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Purpose To assess an intensified treatment in the context of clinical and biologic risk factors in metastatic medulloblastoma. Patients and Methods Patients (4 to 21 years old, diagnosed between 2001 and 2007) received induction chemotherapy, dose-escalated hyperfractionated craniospinal radiotherapy, and maintenance chemotherapy. Subgroup status and other biologic parameters were assessed. Results In 123 eligible patients (median age, 8.2 years old; median follow-up, 5.38 years), 5-year event-free survival (EFS) and overall survival (OS) were 62% (95% CI, 52 to 72) and 74% (95% CI, 66 to 82), respectively. OS was superior compared with the precedent HIT ’91 trial. The 5-year EFS and OS were both 89% (95% CI, 67 to 100) for desmoplastic/nodular (n = 11), 61% (95% CI, 51 to 71) and 75% (95% CI, 65 to 85) for classic (n = 107), and 20% (95% CI, 0 to 55) and 40% (95% CI, 0 to 83) for large-cell/anaplastic (n = 5) medulloblastoma ( P < .001 for EFS; P = .001 for OS). Histology (hazard ratio, 0.19 for desmoplastic/nodular and 45.97 for large-cell/anaplastic medulloblastoma) and nonresponse to the first chemotherapy cycle (hazard ratio, 1.97) were independent risk factors (EFS). Among 81 (66%) patients with tumor material, 5-year EFS and OS differed between low-risk (wingless [WNT], n = 4; both 100%), high-risk ( MYCC/ MYCN amplification; n = 5, both 20%), and intermediate-risk patients (neither; n = 72, 63% and 73%, respectively). Survival rates were different between molecular subgroups (WNT, n = 4; sonic hedgehog [SHH; n = 4]; group 4 [n = 41]; group 3 with [n = 3] or without [n = 17] MYCC/MYCN amplification; P < .001). All cases showed p53 immuno-negativity. There was no association between patients with nonresponding tumors to induction chemotherapy and WNT ( P = .143) or MYCC/MYCN status ( P = .075), histologic subtype ( P = .814), or molecular subtype ( P = .383), as assessed by Fisher’s exact test. Conclusion This regimen was feasible and conferred overall favorable survival. Our data confirm the relevance of subgroup status and biologic parameters (WNT/ MYCC/ MYCN status) in a homogeneous prospective trial population, and show that metastatic group 3 patients do not uniformly have poor outcomes. Biologic subgroup, MYCC/ MYCN status, response to induction chemotherapy, and histologic subtype may serve for improved treatment stratification.

Background Due to the rarity of metastatic medulloblastoma in adults, knowledge about the efficacy and toxicity of intensified chemotherapy and radiotherapy is limited. Patients and methods Adults with disseminated medulloblastoma registered in the HIT2000 trial as observational patients and treated according to one of two different treatment regimens were analysed. The sandwich strategy MET-HIT2000AB4 consists of postoperative chemotherapy, hyperfractionated craniospinal radiotherapy, and maintenance chemotherapy; while the HIT′91 maintenance strategy consists of postoperative craniospinal radiotherapy, and maintenance chemotherapy. Results Twenty-three patients (median age: 30.7 years), diagnosed from November 2001 to July 2009, and treated in 18 institutions in Germany and Austria, were eligible. The median follow-up of surviving patients was 3.99 years. The 4-year event-free survival (EFS) and overall survival (OS) ± standard error (SE) were 52% ± 12% and 91% ± 6%, respectively. The survival was similar in both treatment groups (HIT′91 maintenance strategy, n = 9; MET-HIT2000AB4 sandwich strategy, n = 14). Patients with large cell/anaplastic medulloblastoma relapsed and died (n = 2; 4-year EFS/OS: 0%) and OS differed compared to patients with classic (n = 11; 4-year EFS/OS: 71%/91%) and desmoplastic medulloblastoma (n = 10; 4-year EFS/OS: 48%/100%), respectively (p = 0.161 for EFS and p = 0.033 for OS). Treatment-induced toxicities consisted mainly of neurotoxicity (50% of patients, ⩾ °II), followed by haematotoxicity and nephrotoxicity/ototoxicity. The professional outcome appeared to be negatively affected in the majority of evaluable patients (9/10). Conclusions Treatment of adults with metastatic medulloblastoma according to the intensified paediatric HIT2000 protocol was feasible with acceptable toxicities. EFS rates achieved by both chemotherapeutic protocols were favourable and appear to be inferior to those obtained in older children/adolescents with metastatic disease.

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.

PURPOSE: We aimed to validate a controversial prognostic model for the survival of relapsed malignant glioma patients after reirradiation with an independent, multicentric patient cohort.METHODS AND MATERIALS: A total of 165 malignant glioma patients underwent reirradiation at 4 different institutions between 1994 and 2012. Twenty-two patients had a good (score 1), 44 had a moderate (score 2), and 99 had a poor prognosis (score 3 or 4). Four statistical methods were used to validate the prognostic model: First, we compared survival according to prognostic group in the construction and the validation cohort by visual comparison of the respective Kaplan-Meier plots. Second, discrimination was quantified by calculating hazard ratios for death for each prognostic group, with the worst prognostic group serving as the reference. Calibration was assessed by a calibration plot for the time point 12 months after reirradiation. Finally, we compared the predictive performance of the score and a hypothetical prognostic model ignoring all predictor variables over time by means of a prediction error curve.RESULTS: On visual validation, the survival curves of the 3 patient groups with good, moderate, and poor prognoses nicely separated from each other. Median survival rates after reirradiation were 17.9, 9.0, and 7.7 months in the patient groups with good, moderate, and poor prognosis, respectively. Hazard ratios confirmed satisfactory discrimination. Calibration was satisfactory for all and most accurate for the worst prognostic group. The score improved the prognostic performance in comparison to the "zero-model."CONCLUSIONS: We successfully validated a prognostic model for the survival of malignant glioma patients after reirradiation with a multicentric, independent dataset. Being reliable and easy to handle, the model can be useful in personalized patient counseling and clinical decision-making.

Purpose To evaluate the efficacy of craniospinal irradiation (CSI) in the management of recurrent infant medulloblastoma after surgery and chemotherapy alone. Methods and Materials Seventeen pediatric medulloblastoma patients registered in the HIT-REZ 1997 and 2005 studies underwent CSI as salvage treatment at first recurrence. All patients had achieved complete remission after first-line treatment consisting of surgery and chemotherapy. Eleven patients showed metastatic disease at relapse. Five patients underwent surgery prior to radiation therapy, which resulted in complete resection in 1 case. In 1 patient, complete resection of the residual tumor was performed after CSI. Eleven patients received chemotherapy prior, 6 patients during and 8 patients after CSI. All patients received CSI with a median total dose of 35.2 Gy, and all but 1 received a boost to the posterior fossa (median total dose, 55.0 Gy). Metastases were boosted with an individual radiation dose, depending on their location and extent. Results During a median follow-up time of 6.2 years since recurrence, 11 patients showed progressive disease and died. Median progression-free (overall) survival was 2.9 ± 1.1 (3.8 ± 0.8) years. Progression-free survival (PFS) rates at 1, 3, and 5 years were 88% ± 8%, 46% ± 12%, and 40% ± 12%, respectively. Overall survival (OS) rates at 1, 3, and 5 years were 94% ± 6%, 58% ± 12%, and 39% ± 12%, respectively. For 11 patients with classic medulloblastoma, 3-year (and 5-year) PFS and OS were 62% ± 15% and 72% ± 14% (52% ± 16% and 51% ± 16%), respectively. On univariate analysis, metastatic disease was not associated with poorer progression-free and overall survival. Conclusions Our results suggest that salvage treatment of relapsed medulloblastomas consisting of CSI and chemotherapy offers a second chance for cure, even for patients with classic histological findings. Metastatic disease at relapse did not have an impact on survival. However, this may be explained by the small number of patients.

Central nervous system primitive neuroectodermal tumors (CNS-PNET) and pineoblastomas (PBL) are rare in adulthood. Knowledge on clinical outcome and the efficacy and toxicities of chemotherapy in addition to radiotherapy is limited. Patients older than 21 years at diagnosis were followed in the observational arm of the prospective pediatric multicenter trial HIT 2000. After surgery, craniospinal irradiation and maintenance or sandwich chemotherapy were recommended. Radiotherapy was normo- (35.2 Gy; tumor region, 55.0 Gy; metastasis, 49.6 Gy) or hyperfractionated (40.0 Gy; tumor bed, 68.0 Gy; metastasis, 50-60 Gy). Maintenance chemotherapy consisted of eight courses (vincristine, lomustine, cisplatin). Sandwich chemotherapy included two cycles of postoperative chemotherapy followed by radiotherapy, and four courses of maintenance chemotherapy. Seventeen patients (CNS-PNET, n = 7; PBL, n = 10), median age 30 years, were included. Eight patients had a postoperative residual tumor and four patients metastatic disease. The median follow-up of ten surviving patients was 41 months. The estimated rates for 3-year progression-free survival (PFS) and overall survival were 68 ± 12 and 66 ± 13%, respectively. PBL compared to CNS-PNET tended towards a better PFS, although the difference was not clear (p = 0.101). Both chemotherapeutic (maintenance, n = 6; sandwich, n = 8) protocols did not differ in their PFS and were feasible with acceptable toxicities. Intensified regimens of combined chemo- and radiotherapy are generally feasible in adults with CNS-PNET/PBL. The impact of intensified chemotherapy on survival should be further assessed.

Medulloepithelioma of the central nervous system (CNS) is an uncommon primitive neuroectodermal tumor (PNET) usually occurring in early childhood. It is characterized by highly malignant behavior with a propensity for progression, recurrence, and dissemination despite intensive therapy. Due to its rarity, the optimal management is still unknown. However, gross total resection (GTR) has been considered crucial to achieve cure. In this article, the authors report on 2 cases of CNS medulloepithelioma in which long-term survival (more than 6 years) could be achieved despite evidence of, or suspected postoperative residual disease with an otherwise dismal prognosis. The patients were treated according to different strata of the protocol for primitive neuroectodermal tumors (PNET) of the German–Austrian multicenter trial of the German Society for Pediatric Oncology and Hematology (GPOH) for childhood brain tumors (HIT 2000). Treatment included postoperative hyperfractionated radiotherapy of the craniospinal axis followed by a boost to the tumor site in combination with chemotherapy. A review of the 2 reported and 37 previously published cases confirmed GTR and older age as positive prognostic factors.

The arthropod Oelandocaris oelandica from the upper Middle Cambrian “Orsten” of Sweden was recently recognized as a member of the early phase of crustacean evolution based on additional morphological detail from new specimens. Here we present a detailed investigation of all available material. It includes the description of a 400 µm long specimen probably representing an early developmental stage. Variation in size correlated with variation of trunk-segment numbers allowed recognition of different instars. The largest specimens do not exceed an estimated length of about 1 mm, indicating that our material may consist only of immature specimens. The characteristic, extremely long antennula of O. oelandica branches into three long rods. It may have served as the major structure to sweep in food, aided by the two subsequent appendages. These and the more posterior limbs were also responsible for locomotion. Minute pores on the outer edges of the posterior limbs and on the trunk tergites possibly contained sen...

In several areas of southern Sweden, limestone nodules, locally called Orsten occur within bituminous alum shales. These shales and nodules were deposited under dysoxic conditions at the bottom of what was most likely a shallow sea during the late Middle to Upper Cambrian (ca. 500 million years ago). Subsequently, the name 'Orsten' has been referred to particular, mainly arthropod, fossils from such nodules, and, in a wider sense, to the specific type of preservation of minute fossil through secondarily phosphatization. This preservation is exceptional in yielding uncompacted and diagenetically undeformed three-dimensional fossils. 'Orsten'-type preservation resulted from incrustation of a thin external layer and also by impregnation by calcium phosphate and, therefore, mineralization of the surface of the former animals during early diagenesis. Primarily, this type of preservation seems to have affected only cuticle-bearing metazoans such as cycloneuralian nemathelminths and arthropods. 'Orsten' preservation in this sense seems to be limited by size, in having yielded no partial or complete animals larger than 2 mm. On the other end of the scale, even larvae 100 μm long are preserved, often more complete than larger specimens, and details such as setules and pores smaller than 1 μm can be observed. Fossils preserved in such a manner are almost exclusively hollow carcasses, but can be filled secondarily; less common are completely phosphatized compact specimens. The high quality of preservation makes the Swedish 'Orsten' a typical Konservat-Lagerstätte. Yet, its special type of preservation is more widespread in time and geographical distribution than assumed initially, and the origin of the phosphate is not necessarily restricted just to one source. Subsequent to the first discoveries of limb fragments of Cambrian arthropods in 1975, animals in this special preservational type have been discovered in several continents and across a broad stratigraphic range including even Proterozoic strata. The latter have yielded early cleavage and metazoan embryonic stages, expanding knowledge on the preservational capacities of the 'Orsten'. Here, we report the recent status of our research on the 'Orsten' and give perspectives for future exploration on a worldwide scale, particularly in light of a recently formed international research group named Center of Orsten Research and Exploration (C.O.R.E.). © 2006.

BACKGROUND: Accurate predictive scores for the survival after salvage-treatment which are based on simple clinical parameters would be beneficial for the management of progressive high-grade gliomas (HGG). However, such scores should not enter clinical practice unless being validated with an independent dataset. Universal validity of a prognostic score is reflected by its capability to discriminate between different prognostic groups and good calibration. PATIENTS AND METHODS: Focusing on reirradiation, we assessed three different prognostic scores suggested by Combs et al., 2013 (Score A), De Vleeschouwer et al., 2012 (Score B) and Carson et al., 2007 (Score C). The scores were based on the following clinical parameters: Score A: age, time between initial radiotherapy and reirradiation and WHO grading; Score B: age, karnofsky performance score, WHO grading and minimal mental score; Score C: KPS, age, tumor location, use of steroids and WHO grading. Validation was performed with an independent dataset containing 175 HGG patients from 4 different institutions in Germany, Switzerland and the Netherlands, who all underwent a second course of radiotherapy at disease progression. Discrimination was checked by visual comparison of the respective Kaplan-Meier plots and by calculating the hazard ratios of the better prognostic groups in relation to the worst prognostic group defined by each score. Calibration was assessed generating calibration curves and prediction error curves. RESULTS: Median survival in the validation cohort was 9.2 ± 0.2 months from the start of reirradiation. Each score discriminated well between at least 3 different prognostic groups (good - intermediate -poor). However, scores A and B overestimated survival in the intermediate group, whereas score C tended to underestimate survival in the case of poor prognosis. Score A was most accurate in predicting an individual patient's short-term prognosis (< 10 months). For long-term prognosis (>10 months) score B should be preferred. CONCLUSIONS: We conducted a validation study to assess discrimination and calibration of 3 different prognostic models predicting survival after reirradiation of progressive high-grade gliomas on an independent dataset. Each score serves its purpose, with score A being easiest to handle. Differences in performance are marginal and depend on the explicit question.

Dissemination of high-grade gliomas (WHO IV) has been investigated poorly so far. We conducted an extensive analysis of the characteristics, treatments and outcomes of the glioblastoma multiforme (GBM)/gliosarcoma (GS) patients with central nervous system (CNS) metastases reported in literature until April 2013. PubMed and Web of Science searches for peer-reviewed articles pertaining to GBM/GS patients with metastatic disease were conducted using predefined keywords. Additionally, we performed hand search following the references from the selected papers. Cases in which the metastases exclusively occurred outside the CNS were excluded. 110 publications reporting on 189 patients were eligible. There was a significant increase in the number of reported cases over the last decades. We calculated a median overall survival from diagnosis of metastasis (from initial diagnosis of GBM/GS) of 3.0 ± 0.3 (11 ± 0.7) months. On univariate analyses, gender, age, the histological subtype, the time interval between initial diagnosis and the occurrence of metastases and the location of CNS metastasis (intracranial versus spinal and parenchymal versus leptomeningeal, respectively) did not influence survival after diagnosis of metastasis. There was no substantial treatment progress over the recent decades. GBM/GS with CNS metastasis are associated with a dismal prognosis. Crucial treatment progress is not evident. A central registry should be considered to consecutively gain more information about the ideal therapeutic approach.

High-grade (HGG) and diffuse intrinsic pontine gliomas (DIPG) with primary metastatic spread are extremely rare and have a dismal prognosis. Analogous to simultaneous radiochemotherapy in non-metastatic HGG and DIPG, concurrent craniospinal irradiation (CSI) and metronomic temozolomide (metroTMZ) may represent a reasonable therapeutic approach. However, the antitumor efficacy and toxicity of this treatment still have to be investigated.Between March 2007 and December 2012, six children with primary metastatic HGG (n = 4) or DIPG (n = 2) received CSI and concurrent metroTMZ based on individual treatment recommendations and, in some cases, within the HIT-HGG 2007 multicenter trial. Outcome and treatment-related toxicities were evaluated.All patients received irradiation to the entire craniospinal axis (35.2 Gy, n = 5; 36 Gy, n = 1:) and 5 received a local boost to macroscopic tumor deposits. Simultaneously, metroTMZ (75 mg/m(2)/day, n = 5; 60 mg/m(2)/day, n = 1) was administered. Additionally, 1 patient received nimotuzumab once per week. Within a median follow-up of 10.0 months (range 6.5-18.7 months), all patients experienced disease progression and 5 patients died. Median progression-free survival was 4.0 ± 0.8 months (range 2.4-10.7 months) and median overall survival was 7.6 ± 3.5 months (range 4.0-17.6 months). Acute myelosuppression most severely limited application of this aggressive treatment strategy. Severe hematotoxicities (≥ grade 3) occurred in all patients and metroTMZ had to be interrupted or discontinued in 4 out of 6 cases.Concurrent CSI and metroTMZ might represent a feasible treatment approach for primary metastatic HGG and DIPG. On the basis of our experience, severe but manageable acute hematotoxicity has to be expected. An international effort is warranted to reassess the efficacy and toxicity of this approach within a prospective study.

We evaluated clinical outcomes in the subset of patients who underwent radiotherapy (RT) due to progressive pilocytic astrocytoma within the Multicenter Treatment Study for Children and Adolescents with a Low Grade Glioma HIT-LGG 1996.Eligibility criteria were fulfilled by 117 patients. Most tumors (65 %) were located in the supratentorial midline, followed by the posterior fossa (26.5 %) and the cerebral hemispheres (8.5 %). Median age at the start of RT was 9.2 years (range 0.7-17.4 years). In 75 cases, external fractionated radiotherapy (EFRT) was administered either as first-line nonsurgical treatment (n = 58) or after progression following primary chemotherapy (n = 17). The median normalized total dose was 54 Gy. Stereotactic brachytherapy (SBT) was used in 42 selected cases.During a median follow-up period of 8.4 years, 4 patients (3.4 %) died and 33 (27.4 %) experienced disease progression. The 10-year overall (OS) and progression-free survival (PFS) rates were 97 and 70 %, respectively. No impact of the RT technique applied (EFRT versus SBT) on progression was observed. The 5-year PFS was 76 ± 5 % after EFRT and 65 ± 8 % after SBT. Disease progression after EFRT was not influenced by gender, neurofibromatosis type 1 (NF1) status, tumor location (hemispheres versus supratentorial midline versus posterior fossa), age or prior chemotherapy. Normalized total EFRT doses of more than 50.4 Gy did not improve PFS rates.EFRT plays an integral role in the treatment of pediatric pilocytic astrocytoma and is characterized by excellent tumor control. A reduction of the normalized total dose from 54 to 50.4 Gy appears to be feasible without jeopardizing tumor control. SBT is an effective treatment alternative.

Introduction Radiation therapy plays an essential role in the treatment of brain tumors, but neurocognitive deficits remain a significant risk, especially in pediatric patients. In recent trials, hippocampal sparing techniques are applied to reduce these adverse effects. Here, we investigate dose-dependent effects of ionizing radiation (IR) on juvenile hippocampal neurogenesis. Additionally, we evaluate the radioprotective potential of resveratrol, a plant polyphenol recognized for its bifunctional tumor-preventive and anticancer effects. Methods Organotypic entorhinal–hippocampal slice cultures from transgenic nestin-CFPnuc C57BL/J6 mice, postnatal days 3–6, were irradiated on a X-ray machine (4.5, 8, 12, and 16 Gy, single doses) after about 2 weeks. Nestin-positive neural stem cells were counted at a confocal live imaging microscope 0, 2, 4, 14, 25, and 42 days after IR. Resveratrol (15 μmol/L) was added 2 hr before and 24 hr after IR. Proliferation and cell death were assessed by BrdU pulse label, 48 hr after and by propidium iodide staining 96 hr after IR. GFAP- and NeuN-positive cells were counted 42 days after IR in cryosectioned immunofluorescence-stained slices. Results The observed age-related changes of nestin-positive stem cells in the organotypic slice culture model resembled the reduction of neural stem cells in vivo. IR (4.5–16 Gy) led to a dose-dependent damage of the neural stem cell pool in the dentate gyrus. No recovery was seen within 42 days after doses from 4.5 Gy onward. The decline of nestin-positive cells was paralleled by increased cell death and decreased proliferation. The number of GFAP-positive cells was significantly enhanced. No significant change was detected in the overall NeuN-positive cell population, whereas the number of newborn, NeuN/BrdU double-positive neurons was reduced. Resveratrol treatment reversed the irradiation-induced decline of neural stem cells. Conclusion The neuroprotective action of resveratrol on irradiated hippocampal tissue warrants further investigation as a possible supplement to hippocampal sparing procedures.

BACKGROUND: Intracranial peripheral primitive neuroectodermal tumors (P-PNET) are extremely rare. They can be easily misdiagnosed as central nervous system primitive neuroectodermal tumors (CNS-PNET) or meningiomas. Little is known about the optimal treatment and prognosis of these tumors. PATIENTS AND METHODS: We evaluated the treatment and outcome of 17 patients with intracranial, nonmetastatic, genetically confirmed P-PNET. Three patients were treated at our institutions. Thirteen other cases providing sufficient treatment and follow-up information were extracted from the literature. RESULTS: The median age at diagnosis was 17 years. All patients underwent initial surgery. Complete resection was achieved in 9 of the 17 cases (53 %). Combined adjuvant treatment consisting of radiotherapy (focal, n = 10; craniospinal, n = 1) and chemotherapy was administered to 11 of the 17 patients (59 %). The median follow-up time was 1.4 years. In 8 of the 17 patients (47 %), the disease progressed; 4 of the 17 patients (24 %) died. The 2-year progression-free and overall survival rates were 64 % and 76 %, respectively. CONCLUSION: The differential diagnosis for intracranial, meningeal-based, small, round-cell tumors should include P-PNET. It is highly probable that complete resection has a positive impact on survival-as previously reported for extracranial P-PNET-but this cannot be shown by our data. Intensive adjuvant treatment consisting of radiotherapy and chemotherapy seems to be essential. A statistically grounded recommendation for the appropriate target volume and radiation dose is not yet possible. However, in most case reports of primary intracranial P-PNET published to date, patients were treated with focal irradiation. The optimal chemotherapy regimen has yet to be established, with both the Ewing tumor and CNS-PNET protocols being promising candidates for effective treatment.

A three-dimensionally and completely preserved phosphatized microfossil has been found in Cambrian–Ordovician boundary bed limestones of the Green Point Formation at Green Point, western Newfoundland, Canada. It represents a new form of larvae, previously described by D. Walossek and K.J. Müller from Upper Cambrian anthraconitic limestones ("Orsten"). These authors identified the fossils as instars of marine stem-group representatives of the "tongue worms," Pentastomida. Pentastomida are parasites that today infest various land tetrapods and are presumed to represent one of the closest extant relatives of the Euarthropoda. This new fossil possesses remarkably well-preserved trunk limb vestigia and anal region. It is another example of exceptional three-dimensionally preserved, phosphatized fossils of the Orsten type that is no longer spatiotemporally restricted to the Upper Cambrian of Sweden.

Small phosphatised fossils from late Cambrian limestones of Västergötland, Sweden, share major external features with larval extant Pentastomida, such as a prominent head with two pairs of stumpy limbs adapted for attachment, and a slender trunk of four portions. Even such details, as paired forehead structures, pores on the inner edges of the head limbs and paired papillae at the rear of the trunk correspond with structures of extant pentastomid larvae. Neither the fossils nor the Recent pentastomids add any additional body segments during growth (segment constancy). Since characters of this kind and in this combination do not occur elsewhere, the fossils are recognised as true Pentastomida. Major differences, such as distinctly divided head limbs, partial occurrence of vestigial trunk limbs, and a different mode of trunk development during growth can be explained as representing merely the plesiomorphic state of characters of Pentastomida, indicating that the fossils are representatives of its stem-group prior to branching into the two Recent lineages. The fossils clearly document the marine origin of the Pentastomida, and that their specific morphology and parasitic life style were already established in the late Cambrian at a high degree of diversification, long before the terrestrialisation of their present final hosts, the tetrapods. General arthropod affinities are recognisable not least in the nature of the limbs, but the morphology of stem- and crown-group pentastomids gives no clues for closer relationship with any of the major (eu)arthropod taxa.

Exceptional three-dimensional preservation of phosphatized Upper Cambrian arthropods of different groups from southern Sweden permits not only description of their morphology in full detail but also assumptions on functional morphology and life habits. Ontogenetic stages, in some cases in complete sequences, give additional information about habitual changes in the life cycle. Altogether this provides a wide data basis for phylogenetic considerations, particularly for the crustacean branch of the Arthropoda. Among the ‘Orsten’ fossils, a number could be recognized as representatives of crown-group crustacean taxa, such as the Skaracarida and Bredocaris as members of each of the two different lineages of Maxillopoda, or Rehbachiella as a member of the Branchiopoda. Another set of forms shares some characters with the crowngroup crustaceans but lacks a large number of others. These fossils, identified as representatives of the stem line of Crustacea, provide a hitherto unknown data set for the interpretation of morphological and functional changes in the evolution towards the crown-group of this taxon.

Phosphorites from the Middle Cambrian Monastery Creek Phosphorite Member, Queensland, Australia, yielded a group of soft-bodied, microscopic fossils of yet unknown affinity. They are three-dimensionally preserved and composed of two structurally different units. In particular one of the described genera has an upper surface pattern that is strikingly similar to the Late Precambrian Dickinsonia; even the quilted pneu structure observed on Vendozoa might be present on the Middle Cambrian material. Alternatively, a possible relationship to sclerites that also consist of two structurally different units is discussed. Three new species of three new genera are described.

Walossek, D. & Muller, K. J. 1990 10 15: Upper Cambrian stem-lineage crustaceans and their bearing upon the monophyletic origin of Crustacea and the position of Agnostus. Lethaia, Vol. 23, pp. 409–427. Oslo. ISSN 0024–1164. Three new arthropods in uncompressed condition have been discovered in Upper Cambrian limestone nodules (Orsten) of Vastergotland, Sweden. Together with Martinssonia elongafa Muller & Walossek, 1986, they are recognized as descendants of early offshoots from the stem-lineage of Crustacea. Their morphology provides new insights into the evolutionary path and progressive development of ground plan characteristics along the stem-lineage and gives further support for the monophyletic origin of Crustacea s. str., which embraces all taxa with extant derivatives. Structures of the ventral morphology shared between these stem-lineage crustaceans and Agnostus lead to the consideration of alternatives for the currently assumed position of agnostids. ▭Crustacea. ontogeny, phosphatization. phylogeny, stem-lineage, Sweden, 3 D-preseroation, Trilobita

Hinz, I., Kraft, P., Mergl, M. & Muller, K. J. 1990 04 15: The problematic Hadimopanella, Kaimenella, Milaculum and Utahphospha identified as sclerites of Palaeoscolecida. Lefhaia, Vol. 23, pp. 217–221. Oslo. ISSN 024–1164. Hadimopanella Gedik, 1977, Kaimenella Marss, 1988 and Milaculum Muller, 1973 have been established on the basis of isolated elements of unknown origin. Recently, the latter genus has been tentatively related to the Agnatha (van den Boogaard 1988). By contrast, Bendix-Almgreen & Peel (1988) assigned Hadimopanella to the chordate stock but definitely excluded it from vertebrates. Well-preserved worm-like organisms of Palaeoscolecida Conway Morris & Robison. 1986 are known from the Lower Cambrian to the Lower Ordovician. They have their outer surface covered with a pattern of sequin-like sclerites which evidence the systematic affiliation with the isolated sclerites mentioned above. Based on similar structures on the outer surface, Utahphospha Miiller & Miller, 1976 is considered to belong to the same group. *Early Palaeozoic fossils, Palaeoscolecida, isolated sclerites, phosphatization.

BACKGROUND AND OBJECTIVE: Radiation therapy plays an essential role in the treatment of primary or metastatic CNS malignancies, but radiation-induced adverse effects remain a significant risk. Radiation-induced damage of the neural stem cell pool in the hippocampus is thought to be one of the major reasons for the long-term decline in neurocognitive performance, especially in pediatric patients. Here, we investigate the short- and long-term dose-response relationship of neurogenesis, covering a dose range relevant for whole and partial brain irradiation. Furthermore, we evaluate the radioprotective potential of resveratrol, a plant polyphenol, which is newly recognized for its bifunctional tumor-preventive and anti-cancer effects. METHODS: Nestin-CFPnuc C57BL/J6 mice, postnatal day 4-6, were decapitated and hippocampal tissue slices, containing the entorhinal-hippocampal formation, cut on a vibratome and cultured on membrane inserts in culture plates. Slices were irradiated on an x-ray machine (0.2-16 Gy) 14-21 days later. Resveratrol (15 µM) was added 2 h before and 24 h after irradiation (IR). BrdU pulse label was conducted for 48 h after IR. Nestin-positive neural stem cells were counted at a confocal life imaging microscope 0, 2, 4, 14, 25, and 42 days after IR. BrdU-positive cells were evaluated by immunofluorescence staining in cryosectioned slices. Cell viability was assessed by CellTiter-Blue fluorometric assay, 3 and 9 days after IR. Dead cells were labelled by propidium iodide (PI). Cytokine concentrations (IL6, KC, MCP-1) were measured in the slice culture medium by cytometric bead array 4 and 24 h after IR. RESULTS: A dose-dependent decline of nestin-positive neural stem cells together with a decrease of proliferation could be detected already at low doses of 0.2 Gy two days after IR. A partial recovery of the stem cell pool was found at late time points (14 and 42 days after IR). PI staining showed a dose-dependent increase of dead cells, reaching significance at 12 Gy. Resveratrol was able to enhance the cell viability significantly in irradiated slices 3 and 9 days after irradiation (4.5 and 8 Gy). IL6, KC and MCP1 release increased 4 and 24 h after IR at 1.5 Gy (IL6) and 3 Gy (KC, MCP1). CONCLUSION: Relatively low IR doses lead to a decrease of nestin-positive stem cells. Our data indicate that this is a result of increased cell death and decreased proliferation but might also be triggered by an increase of inflammation. The neuroprotective action of resveratrol on irradiated hippocampal tissue warrants further investigation.

Publisher Summary This chapter provides an overview of conodonts and other phosphatic microfossils. Phosphatic microfossils are widely distributed in Paleozoic and early Mesozoic sediments and are valuable index fossils for parts of these eras. They can be isolated by washing from shales as well as by etching from limestones with diluted acetic or formic acids. Hence, indurated limestones which otherwise have been regarded as unfossiliferous have yielded identifiable microfossils. Conodonts consist of an organic matrix in which crystallites of apatite similar to the mineral francolite are imbedded. Well preserved material has a whitish-amber color and is translucent. However, they are usually changed by diagenesis or natural staining to grey, black, or brown and become opaque. Most conodonts are easily differentiated by gross outer features. Morphologically, four main groups of conodonts can be distinguished as simple cones, bar-type conodonts, blade-type conodonts, and platform conodonts. The evolutionary trends in conodonts are not well understood. All were originally formed from organic matter in which apatite crystallites have been imbedded. The earliest conodonts are largely composed of organic matter and sometimes retain their shape even when their small amount of phosphate is etched out with hydrochloric acid.

A tiny arthropod, with five growth stages, is described. Three of the instars are metanauplius-like larvae, having unsegmented bodies and four pairs of appendages. The largest stage, with a length of about 1.5 mm, may still be immature. Its body is divided into three tagmata. The cephalon, including five appendiculate segments, h a projecting forehead with a rostral spine and a small shield with a joint between fourth and fifth segments. Eyes are absent. The trunk is composed of seven annular segments, the anterior two with appendages. The caudal end is a long pleotelson-like segment with the anus on its ventral surface. There are seven pairs of appendages: uniramous antennulae, composed of few tubular podomeres; four pairs of biramous postantennular, almost homeomorphic cephalic appendages; two pairs on the trunk, the anterior pair being similar to the cephalic appendages except for the exopodite, the posterior being much smaller, uniramous and apparently rudimentary. Martinssonia was probably benthic, feeding on detritic particles which it stirred up from the bottom. Besides various crustacean-like features, the new form reveals structures different from Crustacea as well as from all other known arthropodan groups. Martinssonia presumably is a descendant of an euarthropodan group, originating from the crustacean branch long before reaching the eucrustacean level of evolution.

Phosphatisation of small, soft-bodied fossils in the Upper Cambrian of Sweden yielded rich faunal assemblages, mainly of arthropods, which have been isolated from the rock by etching techniques. The highly diverse fossils are uncompressed and constitute the best preserved material known from the Paleozoic era, exposing minute details such as fine bristles, pores of glands, and eyes. Agnostus clearly has biramous appendages and therefore, cannot be regarded as trilobite anymore. The Crustacea are the most widespread components of the phosphatised fauna. The representatives of a separate order of Ostracoda already have been studied in some detail. Other primordial crustaceans include nauplius stages and show a surprising diversity in specialisation. A similar occurrence in Upper Devonian from the Carnic Alps demonstrates that this mode of preservation is not restricted to a single environment, but also can be expected elsewhere.

Phosphatic microfossils etched from Upper Cambrian (Trempealeauan Stage) Limestones of the Whipple Cave Formation, Nevada, and other contemporaneous formations in western North America, are colonies, the individuals of which are arranged irregularly around one or more nuclei. No secondary growth has occurred. During their lifetime, however, the individuals partially filled their chambers with phosphatic matter. The highly differentiated morphology of the colonies is strikingly similar to the living ascidian tunicate Botryllus. Ecological conditions and size range of the fossils are likewise similar to those of the Ascidiacea. If recognized as an ascidian, Palaeobotryllus taylori n.g., n.sp. extends the known occurrence of Tunicata into the Upper Cambrian.

Walossek, Dieter & Muller, Klaus J. 1989 07 15: A second type A-nauplius from the Upper Cambrian ‘Orsten’ of Sweden. Lethaia, Vol. 22, pp. 301–306. Oslo. ISSN 0024–1164. Among newly sorted material, two specimens at first considered as nauplius-like larva A (Muller & Walossek 1986, Transactions of the Royal Society of Edinburgh: Earth Sciences 77) differ from this type in their larger sized body and appendages, much smaller caudal spines, and lack of the dorsal hook-like plates. They are regarded as a similar but distinct type, named ‘larva A2’. *Crustacea, ontogeny, phosphatization, 3D-preservation.

Six monotypic new genera of small crustaceans with phosphatised integument are described from Upper Cambrian, mainly bituminous limestone of southern Sweden. These are Dala peilertae, Bredocaris admirabilis, Walossekia quinquespinosa, Rehbachiella kinnekullensis, Skara anulata and Oelandocaris oelandica. The well-preserved details reveal a nauplius-like organisation of the head region. At least in Bredocaris, Walossekia, and Rehbachiella the head tagma has only three to four specialised pairs of appendages; Skara and Oelandocaris have five pairs of headal limbs. The antennae and the mandibulae served for locomotion and for mastication. All species have a filter apparatus with a distinct filter groove and serially constructed appendages. Four of the six forms had developed a conspicuous median compound eye. Specialisation in the development of the limbs, etc., suggests that some of the forms were benthie, while others may have been epibcnthic and active swimmers, Crustacea, Dala, Bredocaris, Walossekia, Rehbachiella, Skara, Oelandocaris, soft-part preservation, Upper Cambrian, Sweden.

Heraultia Cobbold, 1935 (non! Villeneuve, 1920) fallt mit groser Wahrscheinlichkeit in die Synonymie vonWatsonella Grabau, 1900. Es handelt sich um einen sehr ursprunglichen Crustaceen, der mit fruhen Mollusken, den Phyllocariden und den Branchiopoden verglichen und mit Vorbehalt zu den Ostracoden (Bradorina) gestellt wird. Reiches Material aus dem Departement Herault, Languedoc, Frankreich, ermoglichte eine ausfuhrliche Neubearbeitung, wobei allein aus einer Fundschicht uber 800 Exemplare fur die statistische Untersuchung der Ontogenie zur Verfugung standen. Die Haufigkeit nimmt mit zunehmender Grose kontinuierlich ab. Es sind keine definitiven Hautungsstadien wie z. B. bei den spateren Ostracoden vorhanden. Wahrend die teknomorphen Stadien isomorph gewachsen sind, tritt bei den grasten Exemplaren eine Gabelung in der Verteilungskurve im Langen: Hohen-Verhaltnis auf, die als durch einen Geschlechtsdimorphismus verursacht interpretiert wird.

Four tiny obvious larvae unassignable to larger “Orsten” arthropods are described and reconstructed. Two of them have a naupliar appearance and may belong to crustaceans, whereas the other two represent as yet unknown types of euarthropodan larvae.

Extensive preparation since 1975 has yielded thousands of specimens of various minute arthropods, mainly phosphatocopid ostracods and other crustaceans. The whole exoskeleton is exceedingly well preserved in three dimensions, showing even delicate mo1 phological details. The material permits not only the description of the morphology and systematic status of the animals but also interpretation, with a high degree of confidence, of the function, life habit, and ontogeny of these early arthropods.

Mulkr. Klaus 1. 1979 01 IS: Phosphatocopine ostracodes with preserved appendages from the Upper Cambrian of Sweden. Lethaia. Vol. 12. pp. 1–27. Oslo. ISSN 0024–1164. More than 400 specimens of phosphatocopine ostracodes. representing different moult stages of Vestrogothia. Falites and Hesslandona have been recovered, with body and appendage structures preserved in minute detail. from anthraconites in the Upper Cambrian of Sweden and drift boulders deriving from that area. The secondary phosphatization of these structures, leading to preservation. is extensively discussed. It comprises even the inner lamella, but the abdomen is not preserved. Hypostome and lower lip are well developed. The large antennula is composed of a basipodite with probably two podomeres and a long exopodite with up to 18 podomeres bearing long spines, forming a natatory organ, and a broad endopodite of two to three podomeres. The biramous organization of the antennula is a unique, most primitive feature of phylogenetic significance. The antennae and up lo four additional pairs of appendages are also biramous and similar to the antennulae, not yet differentiated for specialized functions. Only the last pair is uniramous, but a second branch may have developed in subsequent moult stages not represented in the material. The movement of food into the mouth was achieved by the endites of antennulae and antennae, a function transferred backwards to other appendages during the course of ostracode phylogeny and reflected in ontogenetic trends among Recent ostracodes. The phosphatocopines were nectobenthic, filtering plankton feeders.

Aus dem oberen Kambrium und Ordovizium von Europa, Asien und Nord-Amerika wird ein aus Phosphat aufgebautes Mikrofossil beschrieben und die stratigraphische Position des Vorkommens festgelegt. Der GattungMilaculum werden 4 Arten (Typusart:M. ruttneri n. sp.; fernerM. perforatum n. sp.;M. scandicum n. sp. undM. ethinclarki n. sp.) zugeordnet, die mit anderen phosphatischen Mikrofossilien des Altpalaozoikums verglichen werden.

Es liegen mehr als 50 Gruppenfunde von Conodonten vor, von denen 7 nach Feinpraparation im einzelnen untersucht worden sind. Die Apparate mitGnathodus integer Schmidt 1934 undGnathodus bilineatus (Roundy 1926) gleichen sich im allgemeinen Bau, und nur in den Einzelelementen weichen sie voneinander ab. Statistische Erfassung der Einbettungslagen fuhrte zu dem Schlus, das der Tierkorper weder ventral noch lateral ausgesprochen abgeplattet war. Die Anordnung der Elemente in den Apparaten zeigt, das die seitherige bei den Einzelelementen vorgenommene Orientierung mit der Neigung der Zahnchen nach „hinten” nicht in jedem Falle der naturlichen Lage im Korper entsprach. Die Zahnchen sind bei den verschiedenen Elementen gegeneinander gerichtet. Von Gruppen mitTripodellus- undMetalonchodina-Elementen lagen einige Exemplare und von einer Gruppe (?) mit Idiognathodontidae g. et sp. indet. und grosenLigonodina-Elementen nur ein Einzelfund vor.

Von 15 Fundpunkten und aus 25 Fundschichten des Ober-Devons in Mitteleuropa und Nordafrika werden 260 aberrant ausgebildete Conodonten aus insgesamt 9 Form-Gattungen beschrieben, die durch eine teilweise Auflosung des Kammes bezw. der Plattform in viele nadelformige Zahnchen gekennzeichnet sind. Ihr Vorkommen ist nicht vom Substrat oder der Region abhangig. Die durchweg kleinen und unreifen Conodonten werden als pathogene, teratologische Bildungen ohne funktionelle Bedeutung angesehen.

Das „Randcenoman“ erstreckt sich uber 220 km als ein der Cenoman-Serie zugehoriger Grenzbereich gegen die Flyschzone am Nordrand der Kalkalpen vom Chiemsee bis in das Grose Walsertal. An einer Anzahl durchgehender Profile wurden stratigraphische und sedimentologische Untersuchungen durchgefuhrt. Nach Mikrofaunen konnten neue stratigraphische Belege fur eine ortliche Sedimentationsfortsetzung ohne erkennbare Schichtunterbrechung vom Alb bis in das Cenoman gefunden werden. Hinweise auf unterturones Alter ergaben sich an zwei Stellen. Die alttertiaren Tratenbachschichten sind tektonisch von „Randcenoman“ und Flysch abgegrenzt. Trotz eines heterogenen Gesteinsaufbaus in vertikaler und horizontaler Ausdehnung mit einer differenzierten Wechsellagerung von Peliten, Psammiten und Psephiten zeigt die Cenoman-Serie petrographische Konstanz in Gefuge und Mineralzusammensetzung, besonders im Gerollspektrum und der Schwermineralassoziation (Chromit-SpinellPicotit). Die Gesteine des „Randcenoman“ sind in einem einheitlichen Ablagerungsraum sedimentiert worden. Das gilt auch fur ihre Anteile in der Arosa-Zone im Allgau und im Bregenzer Wald. Faziesbeziehungen zur Flyschzone gibt es nicht. Auf das Ablagerungsmilieu deuten Flachwasserbildungen hin, die im flachen Randbereich der Geosynklinale wahrend langdauernder Ruhigwasserfazies mit episodischen Unterbrechungen abgelagert wurden. Die petrographische Zusammensetzung der allothigenen Gerolle, ihr Rundungsgrad, ihre metamorphe Beanspruchung und ihr Erhaltungszustand lassen Analogieschlusse mit Gesteinen vom Verrucano-Typ zu. Im Zusammenhang mit der Tonmineralfuhrung der Pelite (Kaolinit) und der typischen Chromit-Spinell-Beteiligung kann auf ein breites Festland geschlossen werden. An der Detritusanlieferung sind neben dem mesozoischen kalkalpinen Untergrund und Gesteinen vom Verrucano-Typ Unterostalpin und Sudpenninikum beteiligt. Damit sind die nordlichen Kalkalpen im Suden der Tauern beheimatet. Der Zeitraum der Uberschiebung uber das Penninikum liegt nicht vor Unterturon. Mittelkretazische Bewegungen werden in der Cenoman-Serie nur untergeordnet wirksam, wo sich Konglomerate und Gerollpsammite an der Wende Alb-Cenoman horizontieren lassen.