcinoma (ESCC), without LGD at the preceding screening. Incidence rate for ESCC was 63 (95% CI 13-183) per 100 000 persons-years. LGD was observed in 4 patients (1.7%, 2 male, age 64 years (range 57-73)), without progression to HGD/ESCC during a follow-up of 9 (IQR 7-14) years. ESCC/LGD was diagnosed 30 (IQR 14-36) years after onset of symptoms and 22 (IQR 4-13) years after diagnosis. Lugol chromoendoscopy tripled the detection rate of suspected lesions (111 lesions white light versus 329 lesions Lugol), but only 8% was histopathological confirmed ESCC or LGD., Conclusion: Achalasia patients with longstanding disease (>20 years) have an increased risk to develop esophageal dysplasia and carcinoma. Endoscopic screening using white light and Lugol chromoendoscopy does not accurately identify precursor lesions for ESCC and therefore cannot be systematically recommended.

Central nervous system-directed prophylactic chemotherapy increases survival in childhood leukemia, but possible late neurocognitive sequelae remain a concern. We compared intellectual performance (WAIS IV), memory (AVLT), and executive functioning (ANT) between adult leukemia survivors (n = 31) and control individuals (n = 35). In survivors, cerebrospinal fluid (CSF) levels of phosphorylated Tau (p-Tau) during treatment and total intrathecal methotrexate dose correlated with adult intellectual performance (Pearson's and Spearman's coefficients, respectively). Long-term memory and attentional control, both maturing before survivors' mean age at diagnosis, were unaffected (P > .05 on all four subtests), in contrast to cognitive flexibility and information processing (P < .05 for eight of the subtests), which mature during adolescence. CSF p-Tau and methotrexate dose negatively correlated with intellectual performance (r = -0.414, P = .04 and r = -0.484, P = .007, respectively), but not with each other (r = 0.219, P = .29). These data identify CSF p-Tau as a predictor of late neurocognitive sequelae (in addition to methotrexate dose). Early identification of children at risk could inspire interventions to prevent or remediate chemotherapy-induced cognitive sequelae.

Innate immune sensing of dying cells is modulated by several signals. Inflammatory chemokines-guided early recruitment, and pathogen-associated molecular patterns-triggered activation, of major anti-pathogenic innate immune cells like neutrophils distinguishes pathogen-infected stressed/dying cells from sterile dying cells. However, whether certain sterile dying cells stimulate innate immunity by partially mimicking pathogen response-like recruitment/activation of neutrophils remains poorly understood. We reveal that sterile immunogenic dying cancer cells trigger (a cell autonomous) pathogen response-like chemokine (PARC) signature, hallmarked by co-release of CXCL1, CCL2 and CXCL10 (similar to cells infected with bacteria or viruses). This PARC signature recruits preferentially neutrophils as first innate immune responders in vivo (in a cross-species, evolutionarily conserved manner; in mice and zebrafish). Furthermore, key danger signals emanating from these dying cells, that is, surface calreticulin, ATP and nucleic acids stimulate phagocytosis, purinergic receptors and toll-like receptors (TLR) i.e. TLR7/8/9-MyD88 signaling on neutrophil level, respectively. Engagement of purinergic receptors and TLR7/8/9-MyD88 signaling evokes neutrophil activation, which culminates into H 2 O 2 and NO-driven respiratory burst-mediated killing of viable residual cancer cells. Thus sterile immunogenic dying cells perform 'altered-self mimicry' in certain contexts to exploit neutrophils for phagocytic targeting of dead/dying cancer cells and cytotoxic targeting of residual cancer cells.

Diffuse intrinsic pontine glioma (DIPG) is a rare and deadly childhood malignancy. After 40 years of mostly single-center, often non-randomized trials with variable patient inclusions, there has been no improvement in survival. It is therefore time for international collaboration in DIPG research, to provide new hope for children, parents and medical professionals fighting DIPG. In a first step towards collaboration, in 2011, a network of biologists and clinicians working in the field of DIPG was established within the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group: the SIOPE DIPG Network. By bringing together biomedical professionals and parents as patient representatives, several collaborative DIPG-related projects have been realized. With help from experts in the fields of information technology, and legal advisors, an international, web-based comprehensive database was developed, The SIOPE DIPG Registry and Imaging Repository, to centrally collect data of DIPG patients. As for April 2016, clinical data as well as MR-scans of 694 patients have been entered into the SIOPE DIPG Registry/Imaging Repository. The median progression free survival is 6.0 months (95% Confidence Interval (CI) 5.6-6.4 months) and the median overall survival is 11.0 months (95% CI 10.5-11.5 months). At two and five years post-diagnosis, 10 and 2% of patients are alive, respectively. The establishment of the SIOPE DIPG Network and SIOPE DIPG Registry means a paradigm shift towards collaborative research into DIPG. This is seen as an essential first step towards understanding the disease, improving care and (ultimately) cure for children with DIPG.

Blocking of costimulatory CD28/B7 and CD40/CD40L interactions is an experimental approach to immune suppression and tolerance induction. We previously reported that administration of a combination of CTLA-4Ig and MR1 (anti-CD40L mAb) for blockade of these interactions induces tolerance in a fully mismatched allogeneic splenocyte transfer model in mice. We now used this model to study whether regulatory T cells (Tregs) contribute to immune suppression and why both pathways have to be blocked simultaneously. Mice were injected with allogeneic splenocytes, CD4(+) T cells, or CD8(+) T cells and treated with MR1 mAb and different doses of CTLA-4Ig. The graft-versus-host reaction of CD4(+) T cells, but not of CD8(+) T cells, was inhibited by MR1. CTLA-4Ig was needed to cover CD8(+) T cells but had only a weak effect on CD4(+) T cells. Consequently, only the combination provided full protection when splenocytes were transferred. Importantly, MR1 and low-dose CTLA-4Ig treatment resulted in a relative increase in Tregs, and immune suppressive efficacy was abolished in the absence of Tregs. High-dose CTLA-4Ig treatment, in contrast, prevented Treg expansion and activity, and in combination with MR1 completely inhibited CD4(+) and CD8(+) T cell activation in a Treg-independent manner. In conclusion, MR1 and CTLA-4Ig act synergistically as they target different T cell populations. The contribution of Tregs to immune suppression by costimulation blockade depends on the concentration of CTLA-4Ig and thus on the degree of available CD28 costimulation., (Copyright © 2016 by The American Association of Immunologists, Inc.)

The immunogenicity of malignant cells has recently been acknowledged as a critical determinant of efficacy in cancer therapy. Thus, besides developing direct immunostimulatory regimens, including dendritic cell-based vaccines, checkpoint-blocking therapies, and adoptive T-cell transfer, researchers have started to focus on the overall immunobiology of neoplastic cells. It is now clear that cancer cells can succumb to some anticancer therapies by undergoing a peculiar form of cell death that is characterized by an increased immunogenic potential, owing to the emission of the so-called "damage-associated molecular patterns" (DAMPs). The emission of DAMPs and other immunostimulatory factors by cells succumbing to immunogenic cell death (ICD) favors the establishment of a productive interface with the immune system. This results in the elicitation of tumor-targeting immune responses associated with the elimination of residual, treatment-resistant cancer cells, as well as with the establishment of immunological memory. Although ICD has been characterized with increased precision since its discovery, several questions remain to be addressed. Here, we summarize and tabulate the main molecular, immunological, preclinical, and clinical aspects of ICD, in an attempt to capture the essence of this phenomenon, and identify future challenges for this rapidly expanding field of investigation.

We aimed to compare two different salvage treatment strategies for relapsed high-grade glioma (HGG) patients by means of a new prognostic model. A simplified version of the so-called HGG-Immuno RPA model estimates the prognosis of relapsed HGG patients and distinguishes three different prognostic classes (I = good, II = intermediate, III = poor). The model has been constructed with a cohort of 117 patients whose salvage treatment consisted of re-operation followed by dendritic cell vaccination (ReOP + DCV). However, using only the predictors histology, age and performance status, the simplified HGG-Immuno RPA model is basically independent from treatment. In the present study we applied the simplified model to the cohort used to construct the original HGG-Immuno RPA model and another cohort of 165 patients who underwent re-irradiation (ReRT) at relapse. Then, we compared the outcomes achieved by the two different salvage treatments in each prognostic class. The model predicted good, intermediate and poor prognosis for 11, 31 and 75 patients of the ReOP + DCV cohort and for 20, 39 and 106 patients of the ReRT cohort, respectively. Neither of the two strategies was superior to the other. In the groups with good, intermediate and poor prognosis 12-months survival rates were 73, 59 and 25 % after ReOP + DCV and 72, 36 and 23 % after ReRT, respectively. Being easy to handle and independent from treatment, the aforementioned model is useful for therapeutic decisions. ReRT and ReOP + DVC seem to be equally effective. The choice of salvage treatment should be based on the expected side effects.

This paper briefly outlines the aim, the objectives, the architecture and the main building blocks of the ongoing large scale integrating transatlantic research project CHIC (http://chic-vph.eu/).

Background: We assessed the diagnostic accuracy of diffusion kurtosis imaging (DKI), dynamic susceptibility-weighted contrast-enhanced (DSC) MRI, and short echo time chemical shift imaging (CSI) for grading gliomas., Methods: In this prospective study, 35 patients with cerebral gliomas underwent DKI, DSC, and CSI on a 3 T MR scanner. Diffusion parameters were mean diffusivity (MD), fractional anisotropy, and mean kurtosis (MK). Perfusion parameters were mean relative regional cerebral blood volume (rrCBV), mean relative regional cerebral blood flow (rrCBF), mean transit time, and relative decrease ratio (rDR). The diffusion and perfusion parameters along with 12 CSI metabolite ratios were compared among 22 high-grade gliomas and 14 low-grade gliomas (Mann-Whitney U-test, P < .05). Classification accuracy was determined with a linear discriminant analysis for each MR modality independently. Furthermore, the performance of a multimodal analysis is reported, using a decision-tree rule combining the statistically significant DKI, DSC-MRI, and CSI parameters with the lowest P-value. The proposed classifiers were validated on a set of subsequently acquired data from 19 clinical patients., Results: Statistically significant differences among tumor grades were shown for MK, MD, mean rrCBV, mean rrCBF, rDR, lipids over total choline, lipids over creatine, sum of myo-inositol, and sum of creatine. DSC-MRI proved to be the modality with the best performance when comparing modalities individually, while the multimodal decision tree proved to be most accurate in predicting tumor grade, with a performance of 86%., Conclusions: Combining information from DKI, DSC-MRI, and CSI increases diagnostic accuracy to differentiate low- from high-grade gliomas, possibly providing diagnosis for the individual patient.

Pelvic gynecological malignancies account for 6% of all cancers. In the relapsed state, classical treatments are limited. There is an urgent need for new and personalized treatment. Wilms' tumor gene 1 (WT1) is the most important tumor-associated antigen. Although highly present in gynecological tumors, active immunotherapy against it is still underexplored. This review gives an insight into the importance of WT1 in pelvic gynecological malignancies and the first taken steps into the world of WT1 immunotherapy.

Regulatory T cells (Treg) play a pivotal role in the immune system since they inhibit the T cell response. It is well known that cyclophosphamide applied at low dose is able to stimulate the immune response while high dose cyclophosphamide exerts inhibitory activity. Data obtained in mice indicate that cyclophosphamide provokes a reduction in the number of Treg and impairs their suppressive activity, resulting in immune stimulation. Here, we addressed the question of the sensitivity of human Treg to cyclophosphamide, comparing Treg with cytotoxic T cells (CTL) and T helper cells (Th). We show that Treg are more sensitive than CTL and Th to mafosfamide, which is an active derivative of cyclophosphamide, which does not need metabolic activation. The high sensitivity of Treg was due to the induction of apoptosis. Treg compared to CTL and Th were not more sensitive to the alkylating drugs temozolomide and nimustine and also not to mitomycin C, indicating a specific Treg response to mafosfamide. The high sensitivity of Treg to mafosfamide resulted not only in enhanced cell death, but also in impaired Treg function as demonstrated by a decline in the suppressor activity of Treg in a co-culture model with Th and Helios positive Treg. Treatment of Treg with mafosfamide gave rise to a high level of DNA crosslinks, which were not repaired to the same extent as observed in Th and CTL. Also, Treg showed a low level of γH2AX foci up to 6 h and a high level 24 h after treatment, indicating alterations in the DNA damage response. Overall, this is the first demonstration that human Treg are, in comparison with Th and CTL, hypersensitive to cyclophosphamide, which is presumably due to a DNA repair defect.

Glioblastoma is the most prevalent form of gliomas with high aggressive nature and high recurrence. Despite aggressive therapy, including surgery, chemotherapy and radiotherapy, median patient survival is only about 15 months. Hence, developing novel and efficient therapies seem urgent. Many fields have begun their work in preclinical studies but gained limited success in clinical phases. One of the most notable reasons is tumor-induced immunosuppression. In recent decade, efforts to dissect this immunosuppressive network have been done vastly. In a number of malignancies such as glioma, myeloid-derived suppressor cells (MDSCs) have been shown to infiltrate malignant tissues having critical role in the network. Many studies, most of them on lab models, were conducted to understand how MDSCs take part in immunosuppression. Here, we reviewed MDSC relations with other immunocellular components like T cell and natural killer cell.

Allogeneic hematopoietic stem cell transplantation and donor leukocyte infusion (DLI) may hold potential as a novel form of immunotherapy for high-risk neuroblastoma. DLI, however, carries the risk of graft-versus-host disease (GvHD). Recipient leukocyte infusion (RLI) induces graft-versus-leukemia responses without GvHD in mice and is currently being explored clinically. Here, we demonstrate that both DLI and RLI, when given to mixed C57BL/6→A/J radiation chimeras carrying subcutaneous Neuro2A neuroblastoma implants, can slow the local growth of such tumors. DLI provoked full donor chimerism and GvHD; RLI produced graft rejection but left mice healthy. Flow cytometric studies showed that the chimerism of intratumoral leukocytes paralleled the systemic chimerism. This was associated with increased CD8/CD4 ratios, CD8+ T-cell IFN-γ expression and NK-cell Granzyme B expression within the tumor, following both DLI and RLI. The clinically safe anti-tumor effect of RLI was further enhanced by adoptively transferred naïve recipient-type NK cells. In models of intravenous Neuro2A tumor challenge, allogeneic chimeras showed superior overall survival over syngeneic chimeras. Bioluminescence imaging in allogeneic chimeras challenged with luciferase-transduced Neuro2A cells showed both DLI and RLI to prolong metastasis-free survival. This is the first experimental evidence that RLI can safely produce a local and systemic anti-tumor effect against a solid tumor. Our data indicate that RLI may provide combined T-cell and NK-cell reactivity effectively targeting Neuro2A neuroblastoma.

Evaluation of: Lasky JL 3rd, Panosyan EH, Plant A et al. Autologous tumor lysate-pulsed dendritic cell immunotherapy for pediatric patients with newly diagnosed or recurrent high-grade gliomas. Anticancer Res. 33, 2047-2056 (2013). Immunotherapy for children and adults with high-grade glioma (HGG) is an emerging innovative treatment approach, which aims at stimulating the body's own immune system against HGG by using autologous dendritic cells pulsed with autologous tumor lysate as a therapeutic vaccine. This is the third report on immunotherapy for HGG in children, bringing additional knowledge and experience to the scientific community. However, at the same time, this and other manuscripts urge for the next step in treatment development.

These guidelines for the management of patients up to 18 years with Langerhans cell histiocytosis (LCH) have been set up by a group of experts involved in the Euro Histio Net project who participated in national or international studies and in peer reviewed publications. Existing guidelines were reviewed and changed where new evidence was available in the literature up to 2012. Data and publications have been ranked according to evidence based medicine and when there was a lack of published data, consensus between experts was sought. Guidelines for diagnosis, initial clinical work-up, and treatment and long-term follow-up of LCH patients are presented., (Copyright © 2012 Wiley Periodicals, Inc.)

The recruitment and activation of regulatory T cells (Tregs) in the micro-environment of malignant brain tumors has detrimental effects on antitumoral immune responses. Hence, local elimination of Tregs within the tumor micro-environment represents a highly valuable tool from both a fundamental and clinical perspective. In the syngeneic experimental GL261 murine glioma model, Tregs were prophylactically eliminated through treatment with PC61, an anti-CD25 mAb. This resulted in specific elimination of CD4+CD25hiFoxp3+ Treg within brain-infiltrating lymphocytes and complete protection against subsequent orthotopic GL261 tumor challenge. Interestingly, PC61-treated mice also showed a pronounced infiltration of CD11b+ myeloid cells in the brain. Phenotypically, these cells could not be considered as Gr-1+ myeloid-derived suppressor cells (MDSC) but were identified as F4/80+ macrophages and granulocytes.

Purpose: Adult patients with relapsed high-grade glioma are a very heterogenous group with, however, an invariably dismal prognosis. We stratified patients with relapsed high-grade glioma treated with re-operation and postoperative dendritic cell (DC) vaccination according to a simple recursive partitioning analysis (RPA) model to predict outcome., Patients and Methods: Based on age, pathology, Karnofsky performance score, and mental status, 117 adult patients with relapsed malignant glioma, undergoing re-operation, and postoperative adjuvant dendritic cell (DC) vaccination were stratified into 4 classes. Kaplan-Meier survival estimates were generated for each class of this HGG-IMMUNO RPA model. Extent of resection was documented but not included in the prognostic model., Results: Kaplan-Meier overall survival estimates revealed significant (p < 0.0001) differences among the 4 HGG-IMMUNO RPA classes. Long-term survivors, surviving more than 24 months after the re-operation and vaccination, are seen in 54.5, 26.7, 11.5, and 0 % for the classes I, II, III, and IV respectively., Conclusion: This HGG-IMMUNO RPA classification is able to predict overall survival in a large group of adult patients with a relapsed malignant glioma, treated with re-operation and postoperative adjuvant DC vaccination in the HGG-IMMUNO-2003 cohort comparison trial. The model appears useful for prognostic patient counseling for patients participating in DC vaccination trials. A substantial number of long-term survivors after relapse are seen in class I to III, but not in class IV patients.

Aggressiveness of advanced melanomas relates in part to their marked propensity to develop neoangiogenesis and metastases. Among its numerous pro-cancer roles, galectin (gal)-1 expressed and/or secreted by both cancer and endothelial cells stimulates proliferation and angiogenesis. This study first shows that gal-1 is more highly expressed at both mRNA and protein levels than its congeners in melanomas and particularly in advanced lesions. The roles of gal-1 were further investigated in vivo in the highly proliferating and vascularized pseudometastatic B16F10 mouse melanoma model using stable knockdown B16F10 cells and wild-type versus gal-1 knockout mice, and then in vitro in B16F10 tumoral and lung microvascular cells. Gal-1 depletion in the B16F10 tumor cells but not in the tumor-bearing mice significantly increased melanoma-bearing mice survival. Tumor-derived gal-1 thus seems to have more critical roles than the host-derived one. In fact, gal-1 displays distinct effects on the H-Ras-dependent p53/p21 pathways: in primary lung microvessel endothelial cells, gal-1 seems to be involved in the maintenance of senescent status through the induction of both p53 and p21 while it stimulates B16F10 cancer cell proliferation through a p53/p21 decrease. Altogether, these data point to gal-1 as a potential target to combat melanomas.

Despite resection, radiochemotherapy, and maintenance temozolomide chemotherapy (TMZm), the prognosis of patients with glioblastoma multiforme (GBM) remains poor. We integrated immunotherapy in the primary standard treatment for eight pilot adult patients (median age 50 years) with GBM, to assess clinical and immunological feasibility and toxicity in preparation of a phase I/II protocol HGG-2006. After maximum, safe resection, leukapheresis was performed before radiochemotherapy, and four weekly vaccinations with autologous GBM lysate-loaded monocyte-derived dendritic cells were given after radiochemotherapy. Boost vaccines with lysates were given during TMZm. During the course of vaccination, immunophenotyping showed a relative increase in CD8+CD25+ cells in six of the seven patients, complying with the prerequisites for implementation of immunotherapy in addition to postoperative radiochemotherapy. In five patients, a more than twofold increase in tumor antigen-reacting IFN-gamma-producing T cells on Elispot was seen at the fourth vaccination compared with before vaccination. In three of these five patients this more than twofold increase persisted after three cycles of TMZm. Quality of life during vaccination remained excellent. Progression-free survival at six months was 75%. Median overall survival for all patients was 24 months (range: 13-44 months). The only serious adverse event was an ischemic stroke eight months postoperatively. We conclude that tumor vaccination, fully integrated within the standard primary postoperative treatment for patients with newly diagnosed GBM, is feasible and well tolerated. The survival data were used to power a currently running phase I/II trial.

The prognosis of patients with malignant glioma is poor in spite of multimodal treatment approaches consisting of neurosurgery, radiochemotherapy and maintenance chemotherapy. Among innovative treatment strategies like targeted therapy, antiangiogenesis and gene therapy approaches, immunotherapy emerges as a meaningful and feasible treatment approach for inducing long-term survival in at least a subpopulation of these patients. Setting up immunotherapy for an inherent immunosuppressive tumor located in an immune-privileged environment requires integration of a lot of scientific input and knowledge of both tumor immunology and neuro-oncology. The field of immunotherapy is moving into the direction of active specific immunotherapy using autologous dendritic cells (DCs) as vehicle for immunization. In the translational research program of the authors, the whole cascade from bench to bed to bench of active specific immunotherapy for malignant glioma is covered, including proof of principle experiments to demonstrate immunogenicity of patient-derived mature DCs loaded with autologous tumor lysate, preclinical in vivo experiments in a murine orthotopic glioma model, early phase I/II clinical trials for relapsing patients, a phase II trial for patients with newly diagnosed glioblastoma (GBM) for whom immunotherapy is integrated in the current multimodal treatment, and laboratory analyses of patient samples. The strategies and results of this program are discussed in the light of the internationally available scientific literature in this fast-moving field of basic science and translational clinical research.

The value of bioluminescence imaging (BLI) for experimental cancer models has become firmly established. We applied BLI to the GL261 glioma model in the context of dendritic cell (DC) immunotherapy. Initial validation revealed robust linear correlations between in vivo, ex vivo and in vitro luciferase activity measurements. Ex vivo BLI demonstrated midline crossing and leakage of tumor cells. Orthotopically challenged mice followed with BLI showed an initial adaptation phase, after which imaging data correlated linearly with stereologically determined tumor dimensions. Transition from healthy to moribund state corresponded with an increasing in vivo flux but the onset of neurological deficit was clearly delayed compared to the onset of in vivo flux increase. BLI was implemented in prophylactic immunotherapy and imaging data were prognostic for therapy outcome. Three distinct response patterns were detected. Our data underscore the feasibility of in vivo BLI in an experimental immunotherapeutic setting in the GL261 glioma model.

CMV colitis in an immunocompetent host is a rare occurrence. We report a case of CMV colitis after biliopancreatic diversion surgery. The diagnosis of primary CMV infection with CMV colitis was based on histological examination of tissues biopsies obtained at colonoscopy, serology positive for CMV-IgM and CMV-IgG antibodies and a good response to systemic gancyclovir treatment. Malnutrition and colonic mucosal damage, both consequences of biliopancreatic diversion surgery, were thought to be predisposing factors. To our knowledge this is the first report in the English language literature of an association between CMV colitis and status following biliopancreatic diversion surgery.

Langerhans cell histiocytosis, previously known as histiocytosis X, is a complex disease consisting of three entities that are all characterized by a proliferation of the Langerhans cell. The clinical course is variable and ranges from a solitary lytic bone or skin lesion with complete remission to a multisystem disorder with possible lethal outcome. The clinical suspicion can be increased based on radiological findings that are important criteria in defining the extent of the disease involvement. A biopsy is often necessary for establishing the final diagnosis. The lytic craniofacial bone lesions are the most common craniospinal abnormality in Langerhans cell histiocytosis. Abnormalities in the hypothalamic-pituitary region are the most frequent manifestations, often accompanied with diabetes insipidus as the presenting symptom. A range of different central nervous system abnormalities can be recognized. It is important to be able to recognize the extensive spectrum of neuroradiological abnormalities in order to arrive at the diagnosis. Neuroimaging plays an even more important role in assessing the response to treatment or possible relapse.

We report a patient presenting with bilateral lacrimal gland involvement and perioptic nerve sheath lesions due to Langerhans cell histiocytosis (LCH) invasion. LCH is a rare multisystemic disease characterized by a clonal proliferation of Langerhans cells. All organs may be involved with a clinical spectrum ranging from a solitary bone lesion to a severe life-threatening multisystem disease. Osteolytic orbital bone lesions with extension into the adjacent orbital soft tissues have been described. To our knowledge, lacrimal gland involvement has probably been described only once before. Perioptic nerve lesions are also very rare, having been described only three times before.

Objective: Despite recent advances in neurosurgical resection techniques, radiation therapy, and chemotherapy, malignant gliomas continue to have a dismal prognosis because relapses are unavoidable., Methods: Dendritic cell vaccination has recently emerged as a promising type of active immunotherapy that aims to induce rather than transfer specific antitumor immune responses in patients. Active immunotherapy is the only type of immunotherapy able to induce immunological memory., Results: Although an increasing number of small clinical trials show safety, feasibility, and immunological and clinical responses, this technology requires further clarification of some critical basic and clinical issues before its presumed place in the treatment of malignant gliomas can be specified. This article addresses the basic and clinical pitfalls that, more than with conventional therapies, may interfere with the potential benefits of this approach., Conclusion: Considering the particular mechanisms involved in the immune modulation of tumor biology using dendritic cell-based vaccinations, the authors summarize the arguments in favor of a further, appropriate assessment of this technology.

The present study was performed to investigate the prognostic impact of tumor resection on survival in children and adolescents with malignant gliomas. From the HIT-GBM data base of the Gesellschaft für Paediatrische Onkologie und Haematologie (GPOH), 85 pediatric patients with malignant non-pontine gliomas were analyzed. Histological diagnosis and extent of tumor resection had been confirmed by central neuropathological review and post-surgical imaging. The extent of tumor resection represented the most prominent prognostic factor for overall (OS) and event-free survival (EFS) in univariate and Cox regression analyses. Four-year survival after gross total tumor resection was 48.0 +/- 12.0% (OS) and 14.1 +/- 8.9% (EFS), after non-total resection 13.2 +/- 6.1% and 2.9 +/- 2.8%, respectively. From several clinical parameters, only histological grading displayed a similar statistical significance in Cox regression analysis. In conclusion, gross total tumor resection improves survival in pediatric patients with malignant gliomas and should always be attempted when possible.

Background: Recent observations in limited numbers of patients suggest a potential benefit of intrapyloric injection of botulinum toxin in the treatment of gastroparesis., Aim: To characterize the effect of botulinum toxin on solid and liquid gastric emptying and on meal-related symptoms., Methods: In 20 gastroparesis patients (17 women, mean age 37 +/- 3 years, three diabetic and 17 idiopathic), gastric emptying for solids and liquids was measured before and one month after intrapyloric botulinum toxin 4 x 25 units. Before the meal and at 15-min intervals up to 240 min postprandially, the patient graded the intensity of six gastroparesis symptoms, and a meal-related severity score was obtained by adding all intensities. Data (mean +/- S.E.M.) were compared using paired Student's t-test., Results: Treatment with botulinum toxin significantly enhanced solid (t(1/2) 132 +/- 16 vs. 204 +/- 35 min, P < 0.05) but not liquid (92 +/- 10 vs. 104 +/- 11 min, N.S.) emptying. This was accompanied by a significant decrease in cumulative meal-related symptom score (73.5 +/- 16.3 vs. 103 +/- 17.1 baseline, P = 0.01) as well as individual severity scores for postprandial fullness, bloating, nausea and belching (all P < 0.001, two-way anova)., Conclusions: Botulinum toxin improves solid but not liquid gastric emptying in gastroparesis, and this is accompanied by significant improvement of several meal-related symptoms.

CD25+CD4+ regulatory T cells (Tregs) contribute to the maintenance of peripheral tolerance against self and non-self. The modulatory effects of cytokines, such as interleukin 4 (IL-4) on the function of Tregs have not been explored in detail. We here report that IL-4 prevents spontaneous apoptosis and the decline of foxp3 mRNA which were found to occur during culture of isolated Tregs. Tregs exposed to IL-4 were more potent in suppressing the proliferation of naïve CD4+ T cells and they better inhibited IFN-gamma production by CD4+ T cells as compared to Tregs cultured in medium. IL-4 also enhanced membrane IL-2Ralpha (CD25) expression on Tregs above the levels observed on freshly isolated cells. IL-4-mediated effects on Treg function persisted in Tregs from Stat6-/- mice, pointing to a Stat6-independent intracellular transduction pathway. In conclusion, our data suggest that the anti-inflammatory function of IL-4 could partly be mediated by effects on Tregs function.

Background: Brain stem dermoid cysts are very rare lesions, and in most, the outcome has been very poor. Because of the dangers of dissecting the cyst wall away from the brain stem parenchyma, some authors have advocated not to attempt a radical resection., Methods: We describe a child in whom the brain stem dermoid cyst recurred rapidly after a conservative approach. We therefore attempted a radical removal., Results: During surgery, the almost complete resection of the cyst wall was not very difficult, leading to an apparent cure after 4 years., Conclusion: In exceptional cases, it may be possible to remove a brain stem dermoid cyst without prohibitive morbidity and with long-term cure.

Peripheral primitive neuroectodermal tumor (PNET)/Ewing's sarcoma (ES) of the central nervous system is extremely rare and should be differentiated from central PNET and other small blue round cell tumors. We describe a case of a meningeal peripheral PNET/ES of the spinal cord in an 11-year-old boy. Immunohistochemically, the small blue round cell tumor showed expression of epithelial markers and of CD99, thus posing an important differential diagnostic problem with a poorly differentiated synovial sarcoma. Fluorescence in situ hybridization revealed rearrangement of the EWS gene, as seen in peripheral PNET/ES. Peripheral PNET/ES does occur in the central nervous system, but its diagnosis can be extremely difficult on morphologic and immunohistochemical grounds alone. Genetic analysis plays a key role in its distinction from other small blue round cell tumors.