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To the best of our knowledge, this is the first molecular dynamics simulation study on the dimeric form of the LuxS enzyme from Vibrio cholerae to evaluate its structural and dynamical properties including the dynamics of the interface formed by the two monomeric chains of the enzyme. The dynamics of the interfacial region were investigated in terms of inter-residual contacts and the associated interface area of the enzyme in its ligand-free and ligand–bound states which produced characteristics contrast in the interfacial dynamics. Moreover, the binding patterns of the two inhibitors (RHC and KRI) to the enzyme forming two different enzyme–ligand complexes were analyzed which pointed towards a varying inhibition potential of the inhibitors as also revealed by the free energies of ligand binding. It is shown that KRI is a more potent inhibitor than RHC – a substrate analogue, showing correlation with experimental data. Moreover, the role of a loop in chain B of the enzyme was found to facilitate the binding of RHC similar to that of the substrate, while KRI demonstrates a differing binding pattern. The computation of the free energy of binding for the two ligands was also carried out via thermodynamic integration which ultimately served to correlate the dynamical properties with the inhibition potential of two different ligands against the enzyme. Furthermore, this successful study provides a rational to suggest novel LuxS inhibitors which could become promising candidates to treat the diseases caused by a broad variety of bacterial species.

Study question Is impaired sexual functioning correlated to sperm quality in cancer survivors? Summary answer Erectile dysfunction affects 25.0% of cancer survivors, independent of sperm quality. 22.9% of patients show symptoms consistent with a reduced testosterone level. What is known already Gonadotoxic treatment in male cancer patients can end up in reversible or permanent impaired spermatogenesis, testosterone insufficiency, and sexual dysfunction. Study design, size, duration In this prospective single-center study, sexual functioning was assessed in male cancer survivors, who underwent sperm cryopreservation at the Department of Gynecological Endocrinology and Reproductive Medicine, Medical University Innsbruck, Austria from 01/2010 to 12/2018. Sexual functioning was assessed between 03–12/2020 via two questionnaires: Aging Male Score (AMS) and International Index of Erectile Function (IEEF-EF). Participants/materials, setting, methods Thirty-five cancer survivors (testicular cancer: n = 16 [45.7%], hematological malignancies: n = 15 [42.9%], others: n = 4 [n = 11.4%]) filled in two questionnaires (AMS and IEEF-EF) during routine follow-up visit at the Department of Gynecological Endocrinology and Reproductive Medicine, Medical University Innsbruck and the Department of Urology, Medical University Innsbruck, Austria. Moreover, sperm quality was assessed and normozoospermia was defined in accordance with the 2010 WHO criteria (sperm concentration ≥15 million/mL, progressive motility ≥32%, and ≥4% normal morphology). Main results and the role of chance Mean age at sperm cryopreservation and follow-up visit was 25.1±4.2 and 31.9±6.3 years, respectively with a mean follow-up time of 81.4±12.5 months. Rate of erectile dysfunction was low (75.0% no dysfunction, 15.6% low dysfunction, 3.1% low-moderate dysfunction, 3.1% moderate, 3.1% severe dysfunction). Moreover, AMS score indicated no, low, moderate and severe symptoms consistent with a low testosterone level in 77.1%, 8.6%, 2.9%, and 2.9% of patients, respectively. Oligozoospermia was observed in up to 48% of the patients with TM and in only 23% patients with HM. Patients with TM showed significantly reduced sperm count (18.7 × 106/mL [5.3–43.0]) and total sperm count (42.4 × 106/ejaculate [13.3–108.5]) compared to HM (p = 0.03). There was no difference in sexual functioning between patients with HM or TM. Sexual functioning did no correlate with sperm count, progressive motility or morphology. Limitations, reasons for caution Although the study may be limited by its small sample size, it is the first to assess a correlation of sperm quality and sexual dysfunction in cancer survivors. Wider implications of the findings: As every fourth male cancer patient suffers from impaired sexual functioning after gonadotoxic treatment, this important topic should be addressed in clinical and scientific future. Future studies should focus on both, somatic and psychosomatic reasons for sexual dysfunction. Trial registration number none

Study question Within this prospective study, we aim to differentiate immune cell subpopulations in recurrent implantation failure (RIF) patients and fertile controls. Summary answer A misbalanced immune profile of NK cell subpopulations is present in RIF patients and might be a potential risk factor that requires further detailed analysis. What is known already So far, there is no conclusive opinion on the prognostic value of testing immune cell populations in women with RIF. Increased numbers of cytotoxic (CD56dimCD16bright) peripheral natural killer (pNK)-cells and CD56brightCD16dim mainly in the uterus occurring NK cells (uNK) seemed to be more prevalent in RIF patients. NK cell cytotoxicity is regulated by a complex interaction of activating and inhibiting receptors, such as the NKGD2 and natural cytotoxicity receptors including NKp46, NKp30 and NKp44. Dysregulated pNK cells could affect the adhesion and implantation of the embryo thereby contributing to RIF. Study design, size, duration Within this prospective study between March 2018 and August 2020 immune diagnostics of pNK cells and subpopulations as well as regulatory T-cells in RIF patients (defined as ≥ 3 failed fresh or frozen embryo transfers of good quality embryos (Istanbul criteria) and non-pregnant controls (nulli- and multipara) were performed using flow cytometry analysis. Participants/materials, setting, methods In total, n = 42 RIF and n = 85 controls were included. Absolute numbers and percentages of total lymphocytes of CD56dimCD16bright, CD56brightCD16dim NK cells, CD45+CD25+FoxP3+-regulatory T-cells and activation markers (CD57+, CD62L+, NKGD2+, NKp46+) were measured in patients and controls (n = 60 nulligravida, n = 25 para) in the mid-luteal phase. Statistical analysis was performed using SPSS Version 26 considering p Main results and the role of chance RIF patients showed significantly lower numbers and percentages of CD56dimCD16bright pNK cells (mean±SD per µl: 187,5±113,3 vs. 281,9±163,4 p = 0.001;%: 87,4±8,8 vs. 90,6±6,0 p = 0.017) and higher levels of CD56brightCD16dim pNK cells (mean±SD per%: 10,5±8,3 vs. 7,6±5,5 p = 0.021) compared to controls. Further, lower percentages of CD56dimCD16brightCD62L + (mean±SD per%: 23,5±11,1 vs. 32,0±14,0 p = 0.001), CD56dimCD16brightNKGD2 + (mean±SD per%: 94,0±6,8 vs. 96,4±4,2 p = 0.014) and CD56dimCD16brightNKp46 + (mean±SD per%: 65,8±19,5 vs. 76,1±14,0 p = 0.001) were observed in RIF patients (p Limitations, reasons for caution As controls composed out of not only nulli- but also multipara, higher levels of pNK cells in controls, could be induced by fetal microchimerism in multiparas, however, results remained significant after removing multipara from statistical analysis. Wider implications of the findings: These findings condense into the assumption of a non-linear association between NK cytotoxicity and successful pregnancy. A lower NK cytotoxicity in RIF patients could potentially lead to an altered immune environment impeding a successful implantation process. Trial registration number Drks00020803

Die Einfuhrung der „nicht-Vitamin-K-abhangigen“, direkten oralen Antikoagulanzien (DOAK) bewirkte eine Vereinfachung der thrombembolischen Pravention fur die Patienten. Auf arztlicher Seite herrscht allerdings zum einen immer noch eine grose Unsicherheit im Rahmen des pra- und postoperativen Ab- und Wiederansetzens der Antikoagulation. Zum anderen erfordern Blutungen unter DOAK-Therapie spezifische Kenntnisse hinsichtlich diagnostischer und therapeutischer Optionen. Bisherige Therapiestrategien basierten vornehmlich auf Expertenempfehlungen und waren im Rahmen von Plasmasubstitution oder der Verwendung von Faktorenpraparaten relativ unspezifisch. Zudem muss davon ausgegangen werden, dass bei der Verwendung von prokoagulatorischen Substanzen, wie Prothrombinkomplex-Konzentrat (PPSB), das thrombogene Risiko nach erfolgter Therapie potenziell ansteigt. Ein neuer Ansatz resultiert aus der Einfuhrung von Idarucizumab, das als spezifisches, schnell wirkendes und gerinnungsinertes Antidot fur den Thrombininhibitor Dabigatran zur Verfugung steht. Die vorliegende Ubersichtsarbeit soll einen Uberblick uber pharmakologische Daten, Moglichkeiten der Therapie DOAK-assoziierter Blutungen und spezifische Reversierungsmoglichkeiten geben.

Lung cancer was a second common cancer case due to the high cigarette smoking activity both in men and women. One of protein receptor which plays an important role in the growth of the tumor is Epidermal Growth Factor Receptor (EGFR). EGFR protein is the most frequent protein mutation in cancer and promising target to inhibit the cancer growth. In this work, the stability of the hydrogen bond as the main interaction in the inhibition mechanism of cancer will be evaluated using molecular dynamics simulation. There were two compounds (A1 and A2) as new potential inhibitors that were complexed against the EGFR protein. The dynamic properties of each complexed were compared with respect to erlotinib against EGFR. The result revealed that both compounds had an interaction in the main catalytic area of protein receptor which is at methionine residue. Inhibitor A1 showed additional interactions during simulation time but the interactions tend to be weak. Inhibitor A2 displayed a more stable interaction. Following dynamics simulation, binding free energy calculation was performed by two scoring techniques MM/GB(PB)SA method and gave a good correlation with the stability of the complex. Furthermore, potential inhibitor A2 had a lower binding free energy as a direct consequence of the stability of hydrogen bond interaction.

OBJECT Bone morphogenetic protein (BMP) is frequently used for spinal arthrodesis procedures in an “off-label” fashion. Whereas complications related to BMP usage are well recognized, the role of dosage is less clear. The objective of this meta-analysis was to assess dose-dependent effectiveness (i.e., bone fusion) and morbidity of BMP used in common spinal arthrodesis procedures. A quantitative exploratory meta-analysis was conducted on studies reporting fusion and complication rates following anterior cervical discectomy and fusion (ACDF), posterior cervical fusion (PCF), anterior lumbar interbody fusion (ALIF), transforaminal lumbar interbody fusion (TLIF), posterior lumbar interbody fusion (PLIF), and posterolateral lumbar fusion (PLF) supplemented with BMP. METHODS A literature search was performed to identify studies on BMP in spinal fusion procedures reporting fusion and/or complication rates. From the included studies, a database for each spinal fusion procedure, including patient demographic information, dose of BMP per level, and data regarding fusion rate and complication rates, was created. The incidence of fusion and complication rates was calculated and analyzed as a function of BMP dose. The methodological quality of all included studies was assessed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Data were analyzed using a random-effects model. Event rates are shown as percentages, with a 95% CI. RESULTS Forty-eight articles met the inclusion criteria: ACDF (n = 7), PCF (n = 6), ALIF (n = 9), TLIF/PLIF (n = 17), and PLF (n = 9), resulting in a total of 5890 patients. In ACDF, the lowest BMP concentration analyzed (0.2–0.6 mg/level) resulted in a fusion rate similar to the highest dose (1.1–2.1 mg/level), while permitting complication rates comparable to ACDF performed without BMP. The addition of BMP to multilevel constructs significantly (p < 0.001) increased the fusion rate (98.4% [CI 95.4%–99.4%]) versus the control group fusion rate (85.8% [CI 77.4%–91.4%]). Studies on PCF were of poor quality and suggest that BMP doses of ≤ 2.1 mg/level resulted in similar fusion rates as higher doses. Use of BMP in ALIF increased fusion rates from 79.1% (CI 57.6%–91.3%) in the control cohort to 96.9% (CI 92.3%–98.8%) in the BMP-treated group (p < 0.01). The rate of complications showed a positive correlation with the BMP dose used. Use of BMP in TLIF had only a minimal impact on fusion rates (95.0% [CI 92.8%–96.5%] vs 93.0% [CI 78.1%–98.0%] in control patients). In PLF, use of ≥ 8.5 mg BMP per level led to a significant increase of fusion rate (95.2%; CI 90.1%–97.8%) compared with the control group (75.3%; CI 64.1%–84.0%, p < 0.001). BMP did not alter the rate of complications when used in PLF. CONCLUSIONS The BMP doses used for various spinal arthrodesis procedures differed greatly between studies. This study provides BMP dosing recommendations for the most common spine procedures.

Introduction Association of Acute Disseminated Encephalomyelitis (ADEM) with both recent vaccination and viral infections is well described in current literature. However, the coincidence of ADEM and bacterial infections has been rarely documented. In this report, we present a case of ADEM which occurred after bacterial meningoencephalitis and prior vaccination against tetanus, diphtheria, and pertussis (Tdap). Case presentation A 62-year old woman was hospitalized with an upper respiratory tract infection three weeks after Tdap triple vaccination. A few days after admission, she became somnolent and developed meningism. Cerebrospinal fluid (CSF) analysis revealed pleocytosis and increased protein/lactate levels compatible with bacterial meningoencephalitis. The patient was treated with intravenous antibacterial triple therapy in combination with dexamethasone leading to a significant improvement of clinical symptoms and improvement of CSF parameters. Five days later, the patient's condition worsened again, and she developed aphasia and right-sided hemiparesis. A magnetic resonance imaging (MRI) scan revealed distinct fluid-attenuated inversion recovery sequence (FLAIR)-hyperintense lesions in both hemispheres. Following brain biopsy, the diagnosis of ADEM was made and methylprednisolone pulse therapy was initiated for five days leading to a nearly complete remission of symptoms. Conclusion ADEM is a neurological syndrome which may be associated with bacterial infection of the central nervous system (CNS). We hypothesize that the preceding Tdap triple vaccination may have contributed to the development of ADEM.

Background The outcome for patients with unresectable or metastatic soft tissue sarcoma (STS) is poor. Following failure from first-line doxorubicin based chemotherapy no standard therapy has been established. Combination treatment with docetaxel/gemcitabine (gem) has emerged as an effective regimen but administration is limited to fit patients only due to the toxicity profile. Nanoparticle albumin bound paclitaxel (nab-PC) was invented for avoidance of the toxicities related to polyethylated castor oil. In this context, we want to evaluate toxicity and antitumor effect of biweekly nab-PC 150mg/m2 / gem 1000mg/m2 administration in STS patients. Methods We conducted this proof-of-concept phase I trial to assess the safety of biweekly nab-PC/gem administration in the 2nd and 3rd line setting of STS. Results As of 1 April 2019, 6 pts were treated within the phase I. Three pts were male (50%); median age was 67 yrs (range 44 – 72). The current total number of biweekly doses received is 29 (median biweekly doses per patient is 5, range 2 – 7). One dose reduction due to skin toxicity occurred. 3 pts remain on study, 3 stopped treatment due to treatment unrelated reasons (refusal, death unrelated to progression or toxicity and investigator’s decision). The most common treatment-emergent AEs Gr1-2 were fatigue (3 pts), alopecia (3 pts), and neutropenia (2 pts). There were no dose-limiting toxicities or discontinuations due to AEs. We were able to confirm the tolerability of the regimen and are currently accruing patients to a prospective single arm phase II trial. Treatment will be given biweekly until progression, unacceptable toxicity or patient withdrawal. The primary endpoint of the trial is progression-free rate (PFR) at 12 weeks. Secondary endpoints are PFS, overall survival and symptom-specific quality of life. A total of 8 Swiss sites will participate for a total of 37 patients, as required by Simon’s two-stage design. Conclusions These preliminary results indicate that biweekly administration of nab-PC/gem was well tolerated. The phase I established dose and schedule were selected for further evaluation in phase II trial. Clinical trial identification NCT03524898. Editorial acknowledgement Celgene Corporation. Legal entity responsible for the study Swiss Group for Clinical Cancer Research (SAKK). Funding Swiss League Against Cancer, Celgene. Disclosure A. Digklia: Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen, PharmaMar, Servier, BMS; Research grant / Funding (self), Research grant / Funding (institution): Research Funding Recipient Institution. C. Britschgi: Advisory / Consultancy: Roche, Pfizer,takeda,AstraZeneca. Y. Metaxas: Advisory / Consultancy: Roche, MSD, Pierre Fabre, Merck-Serono, BMS. F. Krasniqi: Advisory / Consultancy: Roche Pharma (Schweiz) AG, Mundipharma Medical Company (Schweiz), Celgene GmbH. A. Stathis: Travel / Accommodation / Expenses: Abvie, PharmaMar; Research grant / Funding (institution): Amgen, Bayer, Novartis, Roche, MEI-Pharma. T. Rordorf: Advisory / Consultancy: Bristol-Myers Squibb and Merck KGaA. N. Mach: Honoraria (institution), Advisory / Consultancy: Amgen, AstraZeneca, Bristol-Myers Squibb, F. Hoffmann-La Roche, Merck Sharp and Dohme, Merck Serono, Novartis, Pharma Mar, as well as honorarium for talks in a company’s organised public event from Bristol-Myers Squibb and Pharma Mar. C.A. Rothermundt: Advisory / Consultancy: BMS, Astellas Pharma Schweiz, GSK, Novartis, Roche, Pfizer, PharmaMar; Research grant / Funding (institution): Research Funding Recipient Institution. All other authors have declared no conflicts of interest.

Die jährliche Inzidenz der häufigsten primären Hirntumoren, der Gliome, beträgt 5-6 /100'000 (www.cbtrus.org). In der Schweiz werden etwa 500 Neuerkrankungen bei Erwachsenen pro Jahr diagnostiziert. Etablierte Risikofaktoren für die Entwicklung von Gliomen sind frühere Exposition mit ionisierenden Strahlen und selten eine genetische Prädisposition (i.R. von familiären Tumorsyndromen). Ein Risiko durch den Gebrauch von mobilen Telefonen wird zwar vermutet, ist aber bislang noch nicht durch epidemiologische Langzeitunter­suchungen bewiesen. Die Prognose und Therapieindikationen richten sich weitgehend nach klinischen Faktoren wie Alter und Performance Status des Patienten. Die Primärtherapie von Glioblastomen (GBM, WHO-Grad IV) ist international standardisiert und beinhaltet größtmögliche Resektion, postoperative Radiotherapie des Teilhirns mit konkomitierender Chemotherapie (Temozolomid über 6 Wochen) gefolgt von Temozolomid über 6 Monate. Glioblastome rezidivieren immer innerhalb weniger Monate bis Jahre. Zur Behandlung eines Rezidivs stehen dem Patienten verschiedene individuelle Therapieoptionen zur Verfügung. Je nach Lage und Größe kann sich ein Rezidiv für eine zweite Resektion, für eine stereotaktische Re-Bestrahlung oder für eine Zweitlinienchemotherapie und/oder für die Behandlung mit einer Angiogenesehemmung eignen. Gliome sind diffus infiltrierende Krankheiten des Gehirns und daher von Anfang an nicht kurativ behandelbar, das mittlere Überleben liegt für GBM bei 15 Monaten. Bei Patienten über 70 Jahren und einem guten Allgemeinzustand ist nach der Stratifizierung für den Methylierungsstatus des MGMT Promoter Gens eine alleinige Radiotherapie oder bei methyliertem MGMT Status eine alleinige Chemotherapie als Erstlinientherapie gerechtfertigt. Anaplastische Gliome (WHO-Grad III) können postoperativ mit Radiotherapie oder Chemotherapie behandelt werden und beim Auftreten eines Rezidives mit der entsprechend anderen Modalität. Falls ein WHO-Grad III-Gliom aber eine 1p,19q Co-Deletion aufweist, sollte die Primärtherapie nach neuesten Erkenntnissen immer eine Chemo- und Radiotherapie beinhalten. Das mittlere Überleben variiert je nach prognostischen Faktoren von 3 bis > 7 Jahren. Für WHO-Grad II-Gliomen gibt es bislang keine standardisierte Therapie. Neben einer primären "wait and see" Strategie, stehen bei Tumorprogress die Chemotherapie oder die Radiotherapie zur Verfügung. Die Studienresultate der EORTC Studie (22033/26033), welche die beiden Therapieoptionen in der Erstlinientherapie prüft, stehen noch aus.

The B lymphocyte adaptor molecule of 32 kDa (Bam32) is strongly induced during the maturation of dendritic cells (DC). Most known functions of Bam32 are related to the signaling of the B cell receptor for Ag. Because DC do not express receptors specific for Ags, we aim at characterizing the role of Bam32 in human monocyte-derived DC in this study. Our results show that binding of allogeneic T cells to mature DC causes accumulation of Bam32 on the contact sites and that this translocation is mimicked by Ab-mediated engagement of MHC class I. Silencing of Bam32 in mature monocyte-derived DC results in an enhanced proliferation of CD8+ T cells in an Ag-specific T cell proliferation assay. Further studies identify galectin-1 as an intracellular binding partner of Bam32. Regulating immune responses via regulatory T cell (Treg) modulation is one of the many immunological activities attributed to galectin-1. Therefore, we assayed mixed leukocyte reactions for Treg expansion and found fewer Treg in reactions stimulated with DC silenced for Bam32 compared to reactions stimulated with DC treated with a nontarget control. Based on our findings, we propose a role for Bam32 in the signaling of MHC class I molecules in professional Ag-presenting DC for the regulation of CD8+ T cell activation. It is distinct from that of MHC class I recognized by CD8+ T cells leading to T cell death. Thus, our data pinpoint a novel level of T cell regulation that may be of biological relevance.

Background: The reduction of treatment-related toxic effects is the main goal in the current trials of the German Hodgkin Study Group (GHSG). In this regard, the protection of the ovarian reserve in young women is very important. Therefore, the GHSG investigated the use of gonadotropin-releasing hormone-analogues (GnRH-a) and oral contraceptives (OC) in young women with advanced-stage Hodgkin lymphoma (HL). Patients and methods: Women (18–40 years) were randomly assigned either to receive daily OC or monthly GnRH-a during escalated combination therapy with bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc). Hormonal levels were determined at baseline, during therapy, and at follow-up. Results: The study was closed prematurely after an interim analysis of 12 patients in arm A (OC) and 11 in arm B (GnRH-a), 9 and 10 are assessable for the primary end point. Women’s median age was 25 years in both arms. The anti-Mullerian hormone level after at least 12 months was reduced in all patients. For the entire study cohort, the respective ovarian follicle preservation rate was 0% (95% confidence interval 0% to 12%). Conclusion: We observed no protection of the ovarian reserve with hormonal co-treatment during BEACOPPesc. This result supports efforts of ongoing trials to reduce chemotherapy intensity and toxicity. Alternative strategies for the protection of fertility must be offered to young female HL patients before the start of BEACOPPesc therapy.

Cost effectiveness has been demonstrated for traditional lumbar discectomy, lumbar laminectomy as well as for instrumented and noninstrumented arthrodesis. While emerging evidence suggests that minimally invasive spine surgery reduces morbidity, duration of hospitalization, and accelerates return to activites of daily living, data regarding cost effectiveness of these novel techniques is limited. The current study analyzes all available data on minimally invasive techniques for lumbar discectomy, decompression, short-segment fusion and deformity surgery. In general, minimally invasive spine procedures appear to hold promise in quicker patient recovery times and earlier return to work. Thus, minimally invasive lumbar spine surgery appears to have the potential to be a cost-effective intervention. Moreover, novel less invasive procedures are less destabilizing and may therefore be utilized in certain indications that traditionally required arthrodesis procedures. However, there is a lack of studies analyzing the economic impact of minimally invasive spine surgery. Future studies are necessary to confirm the durability and further define indications for minimally invasive lumbar spine procedures.

When T cells are primed by dendritic cells (DCs) to initiate antigen-specific immune responses screening for matching antigen receptor-MHC/peptide pairs takes place in DC-T-cell conjugates. For an immune response DC-T-cell conjugates formed during priming events need to dissolve. Although detailed knowledge on molecules involved in the conjugate formation is available, dissolving of them has not been considered to be an active process. Here, we identify CYTIP (cytohesin-interacting protein) to mediate DC-T-cell deattachment. CYTIP, which is induced during maturation of DCs, shortly accumulates to the contact zones with T cells within the first hour of coculture. Specific silencing of CYTIP results in stronger adhesion of DCs to T cells and to fibronectin. When a need for deattachment is created in a T-cell priming assay by only partially loading DCs with antigen, CYTIP silencing causes reduced priming capacity. Thus, CYTIP allows DCs to actively control DC-T-cell interactions.

Activins are members of the transforming growth factor-beta (TGF-beta) family and are important for skin morphogenesis and wound healing. TGF-beta1 is necessary for the population of the epidermis with Langerhans cells (LC). However, a role for activin in LC biology is not known. To address this question, we analyzed skin from transgenic mice overexpressing the activin antagonist follistatin in the epidermis. Using immunofluorescence, we observed a striking decrease in the number of LC in the epidermis of transgenic mice in comparison to wild-type mice. Nevertheless, these LC expressed normal levels of major histocompatibility complex (MHC)-class II and Langerin/ CD207 in situ. In explant cultures of whole ear skin the number of dendritic cells (DC), which migrated into the culture medium, was reduced. This reduction was even more pronounced in cultures of epidermal sheets. Virtually all emigrated cutaneous DC displayed typical morphology with cytoplasmic "veils", showed translocation of MHC-class II to the surface membrane, and expressed the maturation marker 2A1. Thus, cutaneous DC from transgenic mice seemed to mature normally. These results demonstrate that overexpression of follistatin in the epidermis affects LC trafficking but not maturation and suggest a novel role of the follistatin-binding partner activin in LC biology.

Background High doses (10(-6)-10(-8) M) of tacrolimus (FK506) were reported to induce a type-2 T-helper cell (Th2)-promoting function in developing dendritic cells (DC). We used a therapeutic dose (2.4 x 10(-9 )M) of tacrolimus to investigate its effect on human monocyte-derived DC. Methods Using untreated and treated immature and mature DC we compared T cell-activating capacity, surface marker expression, T cell and DC cytokine profile and transcription of genes coding for a panel of DC function-related molecules. Results Tacrolimus-treated mature DC had reduced T-cell stimulatory capacity. Although interleukin (IL)-12 production of DC was impaired, they did not promote Th2 development as T cells activated by tacrolimus-treated DC produced less interferon (IFN)-gamma, IL-4 and IL-10. The up-regulation of the T-cell activation marker CD69 and the production of IL-2 were impaired. In addition, tacrolimus-treated DC produced less IP-10 (CXCL10), which is known to be involved in allograft rejection. Other molecules related to DC function remained unchanged. Conclusions Tacrolimus treatment reduces the ability of DC to stimulate T cells and the impaired production of DC-derived IP-10 (CXCL10) and IL-12 might play a role in the immunosuppressive action of tacrolimus.

Locally advanced cutaneous malignancy of the scalp and forehead is a disease that requires an aggressive approach to resection and reconstruction. Free flap reconstruction in these sites has been advocated because of the advantages of importing large amounts of well-vascularized tissue into a recipient site, which has often been compromised by previous surgery or radiotherapy. A consecutive series of 32 free flap reconstructions in 29 patients with cutaneous malignancy of the scalp and forehead was reviewed. The flap failure rate was 6% (two flaps) and the major complication rate was 10%. Of the surviving flaps, 97% (N = 29) were successful in reconstructing a challenging group of defects. Three patients developed local recurrence of the primary malignancy (mean follow-up, 21 months). The use of a broad repertoire of free tissue transfers in reconstruction of the scalp and forehead defects has allowed effective treatment of locally advanced malignancy of this region. Critical analysis of the results, however, indicates that microsurgical reconstruction is not without morbidity and that there are refinements in the diagnostic and operative steps of management that can maximize the functional and aesthetic results.

In systemic lymphoma, a secondary CNS involvement (secondary CNS lymphoma, SCNSL) occurs in 2-5% of patients. With conventional therapy the prognosis of SCNSL is poor with median overall survival (OS) in most series of approx. 6 months. The optimal therapeutic management has not been established; long-term control seems possible only with intensive chemotherapy including high-dose chemotherapy with autologous stem-cell transplantation (HD-ASCT). Since 2011, data on SCNSL patients have been prospectively collected in a multicenter international registry. Thus far, 173 immunocompetent patients with CNS involvement at diagnosis (cohort I, n=30) or at progression/relapse (cohort II, n=143) from 41 centers have been included. The median age was 63 years (26-86), 111 (64%) were male. The median time to CNS involvement in cohort II was 10.6 months Of 155 patients with data available, 122 (79%) had aggressive B-cell lymphoma, 25 (16%) indolent lymphoma, 5 (3%) mantle cell lymphoma and 3 (2%) T-cell lymphoma. Lymphoma localization in the CNS was brain parenchyma in 84 (54%), meningeal compartment in 37 (24%), spinal cord in 2 (1%) and a combination of these compartments in 32 (21%). Simultaneous systemic involvement was found in 42% of patients in cohort II. Therapy for CNS involvement and outcome was analyzed in 99 patients thus far (16 in cohort I and 83 in cohort II). Systemic therapy alone was given to 48 (49%), systemic + intrathecal therapy to 43 (43%), intrathecal therapy alone to 5 (5%), radiotherapy alone to 2 (2%); one patient did not receive any treatment. Systemic chemotherapy was high-dose methotrexate-based in 81 (89%) and high-dose cytarabine-based in 53 (58%); 61 (61% of all) patients received rituximab systemically. Liposomal cytarabine was the most frequent intrathecal therapy given in 30 out of 48 patients (63%). HD-ASCT was performed in 25 (25%) patients. The median progression-free survival (PFS) was 5.9 months (95% CI 3.1-8.7), the median OS 18.6 months (95% CI 10.3-26.9). On univariate analysis, CNS lymphoma at diagnosis, no meningeal involvement, better ECOG performance status, treatment with rituximab, HD-ASCT and response to therapy were associated with better outcome. Multivariate analysis was done using blockwise variable selection, starting with demographic data and findings at first diagnosis, and subsequently enlarging the model by findings at CNS involvement, therapy of CNS involvement and outcome of CNS therapy. Here, a probable prognostic role for cohort I and HD-ASCT (for OS) and no meningeal involvement (for both PFS and OS) was found with response to CNS therapy being the dominating prognostic factor (for both OS and PFS). This is the largest prospective series on SCNSL in the era of modern lymphoma therapies. The results underscore the role of intensive therapy for long-term control of SCNSL. At the meeting, an updated analysis will be presented.

In this article, the role of the clinical nurse specialist (CNS) at the University Hospital Insel in Bern, Switzerland, is described using four examples from daily practice. The first describes how the CNS may influence patient care by direct care, bedside teaching, or case reviews. Therefore, this form of co-operation with the nursing teams is a very important factor for improving nursing care. The second example is about wound care. Although the CNS work as generalists on the wards, they also have their specialist fields, where they have in-depth knowledge, skills and expertise. The third example describes how a CNS initiated an interprofessional working group with the aim of improving palliative care and palliative medicine throughout the hospital. Although such knowledge already existed in the hospital, it was not easily accessible to all the health care professionals. The fourth example is about project management. A CNS acted as a project leader of a multiprofessional group for pain assessment and management in babies, children and adolescents. This example also shows how a problem occurring in daily practice can be worked out and resolved.

The thioether phospholipid ilmofosine (BM 41 440) is a new anti-cancer drug presently undergoing phase II clinical trials. Because resistance to anti-tumour drugs is a major problem in cancer treatment, we investigated the resistance of different cell lines to this compound. Here we report that the multidrug-resistant cell lines MCF7/ADR, CCRFNCR1000, CCRF/ADR500, CEM/VLB100 and HeLa cell lines transfected with a wild-type and mutated (gly/val185) multidrug resistance 1 gene (MDR1) are cross-resistant to ilmofosine compared with the sensitive parental cell lines. In CEMNM-1 cells, in which the resistance is associated with an altered topoisomerase II gene, no cross-resistance to ilmofosine was observed. Ilmofosine is not capable of modulating multidrug resistance and neither does it reduce the labelling of the P-glycoprotein (P-gp) by azidopine nor alter ATPase activity significantly. The resistance to ilmofosine in multidrug-resistant CCRF/VCR1000 cells cannot be reversed by the potent multidrug resistance modifier dexniguldipine-HCI (B8509-035). A tenfold excess of ilmofosine does not prevent the MDR-modulating effect of dexniguldipine-HCl. Treatment of cells with ilmofosine does not alter the levels of MDR1 mRNA. Long-term treatment of an ilmofosine-resistant Meth A subline with the drug does not induce multidrug resistance, indicating that ilmofosine does not increase the level of P-gp. Determination of the MDR2 mRNA levels in the cells revealed that the resistance pattern to ilmofosine is not correlated with the expression of this gene. It is concluded, therefore, that multidrug-resistant cells are cross-resistant to ilmofosine and that the compound is not a substrate of Pgp. No association between the expression of the MDR2-encoded P-gp and resistance to ilmofosine was observed. It is supposed that MDR1-associated alterations in membrane lipids cause resistance to ilmofosine. Images Figure 4 Figure 8 Figure 9

Objective To evaluate the impact of dynamic in vitro culture on initiation of early follicular growth in prepubertal mouse ovaries. Design Ovaries from 8-day-old BALB/c mice were cultured either in a dynamic system (n = 28) or in a static system (n = 20) for 4 days. Uncultured 8-day-old (n = 9) or 12-day-old (n = 17) ovaries served as baseline or in vivo controls, respectively. Setting Academic research center. Animal(s) Newborn female BALB/c mice (n = 37). Intervention(s) None. Main Outcome Measure(s) Histologic follicle classification and counting and assessment of follicular viability via immunofluorescent staining. Result(s) The percentage of secondary follicles after dynamic culture was identical to the 12-day-old in vivo control. In contrast, after static culture ovaries showed a significantly higher percentage of secondary follicles. For immunofluorescent viability assessment 6.78 follicles per ovary could be isolated after dynamic culture, whereas only 3.8 follicles per ovary could be isolated after static culture. Conclusion(s) Dynamic in vitro culture supports physiologic follicular growth initiation, comparable to that observed in vivo. In contrast, accelerated follicular growth was observed after static culture. These findings add additional evidence to the idea that dynamic culture might be a beneficial first step to initiate follicle growth in vitro within the context of fertility preservation.

Background Enormous interest had been paid to the coordination chemistry of alkali and alkaline metal ions because of their role inside body viz; their Li+/Na+ exchange inside the cell lead to different diseases like neuropathy, hypertension, microalbuminuria, cardiac and vascular hypertrophy, obesity, and insulin resistance. It has been presumed that alkali metal ions (whether Na+ or K+) coordinated to chelating ligands can cross the hydrophobic cell membrane easily and can function effectively for depolarizing the ion difference. This unique function was utilized for bacterial cell death in which K+ has been found coordinated valinomycin (antibiotic). Results Distinct sodium adduct (1) with dicoumarol ligand, 4-Hydroxy-3-[(4-hydroxy-2-oxo-4a,8a-dihydro-2H-chromen-3-yl)-phenyl-methyl]-chromen-2-one (L) is isolated from the saturated solution of sodium methoxide. Single crystal X-ray diffraction studies of the adduct reveals that sodium is in the form of cation attached to a methoxide, methanol and a dicoumarol ligand where carbonyl functional groups of the coumarin derivative are acting as bridges. The sodium compound (1) is also characterized by IR, 1H-NMR, and 13C{1H}-NMR spectroscopic techniques. The composition is confirmed by elemental analysis. DFT study for 1 has been carried out using B3LYP/6-13G calculations which shown the theoretical confirmation of the various bond lengths and bond angles. Both the compounds were studied subsequently for the U2OS tumoricidal activity and it was found that L has LD50 value of 200 μM whereas the sodium analog cytotoxicity did not drop down below 60%. Conclusion A sodium analogue (1) with medicinally important dicoumarol ligand (L) has been reported. The crystal structure and DFT study confirm the formation of cationic sodium compound with dicoumarol. The ligand was found more active than the sodium analog attributed to the instability of 1 in solution state. Coumarin compound with sodium was observed to be less cytotoxic than the ligand, its LD50 value never dropped below 60%.

Easily available biomarkers for suicidality would be valuable for the identification of individuals at risk. Oxytocin has been shown to be associated with mental illness. We assessed basal oxytocin plasma levels of patients with (SA, n=41) and without (NSA, n=40) a 1-year history of attempted suicide. SA and NSA groups did not differ with respect to oxytocin levels. Plasma oxytocin may not be a biological suicide marker candidate.

Inflammation is the physiological answer of the organism to damage affecting its integrity, such as infection or trauma. In inflammation, cells of the immune system release cytokines and other mediators, which contribute to the destruction of bacteria and tissue repair. We distinguish here between pro-inflammatory cytokines, e.g., interleukin-1 (IL-1), IL-6 and tumor necrosis factor (TNF)- a, and anti-inflammatory cytokines, e.g., IL-10 and IL-4. Local mechanisms regulate the extent of the inflammatory answer needed to remove the source of the damage and to maintain homeostasis. Humoral as well as neuronal mediators contribute to the regulation of inflammation. Humoral anti-inflammatory mediators, e.g., IL-10 and glucocorticoids, inhibit the release or effect of pro-inflammatory cytokines whereas lipoxins and resolvins contribute to tissue repair. Humoral mediators reach their target cells in distant organs by diffusion or transport by blood flow. Substances which are released by nerves, e.g., norepinephrine and acetylcholine, reach specific cell groups of distant organs rapidly [1].

Multidrug resistance (MDR) is frequently associated with overexpression of a 170-kDa P-glycoprotein (Pgp). Data suggest altered protein kinase C (PKC) activity in cells expressing the multidrug-resistant phenotype. The staurosporine derivative CGP 41251, an experimental anticancer drug, has been shown to exert selectivity for inhibition of protein kinase C activity and to exhibit antitumor activity in vitro and in vivo. Here we show that CGP 41251 is also able to reverse MDR. After treatment of the multidrug-resistant human lymphoblastoid cell line CCRF-VCR1000 with 500 nM Adriamycin, cell proliferation was reduced to 81% of untreated controls. A combination of 500 nM Adriamycin with a non-toxic concentration of 150 nM CGP 41251 (IC50 for inhibition of cell proliferation 420 nM CGP 41251) inhibits cell proliferation of CCRF-VCR1000 cells to 29% of untreated controls. In sensitive CCRF-CEM cells no enhancement of Adriamycin-induced cytotoxicity was observed upon addition of 150 nM CGP 41251. Strong synergism of the inhibition of cell proliferation was also observed after concomitant treatment of KB-8511 cells with CGP 41251 and Vinblastine or Adriamycin. Drug-sensitive KB-31 cells could not be further sensitized to Adriamycin or Vinblastine with CGP 41251 doses above 100 nM. Pretreatment with 50-1000 nM CGP 41251 for 30 min led to a dose-dependent increase in the intracellular accumulation of rhodamine 123, a substrate of P-glycoprotein. Treatment of multidrug-resistant CCRF-VCR1000 cells with CGP 41251 for 10 min was sufficient to inhibit the efflux of rhodamine 123. Preincubation with CGP 41251 for 12 or 24 hr did not alter multidrug resistance gene (mdrI)-mRNA levels. CGP 41251, a drug with antitumor efficacy in experimental systems, might offer an attractive combination partner for the treatment of tumors expressing the MDR phenotype.

Introduction: Ovarian tissue freezing and autotransplantation is a promising option for preserving fertility of female cancer patients. There are several in vivo, but no established in vitro models to evaluate frozen/thawed human ovarian tissue prior to autotransplantation. Objective: To establish a new in vitro model for endocrine assessment of frozen/thawed human ovarian tissue prior to autotransplantation. Materials & Methods: Ovarian tissues were obtained by laparoscopy from 5 patients 19 to 34 years old recently diagnosed with cancer. 200mg cortical tissue from each patient was used and further divided into two groups: 100mg tissue as fresh (control group) and 100mg tissue as frozen/thawed (study group) after using slow freezing/rapid thawing protocol. Either fresh or frozen/thawed tissue from each patient was separately cultured in blank G-MOPS medium (Vitrolife, Sweden) for 6 days, at 37°C in an incubator without CO2. Estradiol (E2), Progesterone (P) and Anti Mullerian Hormone (AMH) were measured every 2 days in all supernatants to evaluate the endocrine function. After culture, all cortical tissues were examined histologically for viability and follicle development assessment. Mean values±SD were calculated. Results: Frozen/thawed tissues (study groups) showed slower recovery of endocrine function. On days 2, 4 and 6 of culture, E2 was 0.5±1.3, 4.4±9.8 & 14±13.3 pg/ml, P was 0.2±0, 0.2±0 & 0.3±0.1ng/ml, and AMH was below the detection limit. Viability after culture was 72±8.36%. Fresh tissues (control groups) showed faster recovery of endocrine function. On days 2, 4 and 6 of culture, E2 was 37.5±33.8, 62±44.7 & 104.2±58.9 pg/ml, P was 0.4±0.3, 0.6±0.4 & 1±0.5ng/ml, and AMH was under the detection limit. Viability after culture was 94±5.47%. Conclusion: For each patient, reasonable endocrine and histological data can be obtained by culturing only 100mg of fresh or frozen/thawed cortical tissue in G-MOPS medium for just 6 days. This new in vitro model can be used for each patient prior to autotransplantation to assess the endocrine function of the frozen/thawed ovarian tissue. These data will be complimented by follicle density assessment to confirm the endocrine results. In addition, oocyte isolation and in vitro maturation will be performed to assess the reproductive function.

PURPOSE: Surgery is the most effective treatment for liver metastases. Some patients, however, cannot tolerate this procedure due to co-morbidity, advanced age, site of the lesion or previous liver surgery. In our institution we have now increasing experience with radiofrequency ablation (RFA), a thermo-ablative modality. We compare our outcome and survival results to standard treatments for liver metastases. MATERIALS AND METHODS: From April 2000 to June 2005, 30 consecutive patients with liver metastases from gastrointestinal primaries were treated with ultrasound guided RFA for their liver metastases (patients mean age 63.5 years, range 37 - 80. Size of lesions, range 0.4 - 6 cm). Main indications were non-operable lesions due to site of the lesion or co-morbidity. RFA was also applied as an additive to liver surgery and as a repetitive palliative treatment. 15 patients underwent one RFA-intervention, 8 patients two, 3 patients three, 1 patient four, 2 patients five and 1 patient six. RFA-interventions (n = 60) were performed either percutaneously (71.5 %), in an open approach without liver surgery (22 %) or in addition to liver surgery (6.5 %). RESULTS: Mean observation time after first RFA was 23.5 months (range 3 - 63). Median survival in our patient cohort is 34 months, which compares favourably with results obtained by hepatic resection, the standard of care for liver metastases. Complication rate, attributed to the RFA procedure, was small in our series (5.5 %) with one pleural effusion and one abscess formation in the ablated lesion due to underlying bacteraemia. CONCLUSION: RFA is an effective and low risk treatment modality in patients with liver metastases. The procedure is safe (complication rate < 6 %) with low morbidity. RFA can be performed repeatedly on an outpatient basis with good palliative effects. Of note, surgery remains the treatment of choice in resectable liver metastases of colorectal origin.

The potent immunomodulator FTY720 elicits immunosuppression via acting on sphingosine 1-phosphate receptors (S1PR), thereby leading to an entrapment of lymphocytes in the secondary lymphoid tissue. To elucidate the potential in vitro effects of this drug on human monocyte-derived DC, we used low nanomolar therapeutic concentrations of FTY720 and phosphorylated FTY720 (FTY720-P) and investigated their influence on DC surface marker expression, protein levels of S1PR and DC effector functions: antigen uptake, chemotaxis, cytokine production, allostimulatory and Th-priming capacity. We report that both FTY720 and FTY720-P reduce chemotaxis of immature and mature DC. Mature DC generated in the presence of FTY720 or FTY720-P showed an impaired immunostimmulatory capacity and reduced IL-12 but increased IL-10 production. T cells cultured in the presence of FTY720- or FTY720-P-treated DC showed an altered cytokine production profile indicating a shift from Th1 toward Th2 differentiation. In treated immature and mature DC, expression levels for two S1PR proteins, S1P1 and S1P4, were reduced. We conclude that in vitro treatment with FTY720 affects DC features that are essential for serving their role as antigen-presenting cells. This might represent a new aspect of the overall immunosuppressive action of FTY720 and makes DC potential targets of further sphingolipid-derived drugs.

Biosynthesis of (6R)-5,6,7,8-tetrahydro-L-biopterin (H4-biopterin), an essential cofactor for aromatic amino acid hydroxylases and NO synthases, is effectively induced by cytokines in most of the cell types. However, human monocytes/macrophages form only a little H4-biopterin, but release neopterin/7,8dihydroneopterin instead. Whereas 6-pyruvoyl tetrahydropterin synthase (PTPS) activity, the second enzyme of H4-biopterin biosynthesis, is hardly detectable in these cells, PTPS mRNA levels were comparable with those of cell types containing intact PTPS activity. By screening a THP-1 cDNA library, we identified clones encoding the entire open reading frame (642 bp) as well as clones lacking the 23 bp exon 3, which results in a premature stop codon. Quantification of the two mRNA species in different cell types (blood-derived cells, fibroblasts and endothelial cells) and cell lines showed that the amount of exon-3-containing mRNA is correlated closely to PTPS activity. The ratio of exon3-containing to exon-3-lacking PTPS mRNA is not affected by differential mRNA stability or nonsense-mediated mRNA decay. THP-1 cells transduced with wild-type PTPS cDNA produced H4-biopterin levels and expressed PTPS activities and protein amounts comparable with those of fibroblasts. We therefore conclude that exon 3 skipping in transcription rather than posttranscriptional mechanisms is a major cause of the low PTPS protein expression observed in human macrophages and related cell types. Ke yw ords: fibroblast, lymphocyte, myeloid cell, pteridine, 6-pyruvoyl tetrahydropterin synthase, RNA splicing.

Leukopenia and anaemia are observed in about a fifth of all patients with systemic lupus erythematosus (SLE) and may be due either to the destruction of blood cells or their decreased production. The former may be humoral or cell-mediated or result from apoptosis of peripheral blood cells. Several observations suggest the occurrence of the latter reduced in vitro proliferation of pluripotent bone marrow progenitors from the bone marrow aspirates of SLE patients,reduced counts of CD34+ cells in bone marrow aspirates in SLE patients, apoptosis of lymphopoietic progenitors and apoptosis of bone marrow cells. The aim of our study was to investigate whether humoral factors may induce suppression of haematopoiesis by increased apoptosis of CD34+ cells. For this purpose, we incubated allogeneic CD34+-enriched cells with sera of 18 leukopenic SLE patients. Apoptosis was induced by four of 18 sera. This effect was independent of complement-inhibition and FAS-blockade. Although reduced proliferation of autologous pluripotent bone marrow progenitors has been attributed to an IgG serum inhibitor, removal of IgG from these four proapoptotic sera had no effect on apoptosis of allogeneic CD34+ cells. The proapoptotic effect was associated with high titres of anti-dsDNA antibodies and low haemoglobin concentrations, but not with high titres of antinuclear antibodies, TNF-alpha and IFN-alpha of the sera tested.

SummaryBackground Radiation dermatitis is a common side-effect of radiation therapy, but there is no current consensus about its appropriate therapy. Objectives To compare treatment with topical 0·1% methylprednisolone vs. 0·5% dexpanthenol in a cohort of patients undergoing fractionated radiation therapy for breast cancer. Methods In a randomized, double-blind design, treatment was initiated at the beginning of radiation therapy and continued for 2 weeks after termination of radiation. Outcomes were compared by three different measures: clinical (symptom score), functional (transepidermal water loss, TEWL) and subjective (quality of life, QOL). Results In a preliminary cohort of untreated patients undergoing radiation therapy, clinical signs and TEWL levels increased progressively during radiation therapy, reaching highest values at 5 and 4 weeks, respectively. Although neither topical treatment reduced the incidence of radiation dermatitis, both delayed the emergence of greatest clinical and TEWL scores until approximately 6 and 5 weeks, respectively. With topical corticosteroids, clinical symptoms and TEWL were less pronounced than with dexpanthenol. Whereas general QOL improved after completion of radiation therapy, skin-related QOL declined. However, the skin-related QOL decline could be at least in part reversed by use of topical corticosteroid vs. dexpanthenol-containing emollient. Conclusions We provide evidence that prophylactic and ongoing use of topical therapy with either topical corticosteroid or a dexpanthenol-containing emollient ameliorates, but does not prevent radiation dermatitis. Our data suggest, but do not prove, a benefit of a topical corticosteroid vs. a dexpanthenol-containing emollient. Further controlled studies with larger cohorts will be needed to determine optimal forms of topical therapy for radiation dermatitis.

We have previously presented preliminary observations on targeting somatostatin receptor-positive malignant gliomas of all grades by local injection of the radiolabelled peptidic vector 90Y-DOTATOC. We now report on our more thorough clinical experience with this novel compound, focussing on low-grade and anaplastic gliomas. Small peptidic vectors have the potential to target invisible infiltrative disease within normal surrounding brain tissue, thereby opening a window of opportunity for early intervention. Five progressive gliomas of WHO grades II and III and five extensively debulked low-grade gliomas were treated with varying fractions of 90Y-DOTATOC. The vectors were locally injected into the resection cavity or into solid tumour. The activity per single injection ranged from 555 to 1,875 MBq, and the cumulative activity from 555 to 7,030 MBq, according to tumour volumes and eloquence of the affected brain area, yielding dose estimates from 76+/-15 to 312+/-62 Gy. Response was assessed by the clinical status, by steroid dependence and, every 4-6 months, by magnetic resonance imaging and fluorine-18 fluorodeoxyglucose positron emission tomography. In the five progressive gliomas, lasting responses were obtained for at least 13-45 months without the need for steroids. Radiopeptide brachytherapy had been the only modality applied to counter tumour progression. Interestingly, we observed the slow transformation of a solid, primarily inoperable anaplastic astrocytoma into a resectable multi-cystic lesion 2 years after radiopeptide brachytherapy. Based on these observations, we also assessed the feasibility of local radiotherapy following extensive debulking, which was well tolerated. Targeted beta-particle irradiation based on diffusible small peptidic vectors appears to be a promising modality for the treatment of malignant gliomas.

We present the therapeutic effect of diffusible brachytherapy (dBT), an innovative approach for the management of symptomatic low grade gliomas [1]. This protocol uses a radiolabelled small diffusible peptidic vector which is a somatostatin analogue to target somatostatin type 2 (sst-2) receptors. The stable radioconjugate [ 9 0 Y]-DOTA 0 -D-Phe 1 -Tyr 3 -octreotide (DOTATOC) is repeatedly injected via catheters placed into the resection cavity or into tumour nodules. We report on the four year follow-up after initiation of dBT to treat progressive disease in a patient with a complex eleven year history of fibrillary low-grade astrocytoma. The radiopharmakon was not only locally injected into the resection cavity following debulking surgery, but also administered by slow infusion technique to target recurrent and infiltrative tumour zones in the subventricular region around the inferior and posterior horns. In conclusion, peptidic vector based dBT was as found to be safe, of mild and transitory toxicity, and effective in long-term tumour control.